Movement Disorder Surgery

............................ Movement Disorder Surgery

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Progress in Neurological Surgery Vol. 15

Series Editor

L.D. Lunsford, Pittsburgh, Pa.

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Movement Disorder Surgery

Volume Editor

A.M. Lozano, Toronto, Ont.

62 figures and 31 tables, 2000

............................ Andres M. Lozano, MD, PhD, FRCS(C) Toronto Western Hospital Research Institute Division of Neurosurgery Department of Surgery University of Toronto Toronto, Ont., Canada

Library of Congress Cataloging-in-Publication Data Movement disorder surgery / volume editor, A.M. Lozano. p. ; cm. – (Progress in neurological surgery; vol. 15) Includes bibliographical references and indexes. ISBN 3805569904 (hard cover : alk. paper) 1. Movement disorders – Surgery. 2. Brain – Surgery. I. Lozano, A.M. (Andres M.), 1959. II. Series. [DNLM: 1. Movement Disorders – surgery. 2. Brain – surgery. WL 390 M9347 2000] RC376.5.M696 2000 616.8€3–dc21 00–037076

Bibliographic Indices. This publication is listed in bibliographic services, including Current ContentsÔ and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Ó Copyright 2000 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0079–6492 ISBN 3–8055–6990–4

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Contents

IX Preface

History 1 History of Movement Disorder Surgery Gildenberg, P.L. (Houston, Tex.)

Anatomical and Physiologic Substrates 21 Anatomical Considerations in Basal Ganglia Surgery Parent, A.; Cossette, M.; Le´vesque, M. (Beauport, Que´.) 31 Pathophysiological Considerations in Basal Ganglia Surgery: Role of the

Basal Ganglia in Hypokinetic and Hyperkinetic Movement Disorders Wichmann, T.; DeLong, M.R.; Vitek, J.L. (Atlanta, Ga.)

58 Functional Models of the Basal Ganglia: Where Are We? Obeso, J.A.; Guridi, J.; Rodriguez-Oroz, M.C. (Pamplona); Macias, R. (La Habana); Rodriguez, M. (La Laguna); Alvarez, L.; Lopez, G. (La Habana)

Patient and Technical Considerations 78 Movement Disorder Surgery: Patient Selection and Evaluation of

Surgical Results Tan, E.-K.; Jankovic, J. (Houston, Tex.)

91 Technical Considerations in Movement Disorder Surgery:

Frames, Imaging and Intraoperative Monitoring Thompson, T.P.; Lunsford, L.D.; Kondziolka, D. (Pittsburgh, Pa.)

103 Microelectrode Recordings in Movement Disorder Surgery Hutchison, W.D.; Lozano, A.M. (Toronto, Ont.)

Procedures and Techniques 118 Rational Basis for Pallidotomy in the Treatment of Parkinson’s Disease Bakay, R.A.E.; Vitek, J.L. (Atlanta, Ga.) 132 Non-Microelectrode Recording-Guided Pallidotomy Bowen, J.; Munro-Davies, L.E. (Oxford); Silburn, P. (Brisbane); Gregory, R. (Oxford); Bain, P. (London); Scott, R.B.; Joint, C. (Oxford); Hall, B. (Brisbane); Stein, J. (Oxford); Aziz, T. (Oxford/London) 148 Stimulation of the Globus pallidus internus Gross, C.E. (Bordeaux) 156 Thalamotomy with Microelectrode Recordings Linhares, M.N.; Tasker, R.R. (Toronto, Ont.) 172 Thalamotomy without Microelectrode Recording Slavin, K.V.; Burchiel, K.J. (Portland, Oreg.) 181 Thalamic Deep Brain Stimulation for Tremor Wilkinson, S.B.; Koller, W.C. (Kansas City, Kans.) 188 Subthalamic Nucleus Lesions Gill, S.S.; Heywood, P. (Bristol) 196 Subthalamic Nucleus Deep Brain Stimulation Benabid, A.L.; Koudsie, A.; Benazzouz, A.; Piallat, B.; Van Blerkom, N.; Fraix, V.; Pollak, P. (Grenoble)

Controversies, Adverse Events, Emerging Insights and Indications 227 Movement Disorder Surgery: Lesions or Stimulation? Clatterbuck, R.E.; Lee, J.-I.; Lenz, F.A. (Baltimore, Md.) 236 What Does Stimulation in the Brain Actually Do? Ashby, P. (Toronto, Ont.) 246 Complications of Movement Disorder Surgery and How to Avoid Them Hariz, M.I. (Umea˚) 266 Neuropsychological Considerations in Movement Disorder Surgery Saint-Cyr, J.A.; Tre´panier, L.L. (Toronto, Ont.) 272 The Gamma Knife in Movement Disorder Surgery Young, R.F. (Los Angeles, Calif.) 279 Stereotactic Neurosurgery for Dystonia Yoshor, D.; Hamilton, W.J.; Desaloms, J.M.; Ondo, W.; Jankovic, J.; Grossman, R.G. (Houston, Tex.)

Contents

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296 Surgery for Spasmodic Torticollis Villavicencio, A.T.; Friedman, A.H. (Durham, N.C.) 331 Neural Transplantation in Parkinson’s Disease Freeman, T.B.; Willing, A.E.; Zigova, T.; Sanberg, P.R.; Hauser, R.A. (Tampa, Fla.) 339 Neurosurgical Treatment of Spasticity Sindou, M.; Mertens, P. (Lyon) 351 Functional Imaging of the Basal Ganglia Nakamura, T.; Edwards, C.; Krch, D.; Mentis, M.; Eidelberg, D. (Manhasset, N.Y.) 371 CNS Drug Delivery for Movement Disorders Penn, R.D.; Kroin, J.S. (Chicago, III.) 381 Gene Therapy Approaches to Parkinson’s Disease Freese, A. (Philadelphia, Pa.) 395 Author Index 396 Subject Index

Contents

VII

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Preface

Never before has functional neurosurgery for movement disorders held such interest and prominence. The convergence of several paths including advances in the understanding of the cellular pathophysiology of motor dysfunction, the development of better brain imaging, refinements in neurophysiologic guidance and the emergence of new and improved implantable devices are setting the stage for novel therapeutic strategies and major advances in this field. The field of movement disorders is now clearly multidisciplinary. Neurosurgeons have joined with neurologists, neuroanatomists, neurophysiologists, psychologists, neuroradiologists, neuroimaging scientists, molecular biologists and others. Each has brought their unique skills and expertise. We have formed strong partnerships. The flow of knowledge has occurred freely and at an intense pace and we are all further ahead for it. The purpose of this volume is to provide an appraisal of the scientific basis and current and potential future usage of neurosurgery for movement disorders. The major clinical problems being treated surgically are covered in depth with, because of space considerations, lesser mention of the surgical management of less common disorders of motor function. An integrated multidisciplinary approach to the diagnosis, evaluation and treatment of patients with movement disorders is emphasized. This work covers the history of movement disorder surgery, its anatomical and physiologic basis and a discussion of which patients are candidates for these procedures. The technical tools and procedures at our disposal are discussed with an emphasis on providing alternate, sometimes even controversial surgical approaches. The operations in current usage are detailed stressing their indications, impact on the

IX

signs and symptoms and their adverse effects and when appropriate, their postulated mechanism of action. Throughout the volume, the scientific rationale for interventions and the insights and discoveries that are emerging related to performing this surgery are highlighted. The contributors have been chosen on the basis of their expertise and important contributions to the field. It is acknowledged that multiauthored texts can often contain conflicting nonreconciled information. This approach has been adopted intentionally. This is a relatively young, rapidly evolving field with several varied approaches and ideas showing promise. It is best at this point to weave these various contributions into the multidimensional and dynamic fabric of the field of movement disorder surgery. I am indebted to my colleagues Drs Anthony Lang, Jonathan Dostrovsky, Bill Hutchison, Ronald Tasker, Karen Davis, Peter Ashby, and Jean SaintCyr for their stimulating input, wise advice and ongoing collaboration. I acknowledge the help of my assistants Mary Anne Browne and Anne Chiacchieri. I would also like to thank the staff at Karger, especially Angela Weber and Rolf Steinebrunner, for their expert handling of this project. Andres M. Lozano

Preface

X

History Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 1–20

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History of Movement Disorder Surgery Philip L. Gildenberg Houston Stereotactic Center, Houston, Tex., USA

The first report on the use of a device to localize a neurological structure in the laboratory in modern scientific literature is credited to Dittmar [1]. In 1873, he described an apparatus to insert a blade into the medulla of the rat to investigate the function of that structure. The technique did not involve a cartesian coordinate system, and consequently cannot be considered to be the introduction of stereotaxis. Admittedly, there had been several reports in the 19th century on the use of localizing devices for human surgery, but none was cartesian in design. All were attempts to locate specific sulci prior to exposure of the brain at surgery, and several, coincidentally, were from Russia [2]. In 1889, Zernov [3] described an encephalometer. It had a dome that fit over the skull, on which were drawn the common location of the major sulci. There was a pointing device that indicated the location on the scalp where an exposure might reveal the planned cortical location. In 1891, Altukhov [4] reported the first successful clinical use of that device. Again, the apparatus was not stereotactic in that it did not involve a cartesian coordinate system. In order to give appropriate credit to the invention of stereotactic surgery, it is first necessary to define it. Stereotaxic or stereotactic1 techniques involve the location of a target in three-dimensional space by reference to a cartesian 1

The spelling of our science is sometimes seen as ‘stereotaxic’ and sometimes ‘stereotactic’ [5]. The original concept, as used by Horsley and Clarke [6], was ‘stereotaxic’, from the Greek ‘stereo’ for three dimensional and ‘taxis’ for arrangement. When the World Society for Stereotactic and Functional Neurosurgery was founded in 1973, the spelling ‘stereotactic’ was adopted for human stereotaxis, with ‘tactic’ derived from the Latin verb to touch, which was felt to be a more accurate reflection of what stereotactic surgery does. Generally, ‘stereotaxic’ is still used for laboratory animal work.

coordinate system, that is, a point in space is defined by its position relative to three planes intersecting at a point, each at right angles to the other two. That is why a stereotactic target is defined by three coordinates, AP, lateral and vertical. It was not until 1908 that the introduction of the stereotaxic techniques into neurological science was credited to Horsley and Clarke [6]. Their apparatus was designed by Clarke [7] for investigations on the monkey and later was adapted to other animals. It involved a head holder that secured the animal’s head symmetrically by adjustable ear plugs. Orbital tabs aligned the head horizontally, similar to the plane between the external ear canals and one inferior orbital rim that is the Frankfurt plane in anthropology. Their original paper is a model for anyone interested in the history of medical publication or in the literary merits of scientific papers. It is a classical presentation in four parts. The first concerns the material and methods of their study, which is a description of their first animal stereotaxic apparatus, the first based on a cartesian coordinate system. Since it was necessary to have a brain atlas of the monkey in order to use the apparatus, the second part of their paper was the first published stereotactic atlas, aligned and sectioned on the same cartesian system as their apparatus. Horsley and Clarke used a direct current to make an electrolytic lesion, and their description of such lesion production has never been surpassed. Finally, they presented their physiologic study of the cerebellum of the monkey. Horsley and Clarke’s contribution has been enormous, since similar stereotaxic techniques have been used commonly in the laboratory ever since, and are responsible for many of the impressive neurophysiologic advances of the last century. It was only through the understanding of the organization of the brain, and particularly the basal ganglia, that there was sufficient information on which to base human functional 2 neurosurgery. The use of bony landmarks did not lend itself well to use in the human, since the variability between the skull anatomy and small targets deep within the brain is too great to define a target safely. Even so, there were at least two apparatuses designed on this principle which, to my knowledge, were never used. Clarke [7] wanted to build such an apparatus, but Horsley did not, and the ensuing argument presumably led to their falling out [8]. Clarke later built such an apparatus, but it never achieved clinical use [9]. In addition, Mussen, 2

The term ‘functional neurosurgery’ is used by stereotacticians to denote surgery that changes the function of the nervous system, particularly to return malfunction toward normal function. When used in this context, it does not denote any psychological or psychogenic illness. Although psychosurgery is one type of functional neurosurgery, functional neurosurgery more commonly involves surgery for movement disorders, epilepsy, and sometimes surgery for pain management.

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an engineer who built a Horsley-Clarke apparatus at Johns Hopkins Medical School, built a similar apparatus based on cartesian coordinates around 1918, but it was also not used in patients. He wrapped it in newspaper and it was found in the attic by his family years later, with the date approximated by the date of the newspaper [10]. In 1930, even experts such as Dandy [11] believed that interruption of the extrapyramidal system within the brain would be fatal. As early as 1932, Bucy and Buchanan [12, 13] demonstrated that ablation of the primary motor cortex might alleviate parkinsonian tremor and athetosis without the total loss of voluntary movement. Putnam [14] was able to modify both Parkinson tremor and rigidity through interrupting proprioceptive input by cervical posterolateral cordotomy. Later, Browder [15] sectioned the anterior limb of the internal capsule, sometimes bilaterally, but the mortality was so great that he questioned the advisability of such procedures [16]. Other procedures were intended to interrupt the primary motor pathways, such as the lateral part of the pyramidal tract [17, 18]. Even before the introduction of human stereotactic surgery there was an appreciation that interruption of the extrapyramidal system might be used to treat patients with movement disorders. Meyers [19, 20] devised adventurous craniotomy approaches to the basal ganglia. He used a transventricular approach in 1939 to resect the head of the caudate nucleus (the approach was used many years later to implant adrenal or fetal tissue for Parkinson’s disease), but the mortality rate was prohibitive, varying between 12 and 41% in various reports. In 1942 he described an interhemispheric approach to interrupt the ansa lenticularis as it emerged from the globus pallidus. However, the mortality rate was 15.7%, which he admitted was unacceptable, so he advised against the use of his own techniques. However, his reports of clinical improvement by interruption of the extrapyramidal system set the stage for the later development of stereotactic functional neurosurgery. In 1949, Walker [21] sectioned the extrapyramidal fibers in the mesencephalic peduncle for treatment of hemiballismus, and Guiot and Pecker [22] used the same procedure to treat parkinsonian tremor [18]. These procedures were not stereotactic, but the resultant observations provided insight into potential targets for stereotactic surgery. The breakthrough in the development of human stereotactic surgery came in 1947 when Spiegel and Wycis [23] decided to use landmarks within the brain, rather than the skull, to reference their cartesian coordinates. Ernest A. Spiegel was a neurologist. Despite his having achieved the rank of docent at the youngest age of any faculty member at the University of Vienna, he lost his laboratory and was at risk for losing his teaching position after the Nazis began to exclude Jewish scientists in the 1930s. His plight was learned by a Philadelphia businessman-tourist, who prompted William Parkinson, the

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Fig. 1. The first Spiegel-Wycis stereoencephalotome consisted of a Horsley-Clarke-type electrode carrier mounted on a ring suspended from a plaster cap made for each patient. M€>Millimeter scale for movement in lateral direction; P€>protractor for adjusting trajectory in frontal plane; and P>in sagittal plane; R>ring.

Dean of Temple Medical School, to invite Professor Spiegel and his wife, Professor of Colloid Chemistry Mona Spiegel-Adolph, to immigrate to Philadelphia in 1936. Dr. Henry T. Wycis worked in Spiegel’s experimental neurology laboratory as a medical student at Temple (where his record of the highest graduating average stood for another 20 years). When he became a neurosurgeon, he joined his teacher and became Dr. Spiegel’s surgical collaborator. The development of intraoperative x-ray made it possible for them to identify the structures about the third ventricle on air encephalograms (later changed to air ventriculograms and then positive contrast ventriculograms). The Model I Spiegel-Wycis stereotactic apparatus, which now resides in the Smithsonian Institute, was essentially a Horsley-Clarke apparatus attached to a halo which encircled the patient’s head suspended from a plaster cap. The microdrive held an electrode vertically over the patient’s head, and was adjusted by sliding along AP and transverse bars. When it lay directly over the target, the electrode was lowered into the brain in a well-controlled manner (fig. 1).

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As with the original Horsley-Clarke system, it was necessary to have an atlas to define the spatial relationship between landmarks that could be visualized in intraoperative x-ray and the target. The stereotactic atlas they developed and later published [24] was the human equivalent of the one Horsley and Clarke [6] had published almost half a century before. Human stereotactic surgery began in 1947, when Spiegel and Wycis [23, 24] described the first human stereotactic apparatus. Nine years later, in 1956, a summer research program for medical students was introduced at Temple Medical School. As a freshman, I was eligible for that program, and went to the head of the Department of Physiology to see if there were some research in neurophysiology that might be available, since I had thought I might be interested in neurosurgery. He confessed that he did not have such a program, but sent me to his old teacher whose Department of Experimental Neurology was down the hall. When I entered Dr. Spiegel’s laboratory, he and Dr. Wycis were reviewing 8-mm movie films of Parkinson patients who had been operated with pallidotomy, my introduction to stereotactic surgery. Two hours later, when they realized I was still there waiting to talk to them, they invited me to begin work in the laboratory that summer, which was the start of a 13-year sojourn. During that time, they introduced me to pioneers such as Leksell, Narabayashi, Riechert, and Hassler, to name a few. Also during that time, the first international meeting in stereotactic surgery was held in Philadelphia in 1961, the International Society for Research in Stereoencephalotomy (later changed to the World and the American Societies for Stereotactic and Functional Neurosurgery) was formed. Dr. Spiegel also introduced me to Thomas Karger, the second-generation publisher of Confinia Neurologica, the journal that Spiegel edited.3 During the time I spent with Spiegel and Wycis, stereotactic surgery was introduced throughout the world, stereotactic radiosurgery was born, and the most adventurous and innovative two decades in human applied neurophysiology took place.

A prime motivation to develop human stereotaxis was Dr. Spiegel’s aversion to psychosurgery as it was then practiced during the era of ice pick prefrontal lobotomy [25]. The first patient operated, however, did not have psychosurgery, but was treated for the movement disorder of Huntington’s chorea [23]. The lesions were made with the instillation of a small volume of alcohol, in hopes of sparing the fibers en passage. One lesion was placed in the globus pallidus to interrupt the extrapyramidal system. Another was placed in the dorsomedian nucleus of the thalamus, which relays to the prefrontal area, since they recognized that increased emotional tone made the involuntary movements worse. Although the patient had only a temporary moderate improvement, it was firmly demonstrated that neurological pathways could be interrupted in the human with improvement rather than impairment of function. 3 Confinia Neurologica was changed to Applied Neurophysiology and then to Stereotactic and Functional Neurosurgery under my editorship. It still represents a large portion of the literature in stereotactic and functional neurosurgery. Karger publishing house remains in the forefront, led by a fourth generation of Kargers.

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Fig. 2. Intraoperative recording was done even in the earliest days of stereotactic surgery, which at that time required grounded copper shielding around the patient’s head. Spiegel is second from the left peering at the Faraday cage. Wycis is sitting with his hand on the electrode.

An important philosophy of stereotactic surgery from the first days was that each insertion of an electrode into the human brain presented a unique opportunity to study human neurophysiology. Even though it was necessary to shield the patient’s head by a grounded copper Faraday cage to record in the electrically noisy operating room of those days, stimulation and recording were used both to identify the physiological location of the electrode and to replicate laboratory studies to study the pathophysiology of the diseases being treated (fig. 2). This prescient approach led to a greater understanding of the diseases of the extrapyramidal nervous system and, in turn, to more indications for stereotactic surgery. Soon after the start of human surgery, Spiegel and Wycis began to use the same type of electrolytic lesions that Horsley and Clarke [6] had reported. There was significant hazard, since the size of the lesion was limited and the patient might experience a huge stimulus if the current were suddenly

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interrupted, so other means of making lesions were sought. Other early techniques involved injection of oil-procaine or oil-procaine-wax [26, 27]. Alcohol injection continued to be used [28], but the diffusion within the brain was variable and unpredictable [29], even when a cavity was made or a coagulating substance was combined with the alcohol [30]. Mechanical disruption with a leukotome [31] had the risk of producing localized bleeding. Radiofrequency lesions were used to coagulate with heat the tissue surrounding the tip of the electrode. Although early electrodes risked lesions along the electrode tract [29], radiofrequency has since become the modality of choice [32, 33]. Meanwhile, Cooper et al. [35] introduced the cryoprobe4 to make lesions by freezing. The early days of stereotactic surgery were difficult for both patient and surgeon. Spiegel and Wycis had already advanced to their Model V apparatus by the time that I joined them, and used that model until they retired. It was attached to the skull by four countersunk screws with detachable posts protruding through the scalp. After alignment, the lengths and positions of the legs of the apparatus were secured by set screws, so the apparatus could be removed and remounted in the same position. This was necessary. Visualization of the third ventricle was done by pneumoencephalography after the apparatus was attached. Understandably, the patient was too sick after the pneumoencephalogram to go directly to surgery. Consequently, the apparatus was fitted and the pneumoencephalogram done on Tuesdays and the surgery took place on Thursdays. Later use of positive contrast ventriculography and intraoperative Polaroid developing made it possible to do the procedure in one stage.

During the decade after the introduction of human stereotactic surgery, a number of neurosurgeons reported on their own apparatus. Leksell [36] returned to Sweden after a visit to Spiegel’s laboratory in 1948 and designed the first arc-centered stereotactic apparatus. Within a year, Talairach’s group [37] in Paris introduced an apparatus that allowed insertion of electrodes from laterally through a fixed grid system. Although it was ideally suited to study epilepsy, its use outside the temporal lobe put at risk the tortuous branches of the middle cerebral artery, so his group came to emphasize the importance of mapping the location of such vascular structures. In Germany, Riechert and Wolff [38] reported in 1951 a system similar to an arc-centered device which used a phantom base to indicate the angular settings. Several burr-hole4

There is an interesting but little known coincidence. The fourth author in the original Spiegel and Wycis [23] paper in Science introducing stereotactic surgery was Arnold St. J. Lee, who was then Spiegel’s laboratory assistant. He subsequently became a consulting engineer and was hired by Cooper to develop the cryoprobe, so that he is also the second author describing that technique [34], which, according to a suit contesting the patent for that device, is actually Lee’s design.

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mounted devices were introduced, primarily in the United States [39, 40]. One interesting side note involved Narabayashi [41, 42]. He was isolated in Japan after the Second World War with no access to Western medical literature, but in 1950 independently came up with the idea for human stereotactic surgery and designed his own apparatus. During the next 10 years, a plethora of stereotactic apparatuses were developed. Since commercial systems had not yet become available, most systems were designed and built by the individual stereotactic neurosurgeons. It is estimated that 40 different systems were in use by 1960. At a meeting in Philadelphia in 1961, participants were invited to display their apparatus, and several dozen were laid out on the benches in the student chemistry laboratory at Temple Medical School. Several stereotactic atlases were published during that time, most with more detail or of larger size than the original Spiegel-Wycis atlas [24]. Talairach et al. [43] produced an atlas organized to facilitate the approach using his apparatus. In 1954, Hassler and Riechert [44] advocated the use of the intercommissural line as consistent internal landmarks. (The original Spiegel-Wycis protocol used the anterior commissure and the pineal gland.) Schaltenbrand and Bailey [45] published an atlas in 1959 related to the intercommissural line and incorporating Hassler’s nomenclature for the thalamic subnuclei. The atlas was further refined by Schaltenbrand and Wahren [46] in 1977. Stereotactic surgery spread rapidly throughout the world, and centers were developed in France by Talairach et al. [47] and Guiot and Brion [48], in Great Britain by Gillingham et al. [49], in Scandinavia by Leksell [36] and by Laitinin [50], in Canada by Jasper and Bertrand [51], in Mexico by VelascoSuarez and Escobedo [52], in Spain by Obrador and Dierrsen [53], and in Russia by Bechtereva et al. [54], among others. By 1965, it was estimated that more than 25,000 stereotactic surgeries had been done [55, 56], and 37,000 were done by 1969 [55]. The majority were for movement disorders. The first two decades of stereotactic surgery were particularly fruitful. There were few medical treatments for movement disorders. There was a huge backlog of tremendously incapacitated patients, partially the result of the influenza epidemic of 1918–1920. Empirical human experimentation, without which stereotactic surgery could not have developed, was considered necessary for the advancement of science. By the end of that period, almost all of the current indications had evolved. Parkinson’s disease, however, provided the greatest challenge and opportunity for stereotactic surgery. The evolution of surgery for that condition provides a guided tour of the developments throughout stereotaxis. Although the first patient treated with stereotactic surgery had a pallidotomy for Huntington’s chorea, Spiegel and Wycis were reluctant to use an

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extrapyramidal target for Parkinson’s disease. In laboratory animals, pallidal lesions cause paucity of spontaneous movement, and they were afraid of making the Parkinson akinesia worse. Hassler et al. [57] in 1951 and Hassler and Riechert [44] in 1954 reported the successful treatment of Parkinson’s disease by making lesions in the ventrolateral nucleus of the thalamus. This emboldened Spiegel and Wycis [58] to treat Parkinson’s disease in 1954 by interrupting the ansa lenticularis as it emerged from the globus pallidus, a procedure they called pallidoansotomy. About that same time, Narabayashi and Okuma [26] reported treatment of Parkinson’s disease by injecting procaine oil into the pallidum. Also at about that time, Cooper [59] came into the picture. In 1952, he reported a ‘surgical accident’, in which he inadvertently interrupted the anterior choroidal artery while performing a Walker pedunculotomy in a Parkinson patient. He ligated the artery and aborted the procedure. The patient awoke with significant improvement in his tremor and no induced neurological deficit, despite an infarction in the distribution of that artery. Consequently, Cooper advocated ligation of the anterior choroidal artery for treatment of Parkinson’s disease. Although his initial reports were optimistic, the variability of the distribution of that vessel [60] make the outcome uncertain, with a significant incidence of postoperative complications and weakness. Cooper considered what structures irrigated by that artery might be involved in the therapeutic response and reasoned that a lesion in the globus pallidus might provide the same benefit more consistently, especially since it was already being reported as a stereotactic target [26, 58]. Consequently, in 1955, Cooper [28] advocated injecting alcohol into the globus pallidus, so-called chemopallidectomy. He did not use stereotactic guidance, although he later developed a frame to hold the injecting needle [61]. His trajectory to the pallidum was angulating upward through the temporal lobe at a trajectory that coincidentally pointed directly to the ventrolateral thalamus. When one of his successful patients died of other causes, an autopsy revealed that the lesion was actually in the thalamus, following which, in 1958, Cooper et al. [62] cited the ventrolateral nucleus as the preferred target. Others had already gravitated to the ventrolateral nucleus. In 1954, Hassler and Riechert [44], who had previously targeted the ventrolateral thalamus, refined their targets as the Vop for tremor and the Voa for rigidity, consistent with Hassler’s subdivisions that he had defined in the meantime [63]. Other authors continued to target the globus pallidus. Spiegel et al. [64] commented that the lesion would be more effective against rigidity if it were placed more posteriorly than the tremor target involving the emerging ansa lenticularis fibers [64]. Leksell also used a lesion more ventral and posterior than that used by other authors – although he did not report that at that

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time. Svennilson et al. [65] reported a retrospective report in 1960. Laitinen [66] recently discovered many of Leksell’s original intraoperative x-ray studies and has verified that target. By the end of the 1950s the target for Parkinson’s disease of most stereotactic surgeons had migrated to the thalamus. In the days before L-dopa, the most apparent symptom of Parkinson’s disease was tremor, and the most dramatic effect of surgery was the sudden abolition of that tremor. By the early 1960s, the optimal target for Parkinson’s disease was defined as Hassler’s Vim nucleus [67, 68]; fewer pallidotomies were done [69]. The exact coordinates that defined the optimal target, however, varied considerably between authors [70]. Meanwhile, rather than following the crowd to the thalamus, Spiegel et al. [71, 72] moved their target to Forel’s field, where the pallidofugal fibers converge into a narrow bundle, so that a small lesion interrupts the greatest number of extrapyramidal fibers. It is important for the reader of articles from that era to note carefully where a ‘subthalamic’ target is, since lesions in Forel’s field are subthalamic, but the subthalamic nucleus per se was avoided for fear of producing hemiballismus. Some of the early meetings of what eventually led to formation of the stereotactic societies were colorful. Almost all of the stereotacticians in the world attended. There were only 25 or 30 at the first meetings, and everyone on a first name basis. The most vocal rivalry perhaps was between Dr. Wycis and Dr. Cooper. At the first meeting, Cooper brought a patient to demonstrate how well he could write on a blackboard. Not to be outdone, we were serenaded the next morning by one of Wycis’ patients playing the piano.

During this time, the use of microelectrode recording was introduced into stereotactic surgery, both to localize targets and for physiologic study of the basal ganglia. Albe-Fessard et al. [73] were the first to report this technique in 1961. They at first used low-impedance electrodes and recorded field potentials related to somatosensory stimulation and tremor. Shortly afterward, Jasper and Bertrand [51] used high-impedance single-unit recordings for physiological localization. Because these high-impedance electrodes required for single-unit recording are particularly sensitive to noise [74], it was not until later technological improvements that such recordings have been generally adopted. Stereotactic management of Parkinson’s disease remained commonplace during the 1960s, until L-dopa became generally available in 1968 [75]. For the next 10 years, stereotactic surgery for parkinsonism was hardly performed, even for those patients with a predominant tremor for whom surgery would have been the best option. Only a few neurosurgeons at specialized centers remained familiar with stereotactic techniques. There continued to be a ground level of activity in treatment of other movement disorders, such as hyperkinesia [76], cerebral palsy [77], or other dyskinesias [78], but interest in the field of stereotactic surgery waned [79, 80].

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Two circumstances joined to reawaken the field of stereotactic functional neurosurgery. CT scanning became a commonly used diagnostic modality, and it was only natural to marry it to stereotactic techniques, since both are based on three-dimensional anatomical constructs derived from a cartesian organization. Many neurosurgeons became interested in stereotaxis as part of their general neurosurgical armamentarium. This increased activity coincided with the gradual realization that L-dopa is not the answer to Parkinson’s disease. The benefit wanes in time, just as the disease progresses. A new group of Parkinson’s disease patients with intractable disability appeared, but they had a far advanced version of the disease, often with dyskinetic complications of their medications as the most disabling symptom. Rigidity and akinesia may be severe, with freezing episodes common. By the early 1980s, a search began for a surgical answer to those problems that remained after medical management was exhausted. Often, the answer was to combine medical and surgical therapy [81]. The first rumbles of revitalization of stereotactic surgery for Parkinson’s disease occurred in 1985, when Backlund’s group [82] in Sweden reported on 2 patients who had autologous transplantation of adrenal medulla into the head of the caudate nucleus. The patients had modest improvement, and the authors concluded that ‘the results merit further clinical trials’. Two years later, much better results on 2 additional patients were reported by Madrazo and coworkers [83, 84] in Mexico. They reported an additional 16 patients within the year, most with good results [83]. This new procedure seemed to address the pathophysiology of Parkinson’s disease directly, rather than merely alleviating symptoms, and several more studies were soon reported [85–87]. However, the results were sometimes modest, short-lived [86], the surgery to remove the adrenal gland was very stressful to this fragile group of patients, and sometimes the adrenal gland was so atrophic that little useful transplant material was obtained [88]. A number of complications were reported from the transventricular craniotomy [89], but stereotactic injection of the transplantation graft was not accompanied by such problems [90]. By 1991, the procedure was essentially abandoned. However, the feasibility of tissue transplantation generated interest in the transplantation of fetal nigral tissue as a renewable source of dopamine. The groundwork for fetal cell transplantation had begun a decade earlier. Fetal tissue had been successfully transplanted into the brains of rats [91], or MPTPtreated monkeys [92]. As early as 1984, a symposium had been held to discuss the potential use of human fetal cells for therapeutic purposes [93]. The first 2 patients to be treated with transplantation of fetal dopamine producing cells into the striatum were reported by Backlund and Lindvall’s groups [94–96]. A consortium of centers in Europe was formed to coordinate

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activity and pool results in that field [87, 97, 98]. Additional series have been reported with moderate success. Even so, the difficulties involved with obtaining fetal tissue at the proper age, dissection of the embryonic tissue, processing, and coordinating the implantation complicate fetal transplantation to the point where it would not be pracical except for a few specialized research centers. However, furture progress in the use of cultured stem cells or similar techniques may circumvent these barriers. In the meantime, pallidotomy has been revisited. In 1992, Laitinen and coworkers [99, 100] published several papers resurrecting pallidotomy. Laitinen had revived Leksell’s old technique, as reported in 1960 by Svennilson et al. [65]. This report revitalized the field of functional stereotactic surgery. Many more reports appeared in rapid succession [101–106] indicating that pallidotomy is a safe and reasonably effective treatment for Parkinson’s disease. Along with the resurgence in pallidotomy came a renewed interest in intraoperative microelectrode recording. Modern recording equipment makes the acquisition and processing of microelectrode information feasible for many functional neurosurgical teams. The making of a lesion outside the intended target carries risk, especially since the pallidum lies just above the optic tract and lateral to the internal capsule. The use of microelectrode recording adds to the confidence that the electrode is within the desired target, although there has been fear raised that the sharp point of the electrode may increase the risk of bleeding [107, 108]. Approximately half the surgeons responding to a recent survey use microelectrodes in pallidotomy [109]. In a further attempt to minimize the risk of pallidotomy or other functional stereotactic procedures, the use of implanted deep-bain stimulators has been resurrected. From the very first days of stereotactic surgery, it became routine to use intraoperative stimulation as one parameter to define physiologically the intended stereotactic target. It had been observed since the 1950s that high-frequency stimulation applied during thalamotomy or pallidotomy might block the physiologic activity of the stimulated area and consequently suppress tremor, although the responses were variable. Prior to the introduction of intraoperative microelectrode recording, response to stimulation was the most commonly used physiological parameter for localization of the target, and still may be. Reports about such technical details were commonly discussed at meetings, but little appears in the literature. The availability of stimulators for the nervous stem grew directly from advances in cardiac pacemakers. Prolonged stimulation of the heart was introduced as early as 1957, with a fully implantable pacemaker available by 1960. The first functional neurosurgical use of implanted stimulators occurred when Shealy et al. [110] introduced spinal cord stimulation for pain in 1967, and Sweet and Wepsic [111] reported the use of an implanted peripheral nerve

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stimulator the following year. The first use of such implanted spinal cord stimulators for motor disorders was reported by Gildenberg [112] in 1977, in a project begun in 1971 which used very high-frequency (up to 1,500 Hz) stimulation for the management of spasmodic torticollis. The hope was that high-frequency stimulation of the upper cervical spinal cord might block proprioceptive input from the abnormally contracting cervical muscles. Half the patients had significant relief. Relief of intractable pain by chronic stimulation of the septal area was reported by Heath and Mickle [113] as early as 1960. In 1973, about the time that laboratory evidence of the analgesic effect of periaqueductal stimulation was obtained [114], Hosobuchi et al. [115] reported the relief of denervation pain by implantation of a permanent stimulating electrode in the somatosensory thalamus. Deep-brain stimulation became a reality when implanted periventricular and thalamic stimulators for pain management were introduced by several investigators in 1977 [116–118]. Unfortunately, this modality for pain management fell out of favor in the US around 1990, at which time the FDA withdrew approval of the use of deep-brain stimulation for chronic intractable pain. Bechtereva et al. [119] were the first to report the use of chronic stimulation for management of motor disorders. However, no implantable stimulators were available in Russia. They implanted electrodes with external connectors, and the patients returned repeatedly for each course of stimulation. In 1980, Brice and McLellan [120] were the first to treat 2 patients with multiple sclerosis induced intention tremor by fully implantable thalamic stimulators. That same year, Mazars et al. [121] reported that the use of a thalamic stimulator to treat a patient with both pain and dyskinesias induced by deafferentation improved both the pain and the motor disorder. This was soon followed by a similar report by Mundinger and Neumu¨ller [122] – implanted deep-brain stimulators both treated chronic pain and in the same patients controlled torticollis, dystonia or spasticity. About that time, Siegfried [123] observed suppression of involuntary movements of the thalamic syndrome in a patient in whom he implanted a thalamic stimulator primarily for pain management, but he did not report the patient until 1986. Siegfried’s group [124, 125] was sufficiently impressed by that observation so that in 1987 he implanted Vim thalamic stimulators for Parkinson tremor. Benabid et al. [126, 127] particularly stressed the need for higher frequency stimulation to block transmission across the site being stimulated. These were the first reports of fully implanted brain stimulators solely for motor control, since all prior reports involved implantation for pain where improvement in the movement disorder was a bonus. The use of an implanted stimulator for treatment of movement disorders was particularly attractive, since no

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permanent lesion was made and the procedure consequently is potentially safer. If stimulation of Vim produces relief of tremor, would not stimulation of the globus pallidus produce the same benefit as pallidotomy, perhaps with less risk, especially in older fragile Parkinson patients with little neurologic reserve? Both Siegfrried and Benabid took this next logical step. Siegfried and Lippitz [128] reported in 1994 their experience since 1985 with bilateral stimulation of the same ventral posterior pallidal target as for pallidotomy, and Siegfried has continued to report on experience with that stimulation site. Patients have equivalent benefit as with pallidotomy with probably less risk, although they require the same dose of medication as preoperatively. Benabid soon turned his attention to the subthalamic nucleus. His group [129] reported in 1993 on bilateral subthalamic nucleus stimulation in Parkinson’s disease. Not only do patients have significant relief of akinesia, but can decrease their medication requirement. At present, it seems that the subthalamic nucleus might be the most beneficial target, but electrode implantation and programming are perhaps more complex. The most recent reports of a new modality for conrol of movement disorders involve stereotactic radiosurgical lesion production. The targets are the same as for pallidotomy or thalamotomy. The lesion is produced with a small collimator, usually with the Gamma Knife. The first report on the use of this technique was by Rand et al. [130], and there are subsequent reports from a number of authors. It would seem that there is little advantage to using this technique. Even though it is mechanically not invasive, the penetration by multiple beams of radiation provides at least as much risk as insertion of an electrode, and there is no opportunity to identify the final target with physiologic evaluation. No review of where we have been is complete without some speculation about where we are going. At present, the use of pallidotomy and thalamotomy are still the most common procedures for the treatment of movement disorders. There is some speculation that the subthalamic nucleus may provide a target, despite past reports of the risk of hemiballismus. Chronic stimulators are on the ascendency. Even though they offer the theoretical advantage of less risk, treatment of many patients is influenced by cost constraints, so that ablative procedures will remain the primary procedure in many places. The use of transplanted cells is in its infancy, and may become the modality of choice as genetically engineered cells, able to replace any transmitter they are designed for, become available. The ideal treatment is, of course, not surgical, but information gained through stereotactic procedures will be important in understanding the pathophysiology of movement disorders to lead eventually to nonsurgical treatment. Even so, it may be necessary to

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place the treating modality at the site of activity, again requiring stereotactic techniques. In the century just started, cerebrovascular disease will be treated by interventional neuroradiologists (many of them neurosurgeons), brain tumors will be treated by neuroimmunologists or neurogeneticists, spine surgery will be invaded more and more by the orthopedic surgeons, so the only things left in neurosurgery will be head trauma and stereotaxis. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

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¨ ber die Lage des sogenannten Gefa¨sszentrums in der Medulla oblongata. Ber Sa¨chs Dittmar C: U Ges Wiss Leipzig (Math Phys) 1873;25:449–469. Kandel EI: Functional and Stereotactic Neurosurgery. New York, Plenum, 1989. Zernov DN: Encephalometer. Device for estimation of parts of brain in human (Russian). Proc Soc Physicomed Moscow Univ 1889;2:70–80. Altukhov NV: Encephalometric Investigations of the Brain Relative to the Sex, Age and Skull Indexes. Moscow, 1891. Gildenberg PL: ‘Stereotaxic’ versus ‘stereotactic’. Neurosurgery 1993;32:965–966. Horsley V, Clarke RH: The structure and functions of the cerebellum examined by a new method. Brain 1908;31:45–124. Fodstad H, Hariz M, Ljunggren B: History of Clarke’s stereotactic instrument. Stereotact Funct Neurosurg 1991;57:130–140. Jensen RL, Stone JL, Hayne R: Use of the Horsley-Clarke stereotactic frame in humans. Stereotact Funct Neurosurg 1995;65:194–197. Levy R: A Short History of Stereotactic Neurosurgery. Park Ridge/Ill, American Association of Neurological Surgeons, 1992. Olivier A, Bertrand G, Picard C: Discovery of the first human stereotactic instrument. Appl Neurophysiol 1983;46:84–91. Dandy WE: Changes in our conceptions of localization of certain functions in the brain. Am J Physiol 1930;93:643–647. Bucy PC, Case TJ: Tremor. Physiologic mechanism and abolition by surgical means. Arch Neurol Psychiatry 1939;41:721–746. Bucy PC, Buchanan DN: Athetosis. Brain 1932;55:479–492. Putnam TJ: Treatment of athetosis and dystonia by section of the extrapyramidal motor tracts. Arch Neurol Psychiatry 1933;29:504–521. Browder J: Section of the fibers of the anterior limb of the internal capsule in parkinsonism. Am J Surg 1948;75:264–268. Bowder J: Parkinsonism – Is it a surgical problem? NY State Med J 1947;47:2589–2592. Oliver LC: Surgery in Parkinson’s disease. Division of lateral pyramidal tract for tremor: Report on forty-eight operations. Lancet 1949;i:910–913. Putnam TJ: Results of treatment of athetosis by section of extrapyramidal tracts in the spinal cord. Arch Neurol Psychiatry 1938;39:258–275. Meyers R: The modification of alternating tremors, rigidity and festination by surgery of the basal ganglia. Res Publ Assoc Res Nerv Ment Dis 1942;21:602–665. Meyers R: Historical background and personal experiences in the surgical relief of hyperkinesia and hypertonus; in Fields W (ed): Pathogenesis and Treatment of Parkinsonism. Springfield, Thomas, 1958, pp 229–270. Walker AE: Cerebral pedunculotomy for the relief of involuntary movements. I. Hemiballismus. Acta Psychiatry Neurol Scand 1949;24:712–729. Guiot G, Pecker J: Tractotomie mesencephalique anterieure pour tremblement parkinsonien. Rev Neurol (Paris) 1949;81:387–388.

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23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53

Spiegel EA, Wycis HT, Marks M, Lee AS: Stereotaxic apparatus for operations on the human brain. Science 1947;106:349–350. Spiegel EA, Wycis HT: Stereoencephalotomy. I. New York, Grune & Stratton, 1952. Freeman W, Watts JW: Psychosurgery: Intelligence, Emotional and Social Behavior following Prefrontal Lobotomy for Mental Disorders. Springfield, Thomas, 1942. Narabayashi H, Okuma T: Procaine oil blocking of the globus pallidus for the treatment of rigidity and tremor of parkinsonism. Proc Jpn Acad 1953;29:310–318. Narabayashi H, Shimazu H, Fujita Y, Shikiba S, Nagao T, Nagahata M: Procaine-oil-wax pallidotomy for double athetosis and spastic states in infantile cerebral palsy. Neurology 1960;10:61–69. Cooper IS: Chemopallidectomy. Science 1955;121:217. Gildenberg PL: Studies in stereoencephalotomy. VII. Comparison of the variability of subcortical lesions produced by various procedures. Confin Neurol 1957;17:299–301. Cooper IS: Chemopallidectomy and chemothalamectomy for parkinsonism and dystonia. Proc R Soc Med 1959;52:47–60. Obrador S: A simplified neurosurgical technique for approaching and damaging the region of the globus pallidus in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1957;20:47–49. Cosman ER, Nashold BS Jr, Bedenbaugh P: Stereotactic radiofrequency lesion making. Appl Neurophysiol 1983;46:160–166. Cosman E: Radiofrequency lesions; in Gildenberg P, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, pp 973–985. Cooper IS, Lee A St J: Cryostatic congelation. J Nerv Ment Dis 1961;133:259–263. Cooper IS, Gioino G, Terry R: The cryogenic lesion. Confin Neurol 1965;26:161–177. Leksell L: A stereotaxic apparatus for intracerebral surgery. Acta Chir Scand 1949;99:229–233. He´caen H, Talairach T, David M, Dell MB: Me´moires originaux. Coagulations limite´es du thalamus dans les algies du syndrome thalamique. Rev Neurol 1949;81:917–931. Riechert T, Wolff M: Die Entwicklung und klinische Bedeutung der gezielten Hirnoperationen. Med Klin 1951;46:609–611. Bailey P, Stein SN: A stereotaxic apparatus for use on the human brain. AMA Scientific Exhibit. Atlantic City 1951. Austin B, Lee A: A plastic ball and socket type of stereotaxic detector. J Neurosurg 1958;15:264–268. Uchimura Y, Narabayashi H: Stereoencephalotom (Japanese). Psychiatr Neurol Jpn 1951;52:265. Narabayashi H: Stereotaxic instrument for operation on the human basal ganglia. Psychiatr Neurol Jpn 1952;54:669–671. Talairach J, David M, Tournoux P, Corredor H, Krasina T: Atlas d’anatomie stereotaxique. Paris, Masson, 1957. Hassler R, Riechert T: Indikationen und Lokalisationsmethode der gezielten Hirnoperationen. Nervenarzt 1954;25:441–447. Schaltenbrand G, Bailey P: Introduction to Stereotaxis with an Atlas of the Human Brain. Stuttgart, Thieme, 1959. Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain, ed 2. Stuttgart, Thieme, 1977. Talairach J, He´caen M, David M, Monnier M, Ajuriaguerra J: Recherches sur la coagulation therapeutique des structures sous-corticales chez l’homme. Rev Neurol 1949;81:4–24. Giot G, Brion S: Traitment neurochirurgical de syndrome choreoathetosique et parkinsoniens. Semaine Hoˆp Paris 1952;49:2095–2099. Gillingham FJ, Watson WS, Donaldson AA, Naughton JAL: The surgical treatment of parkinsonism. Br Med J 1960;ii:1395–1402. Laitinen LV: Short-term results of stereotaxic treatment for infantile cerebral palsy. Confin Neurol 1965;26:258–263. Jasper H, Bertrand G: Stereotaxic microelectrode studies of single thalamic cells and fibres in patients with dyskinesia. Trans Am Neurol Assoc 1964;89:79–82. Velasco-Suarez MM, Escobedo FR: Stereotaxic intracerebral instillation of dopa. Confin Neurol 1970;32:149–157. Obrador S, Dierssen G: Cirurgia de la region palidal. Revta Clin Esp Ano XVII 1956;61:229–237.

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Bechtereva NP, Genkin AA, Moiseeva NI, Smirnov VM: Electrographic evidence of participation of deep structures of the human brain in certain mental processes. Electroencephalogr Clin Neurophysiol 1967(suppl 25):153. Spiegel EA: History of human stereotaxy (stereoencephalotomy); in Schaltenbrand G, Walker AE (eds): Stereotaxy of the Human Brain. Anatomical, Physiological and Clinical Applications. Stuttgart, Thieme, 1982, pp 3–10. Spiegel EA, Wycis HT: Second International Symposium on Stereoencephalotomy. Confin Neurol 1966;27:1–261. Hassler R, Mundinger F, Riechert T: Correlations between clinical and autoptic findings in stereotaxic operations of parkinsonism. Confin Neurol 1965;26:282–290. Spiegel EA, Wycis HT: Ansotomy in paralysis agitans. Arch Neurol Psychiatry 1954;71:598–614. Cooper IS: Ligation of the anterior choroidal artery for involuntary movements of parkinsonism. Psychiatr Q 1953;27:317–319. Rand RW, Brown WJ, Stern WE: Surgical occlusion of anterior choroidal arteries in parkinsonism. Clinical and neuropathologic findings. Neurology 1956;6:390–401. Cooper IS: Involuntary Movement Disorders. New York, Harper & Row, 1969. Cooper IS, Bravo G, Riklan M, Davidson N, Gorek E: Chemopallidectomy and chemothalamectomy for parkinsonism. Geriatrics 1958;13:127–147. Hassler R, Mundinger F, Riechert T: Pathophysiology of tremor at rest derived from the correlation of anatomical and clinical data. Confin Neurol 1970;32:79–87. Spiegel EA, Wycis HT, Baird HW III: Long range effects of electropallido-ansotomy in extrapyramidal and convulsive disorders. Neurology 1958;8:734–740. Svennilson E, Torvik A, Lowe R, Leksell L: Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Neurol Scand 1960;35: 358–377. Laitinen LV: Leksell’s unpublished pallidotomies of 1958–62. Stereotact Funct Neurosurg 2000;74: in press. Riechert T: Long-term follow-up of results of stereotaxic treatment of extrapyramidal disorders. Confin Neurol 1962;22:356–363. Mundinger F, Riechert T: Die stereotaktischen Hirnoperationen zur Behandlung extrapyramidaler Bewegungssto¨rungen (Parkinsonismus und Hyperkinesen) und ihre Resultate: Postoperative und Langzeitergebnisse der stereotaktischen Hirnoperationen bei extrapyramidalmotorischen Bewegungssto¨rungen. Fortschr Neurol Psychiatr 1963;31:69–120. Levy A: Stereotaxic brain operations in Parkinson’s syndrome and related motor disorders. Comparison of lesions in the pallidum and thalamus with those in the internal capsule. Confin Neurol 1967;29:1–70. Laitinen L: Thalamic targets in the stereotaxic treatment of Parkinson’s disease. J Neurosurg 1966; 24:82–85. Spiegel EA, Wycis HT, Szekely EG, Adams J, Flanagan M, Baird HW: Campotomy in various extrapyramidal disorders. J Neurosurg 1963;20:871–881. Spiegel EA, Wycis HT, Szekely EG, Soloff L, Adams J, Gildenberg PL, Zanes C: Stimulation of Forel’s field during stereotaxic operations in the human brain. EEG Clin Neurophysiol 1964;16: 537–548. Albe-Fessard D, Arfel G, Guiot G, Hardy J, Hertzog E, Aleonard P: Identification et de´limitation pre´cise de certaines structures souscorticales de l’homme par l’electro-physiologie. CR Acad Sci (Paris) 1961;243:2412–2414. Rowland LH, Dougherty PM, Lenz F: Microelectrode recording in functional neurosurgery; in Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, pp 935–939. Cotzias GC, Van Woert MH, Schiffer LM: Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967;276:374–379. Mundinger F, Riechert T, Disselhoff J: Long-term results of stereotaxic operations on extrapyramidal hyperkinesia (excluding parkinsonism). Confin Neurol 1970;32:71–78. Siegfried J: Stereotaxic cerebellar surgery. Confin Neurol 1971;33:350–360.

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Divitiis E, Signorelli CD, Cerillo A: Stereotaxic surgery for non-parkinsonian dyskinesias. Neurochirurgia (Stuttg) 1972;15:92–95. Gildenberg PL: Whatever happened to stereotactic surgery? II. Neurosurgery 1987;20:983–987. Tasker RR, Siqueira J, Hawrylshyn P, Organ LW: What happened to Vim thalamotomy for Parkinson’s disease? Appl Neurophysiol 1983;46:68–83. Kelly PJ, Gillingham FJ: The long-term results of stereotaxic surgery and L-dopa therapy in patients with Parkinson’s disease. A 10-year follow-up study. J Neurosurg 1980;53:332–337. ˚: Backlund EO, Granberg PO, Hamberger B, Knutsson E, Martensson A, Sedvall G, Seiger A Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J Neurosurg 1985;62:169–173. Drucker-Colin R, Madrazo I, Diaz V: Open microsurgical autograft of adrenal medulla to caudate nucleus of patients with Parkinson’s disease. Schmitt Neurological Sciences Symposium, Rochester, NY, June 30–July 3, 1987. Madrazo I, Drucker-Colin R, Diaz V: Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N Engl J Med 1987;316: 831–834. Bakay RAE, Herring CJ: Central nervous system grafting in the treatment of parkinsonism. Stereotact Funct Neurosurg 1989;53:1–20. Goetz CG, Olanow CW, Koller WC, Penn RD, Cahill D, Morantz R, Stebbins G, Tanner CM, Klawans HL, Shannon KM, Comella CL, Witt T, Cox C, Waxman M, Gauger L: Multicenter study of autologous adrenal medullary transplantation to the corpus striatum in patients with advanced Parkinson’s disease. N Engl J Med 1989;320:337–341. Hitchcock ER, Clough CG, Hughes RC, Kenny BG: Transplantation in Parkinson’s disease: Stereotactic implantation of adrenal medulla and foetal mesencephalon. Acta Neurochir Suppl (Wien) 1989; 46:48–50. Stoddard SL,Tyce GM, Ahlskog JE, Zinsmeister AR, Carmichael SW: Decreased catecholamine content in parkinsonian adrenal medullae. Exp Neurol 1989;104:22–27. Jankovic J, Grossman R, Goodman C, Pirozzolo F, Schneider L, Zhu Z, Scardino P, Garber AJ, Jhingran SG, Martin S: Clinical, biochemical, and neuropathologic findings following transplantation of adrenal medulla to the caudate nucleus for treatment of Parkinson’s disease. Neurology 1989;39:1227–1234. Gildenberg PL, Pettigrew LC, Merrell R, Butler I, Conklin R, Katz J, DeFrance J: Transplantation of adrenal medullary tissue to caudate nucleus using stereotactic techniques. Stereotact Funct Neurosurg 1990;54–55:268–271. Brundin P, Bjorklund A: Survival, growth and function of dopaminergic neurons grafted to the brain. Prog Brain Res 1987;71:293–308. Bakay RA: Neurotransplantation: A clinical update. Acta Neurochir Suppl (Wien) 1993;58:8–16. Mark VH, Gildenberg PL, Franklin PO: Proceedings of the Colloquium on the Use of Embryonic Cell Transplantation for Correction of CNS Disorders. Appl Neurophysiol 1984;47:1–76. Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B, Bjorklund A, Lindvall O, Langston JW: Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992;327:1556–1563. ˚ : TransLindvall O, Backlund EO, Farde L, Sedvall G, Freedman R, Hoffer B, Nobin A, Seiger A plantation in Parkinson’s disease: Two cases of adrenal medullary grafts to the putamen. Ann Neurol 1987;22:457–468. Lindvall O, Rehncrona S, Brundin P, Gustavii B, Astedt B, Widner H, Lindholm T, Bjorklund A, Tan M: Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol 1989;46:615–631. Hitchcock E: Neural implants and recovery of function: Human work. Adv Exp Med Biol 1992; 325:67–78. Hitchcock E: Stereotactic neural transplantation. Stereotact Funct Neurosurg 1994;62:120–133. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61.

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Laitinen LV, Bergenheim AT, Hariz MI: Ventroposterolateral pallidotomy can abolish all parkinsonian symptoms. Stereotact Funct Neurosurg 1992;58:14–21. Bakay RA, Delong MR, Vitek JL: Posteroventral pallidotomy for Parkinson’s disease. J Neurosurg 1992;77:487–488. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Laitinen LV: Pallidotomy for Parkinson’s disease. Neurosurg Clin North Am 1995;6:105–112. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Baron MS, Vitek JL, Bakay RA, Green J, Kaneoke Y, Hashimoto T, Turner RS, Woodard JL, Cole SA, McDonald WM, Delong MR: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355–366. Ondo WG, Jankovic J, Lai EC, Sankhla C, Khan M, Ben-Arie L, Schwartz K, Grossman RG, Krauss JK: Assessment of motor function after stereotactic pallidotomy. Neurology 1998;50:266–270. Hariz MI, De Salles AA: The side-effects and complications of posteroventral pallidotomy. Acta Neurochir Suppl (Wien) 1997;68:42–48. Hariz MI, Fodstad H: ‘ The pallidotomy debate’: Are micro-electrode-guided pallidotomies always located in the pallidum? Br J Neurosurg 1998;12:595–597. Favre J, Taha JM, Nguyen TT, Gildenberg PL, Burchiel KJ: Pallidotomy: A survey of current practice in North America. Neurosurgery 1996;39:883–892. Shealy CN, Mortimer JT, Reswick JB: Electrical inhibition of pain by stimulation of the dorsal columns. Preliminary clinical report. Anesth Analg (Cleve) 1967;46:489–491. Sweet WH, Wepsic JG: Treatment of chronic pain by stimulation of fibers of primary afferent neuron. Trans Am Neurol Assoc 1968;93:103–107. Gildenberg PL: Treatment of spasmodic torticollis with dorsal column stimulation. Acta Neurochir 1977;9:65–66. Heath RG, Mickle WA: Evaluation of seven years’ experience with depth electrode studies in human patients; in Ramey ER, O’Doherty DS (eds): Electrical Studies on the Unanesthetized Brain. New York, Hoeber, 1960, pp 214–228. Liebeskind JC, Gilubaum G, Besson JM, Oliveras JL: Analgesia from electrical stimulation of the periaqueductal grey in the cat. Behavioral observations and inhibitory effects on spinal cord interneurons. Brain Res 1973;50:441–446. Hosobuchi Y, Adams JE, Rutkins B: Chronic thalamic stimulation for the control of facial anesthesia dolorosas. Arch Neurol 1973;29:158–161. Hosobuchi Y, Adams JE, Linchitz R: Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Science 1977;197:183–186. Richardson DE, Akil H: Long-term results of periventricular gray self-stimulation. Neurosurgery 1977;1:199–202. Bechtereva NP, Kambarova DK, Smirnov VM, Shandurina AN: Using the brain’s latent abilities for therapy: Chronic intracerebral electrical stimulation; in Sweet WH (ed): Neurosurgical Treatment in Psychiatry, Pain, and Epilepsy. Baltimore, University Park Press, 1977, pp 581–613. Bechtereva NP, Bondarchuk AN, Smirnov VM: Therapeutic electrostimulations of the deep brain structures. Vopr Neirokhir 1972;1:7–12. Brice J, McLellan L: Suppresson of intention tremor by contingent deep-brain stimulation. Lancet 1980;i:1221–1222. Mazars G, Merienne L, Cioloca C: Control of dyskinesias due to sensory deafferentation by means of thalamic stimulation. Acta Neurochir Suppl (Wien) 1980;30:239–243. Mundinger F, Neumu¨ller H: Programmed stimulation for control of chronic pain and motor diseases. Appl Neurophysiol 1982;45:102–111. Siegfried J: Effect of stimulation of the sensory nucleus of the thalamus on dyskinesia and spasticity. Rev Neurol (Paris) 1986;142:380–383. Siegfried J, Shulman J: Deep brain stimulation. Pacing Clin Electrophysiol 1987;10:271–272. Blond S, Siegfried J: Thalamic stimulation for the treatment of tremor and other movement disorders. Acta Neurochir Suppl (Wien) 1991;52:109–111.

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Benabid AL, Pollak P, Hommel M, Gaio JM, de Rougemont J, Perret J: Treatment of Parkinson tremor by chronic stimulation of the ventral intermediate nucleus of the thalamus. Rev Neurol (Paris) 1989;145:320–323. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J: Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987;50:344–346. Siegfried J, Lippitz B: Chronic electrical stimulation of the VL-VPL complex and of the pallidum in the treatment of movement disorders: Personal experience since 1982. Stereotact Funct Neurosurg 1994;62:71–75. Pollak P, Benabid AL, Gervason CL, Hoffmann D, Seigneuret E, Perret J: Long-term effects of chronic stimulation of the ventral intermediate thalamic nucleus in different types of tremor. Adv Neurol 1993;60:408–413. Rand RW, Jacques DB, Melbye RW, Copcutt BG, Fisher MR, Levenick MN: Gamma knife thalamotomy and pallidotomy in patients with movement disorders: Preliminary results. Stereotact Funct Neurosurg 1993;61(suppl 1):65–92.

Philip L. Gildenberg, MD, PhD, Houston Stereotactic Center, 6624 Fannin, Suite 1620, Houston, TX 77030 (USA) Tel. +1 713 790 0795, Fax +1 713 669 0388, E-Mail [email protected]

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Anatomical and Physiologic Substrates Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 21–30

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Anatomical Considerations in Basal Ganglia Surgery Andre´ Parent, Martine Cossette, Martin Le´vesque Laboratoire de Neurobiologie, Centre de recherche Universite´ Laval Robert-Giffard, Beauport, Que´., Canada

Bradykinesia or akinesia observed in Parkinson’s disease (PD) is believed to result from increased GABAergic inhibition of thalamic premotor neurons due to excessive glutamatergic excitatory drive from the subthalamic nucleus (STN) to the internal segment of the globus pallidus (GPi). The loss of striatal dopamine that characterizes this neurodegenerative disease is thought to cause a disinhibition of GABA/enkephalin neurons at the origin of the indirect pathway, which leads to a marked hypoactivity of the external segment of the globus pallidus (GPe) followed by a disinhibition of the STN. At the other end of the spectrum, hyperkinetic movements encountered in Huntington’s disease are believed to result from decreased GABAergic inhibition of thalamic premotor neurons due to a lack of excitatory drive from the STN to GPi [1, 2]. This model of the organization of basal ganglia suffers from several shortcomings that have been clearly outlined elsewhere [3]. Most researchers nevertheless agree that both STN and GPi are hyperactive in PD and stereotaxic lesions or high-frequency stimulations (‘reversible lesions’) of the GPi, or highfrequency stimulations of the STN, have been shown to significantly improve motor deficits in PD patients [4–7]. However, as this type of ‘functional neurosurgery’ becomes more and more common, some variations in the results obtained by the different groups begin to emerge. Some of these disparities may be easily explained by methodological differences, but others appear to be due to the heterogeneity of the organization of the target structure and/or the complexity of its connections. For example, high-frequency stimulation of the GPi can produce two completely opposite effects in PD patients depending on which part of the GPi is being stimulated [8]. These results point to the fact that a better knowledge of the anatomy of the human basal ganglia

is needed to obtain optimal neurosurgical results. This paper reviews the arrangement of the major fiber pathways related to the GPi and STN and we provide new information regarding the organization of the dopaminergic (DA) pathways in humans.

Forebrain Fiber Systems Related to Basal Ganglia Among the major forebrain bundles associated with the basal ganglia are the (1) ansa lenticularis, (2) lenticular fasciculus, (3) subthalamic fasciculus, (4) thalamic fasciculus, (5) ansa peduncularis and (6) medial forebrain bundle. Some of these bundles are arranged in a rostrocaudal sequence with the ansa lenticularis most rostral, the lenticular fasciculus in an intermediate position and pallidosubthalamic fibers most caudal. Other fiber systems, like the medial forebrain bundle, run longitudinally along the rostrocaudal axis of the forebrain. Ansa lenticularis Fibers of this bundle arise principally from lateral portions of the GPi and form a well-defined bundle on the ventral surface of the pallidum (fig. 1). Fibers sweep ventromedially and rostrally around the posterior limb of the internal capsule and then course posteriorly to enter Forel’s field H (prerubral field). The abbreviation ‘H’ derives from the first letter of the German word ‘Haubenfeld’ (nightcap-like field). This word was coined by the Swiss psychiatrist August Forel (1848–1931) to designate the thalamic (H1) and lenticular (H2) fasciculi, which both display a comma or nightcap shape. Lenticular fasciculus These fibers originate mainly from inner portions of the GPi, emerge from the dorsomedial margin of the pallidum, slightly caudal to the ansa lenticularis, and traverse ventral parts of the internal capsule in a number of small fascicles (fig. 1). Fibers cross through the internal capsule immediately rostral to the subthalamic nucleus and form a discrete bundle ventral to the zona incerta. Although most of the lenticular fasciculus lies rostral to the subthalamic nucleus, some fibers of this bundle course along its dorsal border. Fibers of the lenticular fasciculus are referred to as Forel’s field H2. While fibers of the lenticular fasciculus pursue a distinctive course through the internal capsule, they pass medially and caudally to join fibers of the ansa lenticularis in Forel’s field H. Fibers of the lenticular fasciculus (H2) and the ansa lenticularis, which merge in Forel’s field H, ultimately enter the thalamic fasciculus (Forel’s field H1) located dorsal to the zona incerta [9].

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Fig. 1. Drawings of coronal and horizontal sections through the human basal ganglia showing the organization of the major output pathways of the internal segment of the globus pallidus. AML>Accessory medullary lamina; GPe>external segment of the globus pallidus; GPi>internal segment of the globus pallidus; H, H1, H2>Forel’s fields; ic>internal capsule; IML>internal medullary lamina; Put>putamen; ZI>zona incerta.

Investigations of the origin of pallidothalamic fibers in the monkey indicate that fibers emerging via the ansa lenticularis and the lenticular fasciculus arise from specific portions of the GPi [10]. These data indicate that fibers of the ansa lenticularis arise predominantly from the ventrolateral part of the GPi (i.e. from that part of the GPi lateral to the accessory medullary lamina).

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These fibers course rostrally, ventrally and medially, and traverse portions of the GPi. Fibers of the lenticular fasciculus arise largely from the dorsomedial part of the GPi (i.e. from the portion medial to the accessory medullary lamina). These fibers course dorsally, rostrally and medially and traverse the peduncular part of the internal capsule (fig. 1A). Subthalamic fasciculus The subthalamic fasciculus consists of pallidofugal fibers that pass through the internal capsule to enter the STN, and of fibers from the STN that project back to the globus pallidus. Pallidosubthalamic fibers arise only from the GPe and directly upon cells of the STN [11, 12]. These fibers are topographically organized. Rostral parts of the GPe project to medial and rostral parts of the subthalamic nucleus. Cells in the central division of the GPe (flanking the GPi) project to the lateral third of the subthalamic nucleus throughout most of its rostrocaudal extent. Pallidosubthalamic fibers traverse ventromedial and caudal parts of the internal capsule, caudal to both the ansa lenticularis and the lenticular fasciculus. Subthalamopallidal fibers also traverse the ventromedial and caudal parts of the internal capsule but in the opposite direction. They are distributed to both pallidal segments where they terminate in the form of vertically elongated bands [9, 12]. The band-like terminal fields formed by the subthalamopallidal fibers are in register with those of the striatopallidal fibers and both subthalamopallidal and striatopallidal fibers converge upon the same pallidal neurons [13, 14]. Thalamic fasciculus Pallidofugal fibers from Forel’s field H pass rostrally and laterally along the dorsal surface of the zona incerta where they form part of the thalamic fasciculus (fig. 1). Some of the fibers of the lenticular fasciculus merely make a C-shaped loop around the medial part of the zona incerta and enter the thalamic fasciculus. The thalamic fasciculus contains pallidothalamic fibers, as well as ascending fibers from the contralateral cerebellar nuclei. This composite bundle projects dorsolaterally over the zona incerta to terminate in specific nuclear subdivisions of the rostral ventral tier thalamic nuclei. In the region dorsal to the zona incerta, where fibers of this bundle are distinct and separate from those of the lenticular fasciculus, the thalamic fasciculus is designated as field H1 of Forel. Ansa peduncularis This fiber bundle represents the medial continuation of the ansa lenticularis. It closely borders the rostromedial pole of the GPi (fig. 2B). One of

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Fig. 2. Drawings of coronal sections through the human basal ganglia depicting the distribution of the dopaminergic (TH-ir) fibers at pallidal levels. The two sections (A, B) are set out in a rostrocaudal order and number in parentheses indicates the anterior plane of each section according to the Atlas of Schaltenbrand and Bailey [22]. AL>Ansa lenticularis; AML>accessory medullary lamina; AP>ansa peduncularis; CD>caudate nucleus; EML> external medullary lamina; LH>lateral hypothalamic area; OT>optic tract; Rt>reticular thalamic nucleus; SN>substantia nigra; ST>stria terminalis; Th>thalamus; STN>subthalamic nucleus. Other abbreviations as in figure 1.

the major components of the ansa lenticularis is the inferior thalamic peduncle, which provides a two-way connection between the basolateral nuclear group of the amygdaloid complex and the medial part of the mediodorsal thalamic nucleus [9]. The ansa peduncularis also contains numerous fibers interconnecting the amygdaloid complex and the preoptico-hypothalamic complex, as well as fibers from temporal, caudal orbitofrontal and piriform cortices en route to the mediodorsal thalamic nucleus. Of particular interest here is the fact that the ansa peduncularis is markedly enriched in DA fibers that course toward the pallidal complex and striatum (fig. 2B). Medial Forebrain Bundle In nonmammalian vertebrates, principally reptiles and birds, the various components of the forebrain are linked together, as well as with the brainstem

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via the so-called medial and lateral forebrain bundles. The striatum and pallidum in these vertebrates are connected with the rest of the forebrain, as well as with the midbrain through the lateral forebrain bundle. In both reptiles and birds the lateral forebrain bundle is divided into a ventral and a dorsal peduncle. The ventral peduncle contains fibers interconnecting the striatopallidal complex with the ventral midbrain tegmentum, which contains a welldeveloped DA substantia nigra, whereas the dorsal peduncle provides a similar relationship with the thalamus [15]. On one hand, the dorsal peduncle in nonmammals corresponds to the portion of the mammalian internal capsule that contains fibers interconnecting the thalamus with the striatum and cerebral cortex, as well as to the thalamic fasciculus described above. On the other hand, the ventral peduncle corresponds to various specific fiber systems, including most of the bundles described above (ansa lenticularis, lenticular fasciculus and ansa peduncularis). Thus, the term lateral forebrain bundle is no longer in use in mammalian terminology. The medial forebrain bundle, however, is a term that is still widely used, even in human nomenclature. The name refers to a phylogenetically old, highly complex, multisynaptic bundle that extends rostrocaudally from the olfactory tubercle to the rostral part of the midbrain. It contains a series of short and long, poorly myelinated fiber systems, together with all their collateral branching systems, that course either rostrally or caudally. The medial forebrain bundle occupies most of the lateral hypothalamic area and ensures local connections between various regions of the preoptico-hypothalamic complex, as well as connections between distant telencephalic and midbrain limbic areas and the hypothalamus [9, 15]. This bundle is also the major route by which virtually all the monoaminergic systems, including the DA mesostriatal and mesolimbic pathways, reach their main telencephalic target (see below).

Dopaminergic Pathways The immunohistochemical analysis of human postmortem tissues with antibodies raised against tyrosine hydroxylase (TH) as a DA marker have revealed many interesting features of the organization of the nigrostriatal projection system in humans. A multitude of TH-immunoreactive (ir) fibers was seen to emerge from the TH-ir neurons of the human substantia nigra pars compacta (SNc). Irrespective of the location of their cell body of origin, the TH-ir fibers swept dorsally and medially to the SNc and formed a massive bundle that coursed through the prerubral field of Forel and ascended within the lateral hypothalamic area, along the medial forebrain bundle.

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At more rostral level, however, a significant number of fibers detached from the main bundle and swept laterally toward the lenticular nucleus (fig. 2). These fibers traveled backward along the lenticular fasciculus caudally and the ansa lenticularis rostrally. The TH-ir fibers associated with the lenticular fasciculus ran along the dorsal surface of STN, traversed the internal capsule and invaded GP principally from its dorsal surface (fig. 2A), whereas those related to the ansa lenticularis reached GP mainly from its ventral surface (fig. 2B). Many of these fibers coursed around the two segments of GP to finally arborize within the putamen. Other TH-ir fibers did not penetrate the internal capsule but, instead, ascended dorsally along the reticular nucleus of the thalamus to reach the caudate nucleus (fig. 2). Rostrally, a significant number of TH-ir fibers occupy the lateral half of the ansa peduncularis. At pallidal level the majority of TH-ir fibers coursed within the accessory, internal and external medullary laminae, but other fibers ran directly through the pallidal complex. Many of the latter fibers coursed backward along the striatofugal myelinated fiber bundles (Wilson’s pencils) that traversed the pallidum. The vast majority of these TH-ir fibers were rather thick and smooth, but many of them gave off thin and varicose collaterals in the STN (fig. 3A), the GPi (fig. 3B), as well as the external segment of the globus pallidus (GPe) (fig. 2C). These fine varicose collaterals were rather poorly branched and often closely apposed to nonimmunoreactive cell bodies in each target structure (fig. 3A). At striatal level, some thick and smooth TH-ir fibers were scattered within an intensely stained neuropil composed of a multitude of small punctate TH-ir structures reminiscent of axon terminals (fig. 3D, E). Patches of low TH-ir occurred throughout the human striatum (fig. 1), and a few moderately stained TH-ir cell bodies were also uniformly scattered within striatal neuropil.

Functional Considerations The present paper has reviewed the organization of several major pathways related to the human GPi and STN, which are the target of numerous stereotaxic interventions to alleviate PD symptoms. The data reveal that several major fiber bundles that are difficult to avoid in the current lesion or stimulation paradigms surround these two structures. Furthermore, the two structures are themselves part of a complex neural network so that it is very difficult to act upon one without affecting the other. The fiber systems that emerged from, or surrounded, the GPi and STN are composed of myelinated and nonmyelinated axons of various diameters, a feature that may play a crucial role in stimulation conditions because the conduction velocity is proportional to the axon diameter. Additionally, single labeling studies in monkeys have revealed that,

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3

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through their highly branched axonal projection, the neurons of the GPi and STN can reach virtually all the major components of the basal ganglia [13, 14]. A detailed knowledge of this complex neural circuitry is thus necessary to design lesion and/or stimulation paradigms that will yield optimal results in patients suffering from movement disorders. Our TH immunohistochemical study in humans shows that axons of the DA nigrostriatal projection course largely backward along the major output pathways of the globus pallidus, particularly the ansa lenticularis and the lenticular fasciculus. Furthermore, our data provides evidence for the existence of nigrostriatal DA axons giving off collaterals that appear to contact en passant neurons of the GPe, GPi and STN in humans. Previous studies in monkeys have reported the presence of numerous TH-ir fibers at pallidal level, particularly in the GPi [16]. At ultrastructural level, these thin and varicose TH-ir fibers were seen to make contact en passant with pallidal neurons, but most immunoreactive axonal varicosities were devoid of typical synaptic junctional apposition [17]. This type of organization appears typical of the entire nigrostriatal DA system, which is believed to use a dual mode of operation, that is, diffuse (asynaptic) and synaptic [18]. Other studies in nonhuman primates have revealed that the DA innervation of the GPi is much less severely affected than that of the striatum in monkeys rendered parkinsonian following injections of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [19, 20]. Although less dense than the striatal input, this extrastriatal innervation allows DA neurons of the SNc to directly affect neuronal activity of the GPi and STN, which are considered respectively as a major output structure and a driving force of the basal ganglia [2, 21]. It would thus be important to determine if the extrastriatal DA innervation is spared in idiopathic PD, as it is the case in parkinsonian (MPTP-treated) monkeys. A detailed knowledge of the course of DA axons around and within the GPi and STN is also needed to correctly interpret the effects of stereotaxic lesions and high-frequency stimulation of these two structures in PD patients. Such information should shed a new light on the overall functional organization of the human basal ganglia, in both health and disease.

Acknowledgment This research was supported by grant MT-5781 of the Medical Research Council of Canada. Fig. 3. Photomicrographs showing examples of TH-ir profiles encountered in the subthalamic nucleus (STN) (A), internal segment of the globus pallidus (GPi) (B), external segment of the globus pallidus (GPe) (C ) and the putamen (PUT) (D, E). Scale bars: A, C 20 lm; B 50 lm; D 200 lm; E 100 lm.

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References 1 2 3 4 5 6

7

8 9 10

11 12 13 14 15 16 17

18

19 20 21 22

Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders. Trends Neurosci 1989;12:366–375. DeLong MR: Primate model of movement disorders of basal ganglia origin. Trends Neurosci 1990; 13:281–859. Parent A, Cicchetti F: The current model of the basal ganglia organization under scrutiny. Mov Disord 1998;13:199–202. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Lozano AM, Lang AE, Galvez-Jimenez N, Miyashi J, Duff J, Hutchinson WD, Dostrowsky JO: Effects of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Baron MS, Vitek JL, Bakay RAE, Green J, Kaneoke Y, Hashimoto T, Tumer RS, Woodward JL, Cole SA, McDonald WM, DeLong MR: Treatment of advanced Parkinson’s disease by GPi pallidotomy: 1 year pilot-study results. Ann Neurol 1996;40:355–366. Limousin P, Pollack P, Benazzouz A, Hoffman D, Le Bas JF, Broussole E, Perret JE, Benabid AL: Effect on parkinsonian signs and symptoms of bilateral subthalamic stimulation. Lancet 1995;345: 91–95. Krack P, Pollack P, Limousin P, Hoffman D, Benazzouz A, Le Bas JF, Koudsie A, Benabid AL: Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43:180–192. Parent A: Carpenter’s Human Neuroanatomy. Baltimore, Williams & Wilkins, 1996. Carpenter MB: Anatomy of the corpus striatum and brain stem integrating systems; in Brook VB (ed): Handbook of Physiology, vol 2: The Nervous System. Bethesda, American Physiological Society, 1981, pp 947–995. Nauta WJH, Mehler WR: Projections of the lentiform nucleus in the monkey. Brain Res 1966;1:3–42. Carpenter MB, Batton RR III, Carleton SC, Keller JT: Interconnections and organization of pallidal and subthalamic nucleus neurons in the monkey. J Comp Neurol 1981;197:579–603. Parent A, Hazrati LN: Functional anatomy of the basal ganglia. I. The cortico-basal gangliathalamo-cortical loop. Brain Res Rev 1995;20:91–127. Parent A, Hazrati LN: Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Rev 1995;20:128–154. Parent A: Comparative Neurobiology of the Basal Ganglia. New York, Wiley, 1986. Lavoie B, Smith Y, Parent A: Dopaminergic innervation of the basal ganglia in the squirrel monkey. J Comp Neurol 1989;288:36–52. Parent A, Lavoie B: Dopaminergic innervation of the basal ganglia in normal and parkinsonian monkeys; in Schneider JS, Gupta M (eds): Current Concepts in Parkinson’s Disease. Seattle, Hogrefe & Huber, 1993, pp 237–257. Descarries L, Watkins KC, Garcia S, Bosler O, Doucet G: Dual character, asynaptic and synaptic, of the dopamine innervation in adult rat neostriatum: A quantitative autoradiographic and immunocytochemical analysis. J Comp Neurol 1996;375:167–186. Parent A, Lavoie B, Smith Y, Be´dard PJ: The dopaminergic nigropallidal projection in primates: Distinct cellular origin and relative sparing in MPTP-treated monkeys. Adv Neurol 1990;53:111–116. Schneider JS, Dacko S: Relative sparing of the dopaminergic innervation of the globus pallidus in monkeys made hemi-parkinsonian by intracarotid MPTP infusion. Brain Res 1991;556:292–296. Kitai ST, Kita H: Anatomy and physiology of the subthalamic nucleus: A driving force of the basal ganglia. Adv Behav Biol 1987;32:357–373. Schaltenbrand G, Bailey P: Introduction to Stereotaxis with an Atlas of the Human Brain. Stuttgart, Thieme, 1959.

Andre´ Parent, PhD, Laboratoire de neurobiologie, Centre de recherche Universite´ Laval Robert-Giffard, 2601, de la Canardie`re, Local F-6500, Beauport, Que´bec G1J 2G3 (Canada) Tel. +1 418 663 5747, Fax +1 418 663 8756, E-Mail [email protected]

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Pathophysiological Considerations in Basal Ganglia Surgery: Role of the Basal Ganglia in Hypokinetic and Hyperkinetic Movement Disorders Thomas Wichmann, Mahlon R. DeLong, Jerrold L. Vitek Department of Neurology, Emory University, Atlanta, Ga., USA

Movement disorders are generally classified into hypokinetic disorders, characterized by poverty of movement (e.g. Parkinson’s disease), and hyperkinetic disorders, characterized by involuntary movement (e.g. dystonia). The majority of these disorders arise from dysfunction of the basal ganglia. Intense research efforts over the past decades have led to hypotheses regarding the function of these structures under normal and disease conditions [1–3]. These models in turn have facilitated the development of new pharmacological and surgical approaches for the treatment of these diseases.

Anatomical and Functional Models of Basal Ganglia Circuitry In current models of basal ganglia function, these structures are viewed as components of larger segregated circuits that involve the cerebral cortex and thalamus [4, 5]. Each circuit’s designation reflects the presumed function of its cortical areas of origin and termination, i.e. ‘motor’, ‘oculomotor’, ‘associative’, and ‘limbic’. Each circuit originates in specific cortical areas, passes through separate portions of the basal ganglia and thalamus, and projects back onto the frontal cortical area of origin in a closed-loop manner. In each of these circuits, the striatum serves as the ‘input’ stage of the basal ganglia, and the internal segment of the globus pallidus (GPi) and the pars reticulata of the substantia nigra (SNr) serve as output stations.

Fig. 1. Schematic diagram of the basal ganglia-thalamocortical circuitry under normal conditions. Inhibitory connections are shown as filled arrows, excitatory connections as open arrows. CM>Centromedian nucleus; GPe>external segment of the globus pallidus; GPi>internal segment of the globus pallidus; PPN>pedunculopontine nucleus; SNr>substantia nigra, pars reticulata; SNc> substantia nigra, pars compacta; STN>subthalamic nucleus; VA>motor thalamus ventralis anterior; VL>ventrolateral thalamus.

The motor circuit (fig. 1) has received particular attention, because of its relevance to movement disorders. It is comprised at the cortical level of preand postcentral sensorimotor areas, and at the subcortical level of sensorimotor areas in the basal ganglia and the basal ganglia receiving areas of the motor thalamus ventralis anterior (VA) and ventralis lateralis pars oralis (VLo), using Olszewski’s terminology. Cortical projections of the motor circuit terminate largely in the putamen. In addition to the monosynaptic corticostriatal inputs, cortical activity may influence the basal ganglia via collaterals of the corticospinal pathway that reach the STN [6–10] and projections that link cortex with the centromedian (CM) and parafascicular nuclei of the thalamus, which in turn project to the striatum [e.g. 11, 12] and to the STN [13]. Putamenal output is directed towards GPi/SNr via two pathways: a direct monosynaptic pathway and an indirect polysynaptic pathway via the external pallidal segment (GPe). GPe output reaches GPi/SNr both directly and via projections to the STN. Basal ganglia output in turn is directed towards the thalamus. GPi efferents reach the thalamic nucleus VLo in the monkey, equivalent to the nucleus ventralis oralis anterioris (Voa) and ventralis oralis posterior (Vop) in man, whereas SNr output reaches the nucleus ventralis anterior pars magnocellularis (VAmc) in both monkey and humans. Collaterals of basal ganglia projections to the thalamus are also directed to brainstem areas, most prominently to the pedunculopontine nucleus (PPN) and midbrain extrapyramidal area (MEA), permitting direct access to bulbar and spinal cord centers [14, 15]. With the exception of the excit-

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atory (glutamatergic) efferents of the STN, intrinsic and output connections of the basal ganglia are all inhibitory (GABAergic). Dopamine is a powerful modulator of the activity of the balance between the direct and the indirect pathway, primarily at the level of the striatum. The dopaminergic input to the striatum arises in the substantia nigra, pars compacta (SNc). Dopamine may have a dual effect on striatal projection neurons, in that it appears to facilitate transmission over the direct pathway and to inhibit transmission over the indirect pathway via dopamine D1 and D2 receptors, respectively [e.g. 16]. The overall effect of striatal dopamine release is, therefore, to reduce basal ganglia output from GPi/SNr, leading to increased activity of thalamocortical projection neurons. In primates, experiments using antero- and retrogradely transported herpes virus as anatomic tracers [17, 18] have provided strong evidence for the segregation of pallidal output pathways directed to discrete precentral motor fields, e.g. motor cortex (MC), the supplementary motor area (SMA), and the arcuate premotor area (APA). The larger motor circuit appears to be composed of several segregated subcircuits related to different cortical motor areas [e.g. 17]. These subcircuits may serve different functions in motor control. For instance, the subcircuit originating in the SMA may be preferentially involved with the processing of information related to motor planning or sequencing, whereas the subcircuit originating in MC may have a role in the control or monitoring of parameters of ongoing movements, such as amplitude or velocity. At present the physiologic function of the basal ganglia remains unknown. Proposed motor functions of the basal ganglia include roles in scaling and focusing of movements, motor sequencing as well as motor learning [4, 19–22]. Furthermore, by way of their projections to the PPN and MEA, the basal ganglia may also participate in some of the proposed functions of these nuclei, such as the regulation of spinal motor mechanisms [23], behavioral reinforcement, attention [14] and sleep [24]. In general terms, however, phasic activation of the motor portion of the direct pathway in conjunction with voluntary movements very likely results in reduction of tonic inhibitory basal ganglia output, leading to disinhibition of thalamocortical neurons, and facilitation of movement. By contrast, phasic activation of the indirect pathway leads to increased basal ganglia output [6] and to inhibition of movement. Concerning the control over specific features of movement, clinical and experimental studies suggest that the basal ganglia play a role in specifying the amplitude or velocity of movement [e.g. 25–30]. The combination of information traveling via the direct and the indirect pathways of the motor circuit has been proposed to serve to either ‘scale’ or ‘focus’ movements [4, 19, 31]. To achieve scaling of movements, striatal output would first inhibit

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specific neuronal populations in GPi/SNr via the direct pathway, thus facilitating movement, followed, after an appropriate delay by disinhibition of the same GPi/SNr neuron via inputs over the indirect pathway, leading to inhibition of the ongoing movement. In the focusing model, by contrast, inhibition of relevant pallidal/nigral neurons via the direct pathway would allow intended movements to proceed, whereas unintended movements would be suppressed by concomitant increased excitatory input via the indirect pathway in other GPi/SNr neurons. Direct anatomical or physiologic support for either of these functions is lacking at the present time [see discussions in 32–34]. Other proposed motor functions of the basal ganglia include roles in selfinitiated (internally generated) movements, in motor learning and in movement sequencing [e.g. 22, 35]. Lesions studies have yielded conflicting evidence regarding the motor functions of the basal ganglia. Most studies have found either no or only short-lived effects on skilled fine movements or mild bradykinesia after such lesions [e.g. 26, 36–39]. A notable exception to this is a study by Mink and Thach [19, 40] in which cocontraction was observed after lesioning or inactivation of GPi. Given the relative paucity of motor side effects of pallidal lesions in animals and humans it could be concluded that, under normal conditions, basal ganglia output may not play a significant role in movement initiation or execution [20]. When output from these structures is abnormal (as is the case in movement disorders), however, the disruption of otherwise normal motor systems produces major abnormalities of movement.

Pathophysiologic Considerations In contrast to the uncertainties regarding the normal function of the basal ganglia, there is greater consensus regarding the pathophysiologic mechanisms underlying movement disorders of basal ganglia origin. The seemingly paradoxical finding that both hypo- and hyperkinetic movement disorders improve with inactivation of GPi (see below) clearly suggests that cortical processing can quite easily function without the basal ganglia output signal, although probably not in the most efficient manner. Thus, hypo- and hyperkinetic movement disorders appear to have in common that cortical functioning is disturbed by aberrant subcortical signals, which, from a cortical perspective, are not identified as abnormal. The phenotypic specifics of movement disorders, of course, depends on specific abnormalities of the subcortical signals. In this regard, it appears that hypokinetic disorders, such as Parkinson’s disease, are associated with increased basal ganglia output, whereas hyperkinetic movement disorders, such as dystonia, are associated with decreased output.

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Hypokinetic Disorders Parkinson’s disease is a syndrome characterized by akinesia (poverty of movement and impaired movement initiation), bradykinesia (slowness of movement), muscular rigidity, and tremor (at rest). A clear genetic etiology for this disorder has been identified in only a few families to date [41, 42], although a genetic predisposition for environmental insults that lead to parkinsonism may be more common [43–46]. The proposed genetic and environmental pro-parkinsonian mechanisms have in common interference with the synthesis, release or action of dopamine in the basal ganglia. The salient pathological feature of idiopathic Parkinson’s disease is relatively selective degeneration of neurons in the SNc, which give rise to nigrostriatal fibers [e.g. 47]. In all stages of human parkinsonism, dopamine depletion occurs earliest and is greatest in the sensorimotor territory of the striatum, i.e. the postcommissural portion of the putamen, suggesting that the motor circuit is preferentially involved in parkinsonian pathophysiology [47–49]. In Parkinson’s disease, this pattern of initial dopamine loss is accounted for by the selective degeneration of the ventrolateral portion of the SNc which innervates the putamen. The study of parkinsonism has been greatly facilitated by the introduction of the MPTP model of primate parkinsonism in the early 1980s. In such primates, dopaminergic cells in the SNc degenerate, and the animals develop a clinical syndrome that closely mimics human parkinsonism [50–54]. Data from microelectrode recordings [55–59], and metabolic studies [60–63] have provided evidence that loss of striatal dopamine is associated with activation of the indirect pathway and decreased activity in the direct pathway (fig. 2). For instance, it has been shown in MPTP-treated primates that neurons in STN and GPi have higher discharge rates, and show prominent changes in their discharge patterns, including a greater tendency to discharge in bursts, a higher degree of synchronization of discharge between neighboring neurons, and a greater proportion of neurons with responses to somatosensory input [55, 57]. Given the circuit model described above, these changes will lead to increased GPi and SNr activity, and thus to increased basal ganglia output to the thalamus, resulting in increased inhibition of thalamocortical and brainstem neurons. The changes in basal ganglia discharge that result from dopamine depletion prominently alter the neuronal activity in the thalamus and brainstem [e.g. 64, 65], as well as cortical metabolic activity, as shown by PET studies in parkinsonian patients [49, 66–68] in a manner consistent with the proposed hypokinetic model. The specificity of these changes in cortical activity is not certain. There is some evidence from the results of lesion studies (see below) that the predominant effect of increased tonic and phasic discharge in the basal ganglia may in fact be a nonspecific increase in the signal-to-

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Fig. 2. Schematic diagram of the basal ganglia-thalamocortical circuitry under normal and parkinsonian conditions. Parkinsonism leads to differential changes in the two striatopallidal projections, which are indicated by the thickness of the connecting arrows. Basal ganglia output to the thalamus is increased. Same abbreviations as in figure 1.

noise ratio of impulses traveling along the thalamocortical projection which disturbs cortical processing [34, 69, 70]. The magnitude of the individual parkinsonian signs such as akinesia, tremor and rigidity is highly variable between patients. Thus, these signs may be the result either of independent pathophysiologic mechanisms, or of the same pathophysiologic mechanism affecting different motor subcircuits, and will therefore be discussed separately in the following. Akinesia/Bradykinesia. Most authors agree that these parkinsonian signs are in large part a direct consequence of changes in cortical processing, due to altered tonic and phasic activity of basal ganglia output [34, 69, 70]. For instance, increased tonic inhibition of thalamocortical neurons by excessive output from GPi/SNr may reduce the responsiveness of cortical mechanisms involved in motor control and may prevent the transmission of phasic reductions in activity that occur during movement execution, which may interfere with the normal scaling of movement. Increased tonic inhibition of thalamocortical neurons by increased basal ganglia output in parkinsonism may also

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render precentral motor areas less responsive to other inputs normally involved in initiating movements or may interfere with ‘set’ functions that have been shown to be highly dependent on the integrity of basal ganglia pathways [71]. One of the older hypotheses regarding basal ganglia function has been that these structures act to compare efferent copies of cortical motor commands with proprioceptive feedback from the periphery, and would generate an appropriate error signal to cortical motor areas to help fine tuning of ongoing movements. In Parkinson’s disease increased phasic activity in the basal ganglia may, thus, erroneously signal excessive movement or velocity to precentral motor areas, leading to a slowing or premature arrest of ongoing movements and to greater reliance upon external clues during movement. Conceivably, the development of akinesia and bradykinesia may depend on abnormalities in different motor subcircuits. Bradykinesia, for example, may result from abnormalities in the subcircuit arising from primary motor cortex [see e.g. discussion in 17, 18], where activity is clearly related to movement execution. In contrast, akinesia may be related to abnormal discharge in the subcircuit whose activity is mostly ‘preparatory’, i.e. the subcircuit emanating from SMA and mesial cortical motor areas. Evidence for abnormal activity in such areas comes from studies of the Bereitschaftspotential (readiness potential), a slow negative cortical potential that precedes self-paced movements and is thought to reflect the neural activity in the SMA [72]. The early portion of the Bereitschaftspotential is smaller in parkinsonian patients than in age-matched controls [73, 74], suggesting a deficit in the normal function of the SMA in the early stages of preparation for self-initiated movements. PET studies of cerebral blood flow in human patients have indeed shown that dopamine loss in the striatum leads to decreased blood flow (thus, by inference, reduced synaptic activity) in the SMA, motor cortex, and dorsolateral prefrontal cortex [e.g. 49, 66, 67, 74–77]. Recent primate experiments have suggested that part of akinesia may also be the effects of abnormalities in PPN/MEA output. Thus, lesions of the PPN/ MEA may result in akinesia [78], possibly because of removal of excitatory drive along the glutamatergic PPN/MEA-SNc projection [79]. It remains to be clarified how important this finding is in parkinsonism, however, because the PPN/MEA region is itself targeted by both increased glutamatergic input from the STN and increased GABAergic input from GPi [e.g. 80, 81] (see fig. 2) in parkinsonism. Although PPN/MEA activity is probably changed in parkinsonism, the type of change remains unclear. Rigidity. Parkinsonian rigidity is characterized by a uniform increase in resistance to passive movements about individual joints. It must ultimately result from changes at the spinal cord level, induced by abnormalities of neuronal activity in the basal ganglia, brainstem and cortex. One of these

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‘downstream’ effects appears to be increased a-motoneuron excitability [82]. Although the precise mechanism for this is elusive, abnormal processing of information transmitted to the spinal cord by Ia afferents has been implicated. In support of this concept, dorsal root section abolishes parkinsonian rigidity [83], although Ia fiber activity appears to be normal in parkinsonian subjects [84]. As a possible explanation, altered basal ganglia output, mediated via the pontine nucleus gigantocellularis and the dorsal longitudinal fasciculus of the reticulospinal projection, may lead to increased inhibition of Ib interneurons which in turn may disinhibit a-motoneurons [85]. Abnormalities of longlatency reflexes (LLRs) may also play a role in abnormal a-motoneuron excitability. In parkinsonian subjects, the reflex gain in LLRs seems to be relatively fixed and abnormally high [86–88], although a quantitative correlation between LLR amplitude and rigidity is not proven, and rigidity is clinically not a reflex phenomenon per se. The abnormal phasic responses found within the basal ganglia and also present in the pallidal receiving area of the motor thalamus of MPTP-treated primates [55, 57, 89] could be responsible for increased LLR production (acting through the motor circuit projection to the supplementary motor area) or may reflect abnormally large inputs to the striatum from the motor or somatosensory cortices that are engaged in the LLR production, and whose altered responsiveness may result from increased tonic output from GPi and SNr. Tremor. Parkinsonian tremor affects the distal limbs and occurs typically at rest, with a frequency of 4–6 Hz. Traditionally, tremor in Parkinson’s disease has been considered as the result of oscillatory activity in thalamic neurons, which has been recorded in different types of tremor in animals [90–93], and intraoperatively in human patients undergoing thalamotomy for tremorpredominant Parkinson’s disease [94–99]. However, abnormal discharge in the basal ganglia may also be involved in tremor production [e.g. 100–102]. In support of this notion, prominent oscillatory discharge with bursts at the frequency of concomitant tremor has been demonstrated both in MPTPtreated primates and in the course of pallidotomy in human patients [e.g. 55, 57, 100–103]. Surgical interruption of pallidal outflow either by disruption of pallidal efferents or by lesions of GPi can produce lasting relief of tremor in parkinsonian patients [38, 39, 104–110]. Moreover, lesions of the STN in MPTP-treated African green monkeys have also been shown to reduce tremor significantly [111]. Conceivably, increased tonic basal ganglia output may promote oscillatory thalamic activity through hyperpolarization of thalamic target cells [39, 112, 113]. This tendency for rhythmic oscillations of thalamocortical neurons may be further enhanced by periodic bursting in reticular thalamus during moments of immobility [114, 115]. Alternatively, it has been speculated that loss of dopamine in GPi/SNr rather than in the striatum may be important

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in the generation of tremor [discussed in 116, 117] by unmasking of pacemakerlike properties [118] in these basal ganglia nuclei themselves. This has been demonstrated by intracellular recordings from GP in brain slices from adult guinea pigs when the recorded cells were abruptly depolarized from a hyperpolarized membrane potential [118]. Synchronized oscillatory discharge of GPe and STN neurons, albeit at lower frequencies, has also been demonstrated recently in a basal ganglia coculture environment which was devoid of dopamine [119]. Oscillatory discharge in GPi/SNr alone, however, is probably not enough to induce tremor, because rhythmic burst discharges persist in GPi of MPTP-treated primates even after overt tremor is abolished by STN lesions [117]. An important additional requirement for tremor of basal ganglia origin may be that the rhythmic bursts of multiple neurons in the basal ganglia output nuclei occur in a synchronized manner. This is suggested by the observation that in MPTP-treated primates whose tremor resolved after STN lesions the degree of synchronization between neighboring GPi cells was significantly reduced, although oscillatory burst discharges persisted in this nucleus [117]. Nonmotor Phenomena. It is likely that some of the nonmotor phenomena of parkinsonism rely on abnormal discharge in nonmotor circuits of the basal ganglia which may be affected by dopamine loss in much the same way as the motor circuit. It has been shown, for instance, that oculomotor abnormalities appear to be the result of dopaminergic loss in the ‘oculomotor’ basal gangliathalamocortical circuit [120, 121], and oculomotor symptoms appear to respond to GPi stimulation in parkinsonian patients [122]. Similarly, some of the cognitive and psychiatric disturbances seen in parkinsonian patients are reminiscent of syndromes seen after lesions of the dorsolateral prefrontal cortex (problems with executive functions) or of the anterior cingulate (apathy, personality changes). These symptoms may be the result of loss of dopamine in the dorsolateral or ventral caudate nucleus, respectively [123]. Finally, disturbance of the normal function of cortical-basal ganglia-thalamocortical circuits has also been implicated in the occurrence of obsessive-compulsive symptoms in some parkinsonian patients, as well as in patients with other diseases of presumed basal ganglia origin, such as Tourette’s syndrome [e.g. 124–128].To what extent alterations in nonmotor circuits contribute to the cognitive impairments of Parkinson’s disease is controversial. Lesions extending into nonmotor portions of GPi in patients undergoing posteroventral pallidotomy, however, may contribute to the cognitive changes reported in some patients [77]. Neurosurgical Implications. The realization that increased basal ganglia output is a major pathophysiologic step in the development of parkinsonian motor signs has provided a rationale for attempts to reduce this output surgically. Although many such procedures were carried out empirically in the

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1950s and 1960s, the effectiveness of this approach was demonstrated anew with lesions involving the STN in MPTP-treated primates. These lesions ameliorate the cardinal signs of parkinsonism [111, 117, 129]. There are several instances of STN lesions in parkinsonian patients occurring spontaneously or inadvertently during thalamotomy which resulted in significant clinical improvement [e.g. 130, 131]. In humans, lesions of the STN have been considered potentially hazardous because of the risk of developing persistent dyskinesias (see below), and because of the risk of lesion-induced hemorrhage in the richly vascularized subthalamic area. Recent reports, however, have studied this issue in humans, and have demonstrated that such lesions can be safely accomplished in patients [132, 133]. Most efforts involving lesions of the basal ganglia output structures, however, have focused on reduction of the activity of cells in the sensorimotor portion of GPi through lesioning. Pallidotomy procedures are effective against akinesia/bradykinesia, rigidity, and tremor, as well as dyskinesia/dystonia, and motor fluctuations [38, 77, 134–136], whereas other symptoms, such as postural disequilibrium, gait abnormalities and freezing episodes may respond less well [38, 137]. Microelectrode recordings done in the course of these procedures have provided evidence that some of the pathophysiologic changes that were previously observed in parkinsonian primates may also hold for human patients with Parkinson’s disease. For instance, in parkinsonian subjects the discharge rates were found to be considerably higher in GPi than in GPe [e.g. 103, 138]. Furthermore, phasic changes in discharge in GPi are very prominent, often with rhythmic grouping of bursts at the parkinsonian tremor frequency [57, 138]. PET studies have provided evidence that pallidotomy restores the reduced cortical activation seen in parkinsonian patients [139–141], although more recent PET studies suggest that pallidotomy procedures do not restore the normal state, but lead to far more complicated changes of cortical activity that involve ipsilateral areas as well as areas otherwise not strictly related to motor performance, such as parietal or occipital cortices [Turner et al., unpubl.]. The differences between these PET results may be the result of using different behavioral activation tasks in the different studies. The clinical experience with pallidotomy has, however, also shown that areas other than GPi may be involved in parkinsonian pathophysiology. For instance, it has become clear that GPi lesions do not ameliorate all motor signs of Parkinson’s disease to the same extent [38, 135, 137] and that most patients who are treated with pallidotomy still need L-dopa therapy after the procedure. These findings suggest that portions of the motor circuit which do not pass through GPi may be involved as well. One of the likely areas involved would be the motor portion of the SNr [142–147]. Neuronal discharge in the SNr is indeed altered in parkinsonian primates, although to a lesser degree than

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that seen in GPi [148]. Compared to lesions of the STN or GPi, inactivation of the SNr is also less effective [Wichmann et al., unpubl.]. The PPN/MEA region is another important underexplored area that may well be involved in parkinsonism. The PPN/MEA area has been shown to be metabolically overactive in parkinsonian animals, consistent with a major increase of input to this region [149]. Additional evidence for involvement of the brainstem circuitry in the development of some parkinsonian motor signs comes from the fact that although akinesia is associated with increased basal ganglia outflow [e.g. 56, 57, 59], and is ameliorated by pallidotomy, it remains unaltered by thalamotomy [150, 151]. A possible explanation for this would be that akinesia may be due in part to increased inhibitory action of descending basal ganglia projections to the PPN/MEA rather than pallidal inhibition of thalamocortical neurons. As mentioned above, lesions of the PPN/MEA have been shown to cause movement deficits reminiscent of akinesia [78]. Since their introduction in the mid-1950s, lesions of the ventrolateral thalamus have been known to be beneficial in the treatment of some aspects of parkinsonism [e.g. 152–156]. Thalamotomies are particularly effective in patients with significant tremor, rigidity or drug-induced dyskinesias, but less in patients with akinesia and bradykinesia [153, 157–160]. Lesions involving the areas of the thalamus that receive basal ganglia outflow (nuclei Voa and Vop) may be more effective for rigidity and drug-induced dyskinesias [see, e.g. 161]. These effects are paradoxical from a pathophysiologic perspective, because lesions of the ‘pallidal-receiving’ areas of the thalamus should induce rather than ameliorate parkinsonian motor signs (but see Canavan et al. [162] for a study in which thalamic lesions did induce akinesia in primates). Lesions in the ‘cerebellar-receiving’ area of the thalamus (Vim) are effective for tremor control and bursting activity is increased in the cerebellar receiving area of the motor thalamus in parkinsonian primates [163, 164], attesting to the fact that changes in cerebellothalamic activity may be as important in the development of parkinsonian tremor as changes in basal ganglia outflow. Over the last few years new approaches have been developed to modify basal ganglia output by nondestructive surgical means, i.e. through implantation of devices for chronic high-frequency stimulation. This technique was first developed as a treatment for tremor, using stimulation of the Vim nucleus of the thalamus [165]. More recently these stimulation techniques have also been applied to the STN, and to GPi [e.g. 166–173] for control of other parkinsonian signs. The available data suggest that lesions and stimulation procedures carried out in thalamus or the basal ganglia output nuclei may have similar efficacy against parkinsonism, although patients with subthalamic nucleus stimulators may be able to reduce dopaminergic medications to a greater extent than those with pallidotomies or GPi stimulators. The mecha-

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Fig. 3. Schematic diagram of the basal ganglia-thalamocortical circuitry under normal conditions and in hyperkinetic disorders (chorea and dystonia). In Huntington’s chorea degeneration of the striato-GPe pathway results in increased inhibition of STN and GPi, leading to reduced basal ganglia output to the thalamus. In dystonia, both direct and indirect pathways are thought to be hyperactive, resulting in reduced and abnormally patterned basal ganglia output to the thalamus. Same abbreviations as in figures 1 and 2.

nism by which high-frequency stimulation of the basal ganglia output areas ameliorates parkinsonism has not been satisfactorily elucidated. A variety of hypotheses have been put forward such as the induction of depolarization block in the stimulated area that would act like a functional lesions of that same region, or jamming of basal ganglia output by either procedure [64, 174], that would cancel out the unwanted ‘noise’ that may characterize parkinsonian pathophysiology at the cortical level [34]. STN stimulation may also result in active inhibition of GPi (and SNr) output by antidromic stimulation of GPe projections to STN which also send strong collateral input to GPi. Hyperkinetic Disorders The main hyperkinetic syndromes, chorea, ballismus and dystonia, are all characterized by reduced basal ganglia output to the thalamus, leading to disinhibition of thalamocortical neurons (fig. 3). The term chorea refers to involuntary arrhythmic jerky movements, whereas ballismus refers to more proximal involuntary movements, resembling throwing motions of larger amplitude. The term dystonia refers to slower, more sustained movements and abnormal postures with cocontraction of agonist-antagonist muscle groups.

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Hemiballism. In most cases, hemiballism results from lesions involving the STN [175–179]. Radiofrequency lesions of the STN in monkeys, carried out in the 1940s and 1950s, demonstrated that lesions which included at least 20% of the STN, but spared pallidofugal fibers lead to long-lasting choreiform movements, most commonly involving the leg [177, 180, 181]. More recent experiments using small fiber-sparing lesions of the STN demonstrated similar dyskinesias, although their duration was much shorter [179]. STN lesions interrupt the portion of the indirect pathway that traverses the STN, leading to a shift of the balance between the two pathways towards the direct pathway. Thus, fiber-sparing STN lesions result in reduced mean discharge rates and reduced responsiveness to somatosensory examination in both GPi and GPe [182]. Similar reductions in mean discharge rate and somatosensory responsiveness were also seen in a patient undergoing pallidotomy for treatment of medically intractable hemiballism [183]. STN lesions in MPTP-treated animals were shown to lead to increases in discharge in thalamic areas that receive input from the basal ganglia, presumably due to lesion-induced reductions of (inhibitory) GPi/SNr output to the thalamus [Kaneoke and Vitek, unpubl. obs.]. Huntington’s Disease. Huntington’s disease, a hereditary disorder resulting from pathologic expansion of CAG-trinucleotide repeat sequences in the Huntingtin gene on chromosome 4 [184], is characterized by the gradual development of chorea, cognitive and psychiatric abnormalities. Pathologic studies have shown widespread neuronal degeneration [e.g. 185, 186], especially involving striatal neurons [e.g. 187–190] in a nonrandom sequence. Initially striatal output neurons projecting to GPe appear to be predominantly affected, leading to reduced inhibition of neurons in GPe, and, subsequently, increased inhibition of STN neurons, resulting in decreased GPi output, the hallmark of hyperkinetic disorders (fig. 3). In later stages of the disease, inhibitory striatal output neurons to GPi also degenerate, which results in disinhibition of GPi neurons. According to this scheme, increased activity of GPi neurons reduces the amount of chorea, and may later even lead to the development of hypokinetic features (e.g. bradykinesia and rigidity [190, 191]. Drug-Induced Dyskinesias. After 3–5 years of dopaminergic therapy, a significant proportion of parkinsonian patients develops drug-induced dyskinesias. It is very likely that drug-induced dyskinesias are due to changes in basal ganglia output, given the fact that they are greatly suppressed and in most cases abolished by pallidal or thalamic lesions [38, 39, 161]. This has been attributed to transient shifts in the balance between the direct and the indirect pathway towards the direct pathway, resulting in decreased basal ganglia output. Dopamine receptor activation may result in activation of the direct pathway (via dopamine D1 receptors), and inhibition of the putamenGPe connection (part of the indirect pathway, via D2 receptors). Both changes

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will again lead to reduced basal ganglia output, and presumably to increased activity of thalamocortical neurons. It is likely that increased activity of GPe, leading to increased inhibition of STN and GPi, is not sufficient to produce drug-induced dyskinesias, since a recent study has shown that excitotoxic lesions of GPe do not resolve L-dopa-induced dyskinesias in parkinsonian primates [192]. A more complex interaction between striatal dopamine D1 and D2 receptors [193, 194] affecting both the indirect and the direct pathway, or dopamine receptor activation at extrastriatal sites may also be at work in druginduced dyskinesias. It is unknown why drug-induced dyskinesias occur predominantly after previous damage to the nigrostriatal system (Parkinson’s disease), and prolonged exposure to L-dopa. Compensatory changes in dopamine receptor number or binding characteristics in response to dopamine depletion may be essential for this phenomenon [for discussion see e.g. 16, 195, 196]. In early parkinsonism, the ‘buffering capacity’ of dopaminergic neurons for L-dopa may protect against the development of L-dopa-induced dyskinesias, by preventing massive stimulation of postsynaptic dopaminergic receptors immediately after L-dopa administration. As more dopaminergic neurons are lost, this buffering capacity may be lost, leading to considerable oscillations in the level of dopaminergic stimulation in patients treated intermittently with L-dopa [e.g. 196]. A glutamatergic mechanism may also play a significant role in the development of drug-induced dyskinesias. For instance, it has been shown that NMDA-receptor blockade can, at least acutely, interrupt these involuntary movements in experimental animals and humans [reviewed in 197]. Dystonia. Dystonia as a clinical sign may arise from a variety of probably unrelated disease processes, the majority of which arise from pathology of the basal ganglia, but some of which are also due to cerebellar [198–200] or brainstem disorders [200, 201]. Dystonia of basal ganglia origin has been divided into cases in which there is no clear etiology identified (‘primary’ dystonias) and those with an underlying structural or biochemical defect (‘secondary’ dystonias). One of the diseases leading to primary dystonia is idiopathic torsion dystonia which is likely caused by a genetic defect affecting chromosome 9 [202, 203], although the affected gene product and the precise nature of the changes in basal ganglia function induced by this mutation are uncertain. Secondary dystonia often develops after focal damage to the striatum (particularly the putamen), often weeks or months after the inciting lesion, but may also occur, although less frequently, following focal damage at any site in the pallidothalamocortical motor circuit [204]. Dystonia is also frequently seen in patients with abnormalities of dopaminergic transmission, although the precise mechanism by which this is linked to the abnormal movements is unclear and may significantly differ between

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patient groups. For instance, dystonia may develop in the context of parkinsonism, usually in patients who have been exposed to dopaminergic drugs, but also as an early sign prior to treatment with antiparkinsonian medication. There is also a group of patients with familial dystonia and parkinsonian features of young onset, who have been shown to respond dramatically to treatment with low-dose L-dopa (e.g. dopamine-responsive dystonia, (DRD) [205, 206]), without the development of the troublesome long-term motor side effects of this drug which are seen in patients with Parkinson’s disease. These patients suffer from a genetic defect of dopamine synthesis, caused by reduced GTP cyclohydrolase activity [207]. These data suggest that in most cases dystonia results from compensatory changes secondary to lesions affecting the striatum or its dopaminergic supply. Such changes may affect the affinity or number of dopamine receptors in the unlesioned portion of the striatum [208], or may lead to reorganization of striatal topography, resulting eventually in altered activity in the basal ganglia output structures. Changes in basal ganglia activity were, for instance, demonstrated with 2-deoxyglucose studies in MPTP-treated monkeys which showed that synaptic activity in GPi and STN was increased when the animals were rendered dystonic by injections of dopaminergic agonists [209]. Furthermore, in monkeys which developed dystonia after small ibotenic-acid lesions of the putamen, the concentration of met-enkephalin in GPe (taken as an indicator of the activity of the putamen-GPe pathway) was reduced [210]. These studies suggest that dystonia in these animals may have been due to reduction of activity along the putamen-GPe connection, which may have resulted in increased inhibition of both STN and GPi by GPe efferents. These activity changes in the indirect pathway are at odds with more recent recording results obtained in human patients undergoing pallidotomy [183, 211–213] (see below). Pharmacologic studies suggest that abnormalities in basal ganglia activity affecting both indirect and direct pathway are important in the development of dystonia. For instance, it has been shown that antagonists at dopamine D2 receptors have a substantial potential of inducing dystonia, presumably by increasing striatal outflow to GPe via the indirect pathway, whereas antagonists at D1 receptors may be beneficial in this regard, presumably by reducing striatal outflow to GPi along the direct pathway [214–216]. In accordance with this concept, the ‘atypical’ neuroleptic clozapine with its greater antagonist action on D1 receptors than on D2 receptors has been found to be associated with a much lower incidence of drug-induced dystonia than classical neuroleptics, such as haloperidol, which has a greater affinity for the D2 receptor [e.g. 217]. These data suggest that a relative increase in the activity along the direct pathway (compared to that along the indirect pathway) may be conducive to the development of dystonia (fig. 3). Supporting this concept, recent recording

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studies in patients undergoing pallidotomy as treatment of dystonia demonstrated that the average discharge rates in both pallidal segments were low [183], in contrast to parkinsonian patients in whom discharge rates in GPi are increased [103, 138, 218, 219]. The reduction of discharge in GPe in these dystonic patients attest to increased activity along the indirect pathway, which by itself would have led to increased GPi discharge. The fact that discharge rates in GPi were, in fact, reduced, argues therefore in favor of overactivity along the direct pathway. Recording in both parkinsonism and dystonia was similar with regard to the phasic responsiveness of pallidal neurons to somatosensory stimuli which appears to be increased in both cases with greater synchronicity between neighboring pallidal neurons [183]. Increased phasic responses in the pallidum have been attributed to increased STN input [182]. These findings suggest that parkinsonism and dystonia may differ with regard to the activity along the direct pathway, but share (or are at least compatible with) increased activity along the indirect pathway, as well as increased phasic responsiveness and synchronization of pallidal discharge, possibly indicative of breakdown of segregation between neighboring basal ganglia subcircuits. The relatively close pathophysiologic relationship between these diseases is further supported by the fact that parkinsonism and dystonia can occur simultaneously in the same patients, as, for instance in those suffering from L-dopa-responsive dystonia. Conceivably, in these patients the dopamine synthesis defect may affect D2 receptor-mediated functions more than D1 receptor-mediated functions. Reduced D2 receptor-mediated function would result in disinhibition of the indirect pathway, and increased net ‘driving’ of GPi, accounting for the parkinsonian features in these patients. At the same time the relative preservation of D1 receptor-mediated transmission would result in an overall shift of the balance of activity towards the direct pathway, leading to inhibition of GPi neurons and dystonia. This model does not explain why the opposing effects on individual GPi neurons do not cancel each other out, or, in clinical terms, how dystonia can coexist with parkinsonism. It is conceivable, however, that direct and indirect pathways may independently affect tonic and phasic activity of different sets of neurons in GPi, which via their projections influence different sets of thalamocortical neurons. Alternatively, activation of these pathways may have different effects on the same basal ganglia output neurons. For instance, increased activity along the indirect pathway may predominantly account for changes in phasic discharge patterns, whereas the activity along the direct pathway would more strongly affect the baseline tonic activity of basal ganglia output neurons. The comparison between the pathophysiologic basis of parkinsonism and that of dystonia stresses particularly the importance of abnormalities in the ac-

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tivity along the direct pathway for the development of dystonia. A second important comparison can be made between the intraoperative recording in dystonic patients [183, 211–213] and the recording in monkeys with experimental hemiballism [182], stressing the importance of phasic changes in pallidal discharge for these diseases. In both hemiballism and dystonia the average discharge rates in GPe and in GPi were found to be lower than normal [183]. The responsiveness of pallidal neurons, however, was reduced in the monkeys with hemiballism and chorea, whereas it was increased in the patients with dystonia. From these speculations, dystonia emerges as a unique syndrome whose pathophysiology may include increased activity along both the direct and indirect pathway, resulting in the coexistence of reduced overall activity but increased phasic responsiveness of neurons in the basal ganglia output nuclei, together with increased synchronization of discharge among related basal ganglia output neurons. Although usually characterized as a hyperkinetic movement disorder, the pathophysiology of dystonia may, therefore, represent a hybrid between hyper- and hypokinetic disorders. Neurosurgical Applications of Models for Hyperkinetic Disorders. Neurosurgical procedures have typically been carried out with less frequency for hyper- than for hypokinetic movement disorders. In selected patients with hemiballism and dystonia, ventral thalamotomy (primarily involving the pallidal receiving areas (Vop), and cerebellar receiving areas (Vim)) can be remarkably effective [109, 218, 220–223]. Furthermore, pallidotomies are known to be very effective treatment for drug-induced dyskinesias [38, 135, 137], and have also been used as treatment for dystonia and hemiballismus [183, 211–213, 224, 225]. These surgical effects cannot be explained by a simple model in which reduced basal ganglia output equates the development of dyskinesias because it would be expected that further lesion-induced reduction of basal ganglia output in patients with hyperkinetic disorders would lead to further worsening of dyskinesias rather than an improvement. These finding support the view that dyskinesias and dystonia may result not only from lowered rates but also from changes in patterning and synchronization between output neurons of the basal ganglia. As discussed above, interventions aimed at altering basal ganglia output may again act in a more general way to prevent disruptive subcortical input, regardless of polarity (e.g. increased or decreased activity) from reaching the cortex and disrupting cortical output.

Conclusions The current models of basal ganglia circuits have provided testable hypotheses and have guided the development of new neurosurgical and pharmaco-

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logical treatment of movement disorders. It is clear that the current models require further refinement to fully ‘explain’ basal ganglia function under normal and disease conditions. Among the more obvious shortcomings, current models do not fully account for many of the observed effects of lesions in patients with movement disorders. Furthermore, a number of newly described or emphasized anatomical connections between the basal ganglia and other brain structures are only recently being incorporated into these models. Most prominent among these are projections of the basal ganglia output nuclei to the brainstem, the projection of GPe to the reticular nucleus of the thalamus, and projections from the CM/Pf nucleus of the thalamus to the striatum and the STN. In terms of physiology, a greater emphasis may need to be placed on phasic discharge patterns of basal ganglia neurons, the degree of synchronization of activity in the basal ganglia, and on the manner in which thalamic and cortical neurons utilize basal ganglia output, an area that is largely unexplored at this time.

References 1 2 3 4

5 6

7

8

9 10 11 12

Albin RL: The pathophysiology of chorea/ballism and parkinsonism. Parkinsonism Relat Disord 1995;1:3–11. Chesselet MF, Delfs JM: Basal ganglia and movement disorders: An update. Trends Neurosci 1996; 19:417–422. Brooks DJ: The role of the basal ganglia in motor control: Contributions from PET. J Neurol Sci 1995;128:1–13. Alexander GE, Crutcher MD, DeLong MR: Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, ‘prefrontal’ and ‘limbic’ functions. Prog Brain Res 1990;85: 119–146. Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357–381. Kita H: Physiology of two disynaptic pathways from the sensorimotor cortex to the basal ganglia output nuclei; in Percheron G, McKenzie JS, Feger J (eds): The Basal Ganglia. IV. New Ideas and Data on Structure and Function. New York, Plenum Press, 1994, pp 263–276. Nambu A, Takada M, Inase M, Tokuno H: Dual somatotopical representations in the primate subthalamic nucleus: Evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area. J Neurosci 1996;16:2671–2683. Hartmann-von Monakow K, Akert K, Kunzle H: Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey. Exp Brain Res 1978;33:395–403. Smith Y, Parent A: Differential connections of caudate nucleus and putamen in the squirrel monkey (Saimiri sciureus). Neuroscience 1986;18:347–371. Fujimoto K, Kita H: Response characteristics of subthalamic neurons to the stimulation of the sensorimotor cortex in the rat. Brain Res 1993;609:185–192. Sidibe M, Smith Y: Synaptic interactions between thalamic afferents and striatal interneurons in monkeys. Soc Neurosci Abstr 1996;22:411. Sadikot AF, Parent A, Smith Y, Bolam JP: Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: A light and electron microscopic study of the thalamostriatal projection in relation to striatal heterogeneity. J Comp Neurol 1992;320:228–242.

Wichmann/DeLong/Vitek

48

13

14 15

16 17 18 19 20 21 22 23

24

25 26

27 28 29 30 31 32 33 34 35 36

Feger J, Bevan M, Crossman AR: The projections from the parafascicular thalamic nucleus to the subthalamic nucleus and the striatum arise from separate neuronal populations: A comparison with the corticostriatal and corticosubthalamic efferents in a retrograde double-labelling study. Neuroscience 1994;60:125–132. Inglis WL, Winn P: The pedunculopontine tegmental nucleus: Where the striatum meets the reticular formation. Prog Neurobiol 1995;47:1–29. Steininger TL, Rye DB, Wainer BH: Afferent projections to the cholinergic pedunculopontine tegmental nucleus and adjacent midbrain extrapyramidal area in the albino rat. I. Retrograde tracing studies. J Comp Neurol 1992;321:515–543. Gerfen CR: Dopamine receptor function in the basal ganglia. Clin Neuropharmacol 1995;18: S162–S177. Hoover JE, Strick PL: Multiple output channels in the basal ganglia. Science 1993;259:819–821. Middleton FA, Strick PL: New concepts about the organization of basal ganglia output. Adv Neurol 1997;74:57–68. Mink JW, Thach WT: Basal ganglia motor control. III. Pallidal ablation: Normal reaction time, muscle cocontraction, and slow movement. J Neurophysiol 1991;65:330–351. Marsden CD, Obeso JA: The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson’s disease. Brain 1994;117:877–897. Martin KE, Phillips JG, Iansek R, Bradshaw JL: Inaccuracy and instability of sequential movements in Parkinson’s disease. Exp Brain Res 1994;102:131–140. Graybiel AM: Building action repertoires: Memory and learning functions of the basal ganglia. Curr Opin Neurobiol 1995;5:733–741. Lee HJ, Rye DB, Hallanger AE, Levey AI, Wainer BH: Cholinergic vs noncholinergic efferents from the mesopontine tegmentum to the extrapyramidal motor system nuclei. J Comp Neurol 1988; 275:469–492. Leonard CS, Llinas RR: Electrophysiology of mammalian pedunculopontine and laterodorsal tegmental neurons in vitro: Implications for the control of REM sleep; in Steriade M, Biesold D (eds): Brain Cholinergic Systems. London, Oxford University Press, 1990, pp 205–223. Turner RS, Grafton ST, Votaw JR, Delong MR, Hoffman JM: Motor subcircuits mediating the control of movement velocity: A PET study. J Neurophysiol 1998;80:2162–2176. Inase M, Buford JA, Anderson ME: Changes in the control of arm position, movement, and thalamic discharge during local inactivation in the globus pallidus of the monkey. J Neurophysiol 1996;75:1087–1104. Contreras-Vidal JL, Stelmach GE: A neural model of basal ganglia-thalamocortical relations in normal and parkinsonian movement. Biol Cybern 1995;73:467–476. Anderson ME, Turner RS: A quantitative analysis of pallidal discharge during targeted reaching movement in the monkey. Exp Brain Res 1991;86:623–632. Brotchie P, Iansek R, Horne MK: Motor function of the monkey globus pallidus. 1. Neuronal discharge and parameters of movement. Brain 1991;114:1667–1683. DeLong MR: The neurophysiologic basis of abnormal movements in basal ganglia disorders. Neurobehav Toxicol Teratol 1983;5:611–616. Mink JW: The basal ganglia: Focused selection and inhibition of competing motor programs. Prog Neurobiol 1996;50:381–425. Wichmann T, Bergman H, DeLong MR: The primate subthalamic nucleus. I. Functional properties in intact animals. J Neurophysiol 1994;72:494–506. Jaeger D, Gilman S, Aldridge JW: Neuronal activity in the striatum and pallidum of primates related to the execution of externally cued reaching movements. Brain Res 1995;694:111–127. Wichmann T, DeLong MR: Functional and pathophysiological models of the basal ganglia. Curr Opin Neurobiol 1996;6:751–758. Schultz W: The phasic reward signal of primate dopamine neurons. Adv Pharmacol 1998;42:686– 690. Alamy M, Pons JC, Gambarelli D, Trouche E: A defective control of small-amplitude movements in monkeys with globus pallidus lesions: An experimental study on one component of pallidal bradykinesia. Behav Brain Res 1995;72:57–62.

Pathophysiology of Movement Disorders

49

37

38 39 40 41 42 43 44 45 46

47 48 49 50 51 52

53 54 55 56

57 58 59 60

DeLong MR, Georgopoulos AP: Motor functions of the basal ganglia; in Brookhart JM, Mountcastle VB, Brooks VB, Geiger SR (eds): Handbook of Physiology. The Nervous System. Motor Control, sect 1, vol II, pt 2. Bethesda, American Physiological Society, 1981, pp 1017–1061. Baron MS, Vitek JL, Bakay RAE, et al: Treatment of advanced Parkinson’s disease by GPi pallidotomy: One-year pilot-study results. Ann Neurol 1996;40:355–366. Lozano AM, Lang AE, Galvez-Jimenez N, et al: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Mink JW, Thach WT: Basal ganglia intrinsic circuits and their role in behavior. Curr Opin Neurobiol 1993;3:950–957. Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047. Kitada T, Asakawa S, Hattori N, et al: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605–608. Duvoisin RC: Role of genetics in the cause of Parkinson’s disease. Mov Disord 1998;13(suppl 1): 7–12. Gasser T: Genetics of Parkinson’s disease. Ann Neurol 1998;44(suppl 1):S53–S57. Langston JW: Epidemiology versus genetics in Parkinson’s disease: Progress in resolving an ageold debate. Ann Neurol 1998;44(suppl 1):45–52. Tanner CM, Langston JW, Ottman R, Goldman S, Ellenberg J, Mayeux R: Parkinson’s disease in the National Academy of Aciences/National Resource Council World War II Veteran Twins Registry. Mov Disord 1998;13(suppl 2):3. Hornykiewicz O, Kish SJ: Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 1987; 45:19–34. Kish SJ, Shannak K, Hornykiewicz O: Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. N Engl J Med 1988;318:876–880. Brooks DJ: Detection of preclinical Parkinson’s disease with PET. Neurology 1991;41(suppl 2): 24–27. DeLong MR: Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281–285. Davis GC, Williams AC, Markey SP, et al: Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979;1:249–254. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ: A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 1983;80: 4546–4550. Forno LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA: Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 1986;20:449–455. Langston JW: MPTP: The promise of a new neurotoxin; in Marsden CD, Fahn S (eds): Movement Disorders. 2. London, Butterworths, 1987, pp 73–90. Filion M, Tremblay L, Bedard PJ: Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys. Brain Res 1988;444:165–176. Miller WC, DeLong MR: Altered tonic activity of neurons in the globus pallidus and subthalamic nucleus in the primate MPTP model of parkinsonism; in Carpenter MB, Jayaraman A (eds): The Basal Ganglia. II. New York, Plenum Press, 1987, pp 415–427. Bergman H, Wichmann T, Karmon B, DeLong MR: The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 1994;72:507–520. Hassani OK, Mouroux M, Feger J: Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neuroscience 1996;72:105–115. Filion M, Tremblay L: Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991;547:142–151. Mitchell IJ, Sambrook MA, Crossman AR: Subcortical changes in the regional uptake of [3H]-2deoxyglucose in the brain of the monkey during experimental choreiform dyskinesia elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus. Brain 1985;108: 405–422.

Wichmann/DeLong/Vitek

50

61

62 63

64

65 66 67 68 69

70

71 72

73 74 75 76 77 78 79

80 81

82 83 84

Crossman AR, Mitchell IJ, Sambrook MA: Regional brain uptake of 2-deoxyglucose in N-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. Neuropharmacology 1985;24:587–591. Schwartzman RJ, Alexander GM, Ferraro TN, Grothusen JR, Stahl SM: Cerebral metabolism of parkinsonian primates 21 days after MPTP. Exp Neurol 1988;102:307–313. Schwartzman RJ, Alexander GM: Changes in the local cerebral metabolic rate for glucose in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson’s disease. Brain Res 1985;358:137–143. Vitek JL, Ashe J, DeLong MR, Alexander GE: Altered somatosensory response properties of neurons in the ‘motor’ thalamus of MPTP treated parkinsonian monkeys. Soc Neurosci Abstr 1990; 16:425. Vitek JL, Ashe J, Kaneoke Y: Spontaneous neuronal activity in the motor thalamus: Alteration in pattern and rate in parkinsonism. Soc Neurosci Abstr 1994;20:561. Eidelberg D: Positron emission tomography studies in parkinsonism. Neurol Clin 1992;10:421. Calne D, Snow BJ: PET imaging in parkinsonism. Adv Neurol 1993;60:484. Leenders KL: Pathophysiology of movement disorders studied using PET. J Neural Transm 1997; 50(suppl):39–46. Vitek JL: Stereotaxic surgery and deep brain stimulation for movement disorders; in Watts RL, Koller W (eds): Movement Disorders: Neurologic Principles and Practice. New York, McGrawHill, 1996, pp 237–255. Vitek JL, Ashe J, DeLong MR, Alexander GE: Altered somatosensory response properties of neurons in the ‘motor’ thalamus of MPTP-treated parkinsonian monkeys. Soc Neurosci Abstr 1990; 16:425. Alexander GE, Crutcher MD: Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends Neurosci 1990;13:266–271. Deecke L: Cerebral potentials related to voluntary actions: Parkinsonism and normal subjects; in Delwaide PJ, Agnoli A (eds): Clinical Neurophysiology in Parkinsonism. Amsterdam, Elsevier, 1985, pp 91–105. Dick JPR, Rothwell JC, Day BL, et al: The Bereitschaftspotential is abnormal in Parkinson’s disease. Brain 1989;112:233–244. Obeso JA, Rothwell JC, Ceballos-Bauman A, et al: The mechanism of action of pallidotomy in Parkinson’s disease: Physiological and imaging studies. Soc Neurosci Abstr 1995;21:1982. Brooks DJ: Functional imaging in relation to parkinsonian syndromes. J Neurol Sci 1993;115: 1–117. Eidelberg D, Moeller JR, Dhawan V, et al: The metabolic topography of parkinsonism. J Cereb Blood Flow Metab 1994;14:783–801. Dogali M, Fazzini E, Kolodny E, et al: Stereotactic ventral pallidotomy for Parkinson’s disease. Neurology 1995;45:753–761. Kojima J, Yamaji Y, Matsumura M, et al: Excitotoxic lesions of the pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the monkey. Neurosci Lett 1997;226:111–114. Charara A, Smith Y, Parent A: Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry. J Comp Neurol 1996; 364:254–266. Lavoie B, Parent A: Pedunculopontine nucleus in the squirrel monkey: Projections to the basal ganglia as revealed by anterograde tract-tracing methods. J Comp Neurol 1994;344:210–231. Shink E, Sidibe M, Smith Y: Efferent connections of the internal globus pallidus in the squirrel monkey. II. Topography and synaptic organization of pallidal efferents to the pedunculopontine nucleus. J Comp Neurol 1997;382:348–363. Marsden CD: The mysterious motor function of the basal ganglia: The Robert Wartenburg Lecture. Neurology 1982;32:514–539. Pollack LT, Davis L: Muscle tone in parkinsonian states. Arch Neurol Psychiatry 1930;23:303–319. Burke D, Gandevia SC, McKeon B: Monosynaptic and oligosynaptic contributions to human ankle jerk and H reflex. J Neurophysiol 1984;52:435–448.

Pathophysiology of Movement Disorders

51

85 86

87 88 89

90 91 92 93

94

95

96 97

98 99 100

101 102

103

104 105 106 107

Delwaide PJ, Pepin JL, Maertens de Noordhout A: Short-latency autogenic inhibition in patients with parkinsonian ridigity. Ann Neurol 1991;30:83–89. Lee RG, Murphy JT, Tatton WG: Long-latency myotatic reflexes in man: Mechanisms, functional significance, and changes in patients with Parkinson’s disease or hemiplegia; in Desmedt JE (ed): Motor Control Mechanisms in Health and Disease. New York, Raven Press, 1983, pp 489–507. Berardelli A, Sabra A, Hallett M: Physiological mechanisms of rigidity in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1983;46:45–53. Tsai CH, Chen RS, Lu CS: Reciprocal inhibition in Parkinson’s disease. Acta Neurol Scand 1997; 95:13–18. Chockkan V, Mewes K, Zhang J, et al: A comparison of discharge pattern of internal segment neurons of the globus pallidus in akinetic and tremor parkinsonian patients (abstract). Soc Neurosci 1997;23:470. Cox B, Potkonjak D: An investigation of the tremorgenic effects of oxotremorine and tremorine after stereotaxic injection into rat brain. Int J Neuropharmacol 1969;8:291–297. Poirier LJ, Sourkes TL, Bouvier G, Boucher R, Carabin S: Striatal amines, experimental tremor and the effect of harmaline in the monkey. Brain 1966;89:37–55. Lamarre Y, Joffroy AJ: Experimental tremor in monkey: Activity of thalamic and precentral cortical neurons in the absence of peripheral feedback. Adv Neurol 1979;24:109–122. Bernard JF, Buisseret-Delmas C, Conpoint C, Laplante S: Harmaline-induced tremor. III. A combined single units, horseradish peroxidase, and 2-deoxyglucose study of the olivocerebellar system in the rat. Exp Brain Res 1984;57:128–137. Lenz FA, Tasker RR, Kwan HC, et al: Functional classes of ‘tremor cells’ in the ventral tier of lateral thalamic nuclei of patients with parkinsonian tremor; in Brock M (ed): Modern Neurosurgery. Berlin, Springer, 1989, pp 205–217. Lenz FA, Tasker RR, Kwan HC, Dostrovsky JO, Murphy JT: Single unit analysis of the human thalamic ventral nuclear group: Correlation of thalamic ‘tremor cells’ with the 3–6 Hz component of parkinsonian tremor. J Neurosci 1988;8:754–764. Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murphy JT: Cross-correlation analysis of thalamic neurons and EMG activity in parkinsonian tremor. Appl Neurophysiol 1985;48:305–308. Narabayashi H, Ohye C: Parkinsonian tremor in nucleus ventralis intermedius of the human thalamus; in Desmedt JE (ed): Progress in Clinical Neurophysiology: Physiological Tremor, Pathological Tremors and Clonus. New York, Karger, 1978, pp 165–172. Tasker RR: Tremor of parkinsonism and stereotactic thalamotomy. Mayo Clin Proc 1987;62:736– 739. Lenz FA, Vitek JL, DeLong MR: Role of the thalamus in parkinsonian tremor: Evidence from studies in patients and primate models. Stereotact Funct Neurosurg 1993;60:94–103. Vitek JL, Wichmann T, DeLong MR: Current concepts of basal ganglia neurophysiology with respect to tremorgenesis; in Findley LJ, Koller W (eds): Handbook of Tremor Disorders. New York, Dekker, 1994, pp 37–50. Bergman H, Raz A, Feingold A, et al: Physiology of MPTP tremor. Mov Disord 1998;13(suppl 3): 29–34. Giroux M, Vitek J: Pallidotomy: A Treatment for Parkinsonian Tremor? in Krauss JK, Grossman RG, Jankovic J (eds): Pallidotomy Surgery in Parkinson’s Disease and Movement Disorders. Philadelphia, Lippincott-Raven, 1997, pp 179–189. Vitek JL, Kaneoke Y, Turner R, Baron M, Bakay R, DeLong M: Neuronal activity in the internal and external segments of the globus pallidus of parkinsonian patients is similar to that in the MPTP-treated primate model of parkinsonism. Soc Neurosci Abstr 1993;19:1584. Svennilson E, Torvik A, Lowe R, Leksell L: Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiat Neurol Scand 1960;35:358–377. Hassler R, Reichert T, Mundinger F, Umbach W, Gangleberger JA: Physiological observations in stereotaxic operations in extrapyramidal motor disturbances. Brain 1960;83:337–350. Spiegel EA, Wycis HT: Ansotomy in paralysis agitans. Arch Neurol Psychiatry 1954;71:598–614. Speelman JD, Bosch DA: Resurgence of functional neurosurgery for Parkinson’s disease: A historical perspective. Mov Disord 1998;13:582–588.

Wichmann/DeLong/Vitek

52

108 109 110 111 112 113 114 115

116

117

118 119 120

121

122 123 124

125 126 127 128 129

130 131

Taha JM, Favre J, Baumann TK, Burchiel KJ: Tremor control after pallidotomy in patients with Parkinson’s disease: Correlation with microrecording findings. J Neurosurg 1997;86:642–647. Hutchison WD, Lozano AM, Tasker RR, Lang AE, Dostrovsky JO: Identification and characterization of neurons with tremor-frequency activity in human globus pallidus. Exp Brain Res 1997;113:557–563. Trepanier L, Saint-Cyr J, Lozano A, Lang A: Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson’s disease. Neurology 1999;51:207–215. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1438. Buzsaki G, Smith A, Berger S, Fisher LJ, Gage FH: Petit mal epilepsy and parkinsonian tremor: Hypothesis of a common pacemaker. Neuroscience 1990;36:1–14. Llinas RR: The intrinsic electrophysiological properties of mammalian neurons: Insights into central nervous system function. Science 1988;242:1654–1664. Destexhe A, Contreras D, Sejnowski TJ, Steriade M: A model of spindle rhythmicity in the isolated thalamic reticular nucleus. J Neurophysiol 1994;72:803–818. Williamson AM, Ohara PT, Ralston DD, Milroy AM, Ralson H Jr: Analysis of gamma-aminobutyric acidergic synaptic contacts in the thalamic reticular nucleus of the monkey. J Comp Neurol 1994; 349:182–192. Dacko S, Smith MG, Schneider JS: Immunohistochemical study of the pallidal complex in symptomatic and asymptomatic MPTP-treated monkeys, normal human, and Parkinson’s disease patients. Soc Neurosci Abstr 1990;16:428. Wichmann T, Bergman H, DeLong MR: The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophysiol 1994;72:521–530. Nambu A, Llinas R: Electrophysiology of the globus pallidus neurons: An in vitro study in guinea pig brain slices. Soc Neurosci Abstr 1990;16:428. Plenz D, Kitai S: A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 1999;400:677–682. Kori A, Miyashita N, Kato M, Hikosaka O, Usui S, Matsumura M: Eye movements in monkeys with local dopamine depletion in the caudate nucleus. II. Deficits in voluntary saccades. J Neurosci 1995;15:928–941. Kato M, Miyashita N, Hikosaka O, Matsumura M, Usui S, Kori A: Eye movements in monkeys with local dopamine depletion in the caudate nucleus. I. Deficits in spontaneous saccades. J Neurosci 1995;15:912–927. Straube A, Ditterich J, Oertel W, Kupsch A: Electrical stimulation of the posteroventral pallidum influences internally guided saccades in Parkinson’s disease. J Neurol 1998;245:101–105. Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873–880. Hollander E, Cohen L, Richards M, Mullen L, DeCaria C, Stern Y: A pilot study of the neuropsychology of obsessive-compulsive disorder and Parkinson’s disease: Basal ganglia disorders. J Neuropsychiatry Clin Neurosci 1993;5:104–107. Cummings JL, Cunningham K: Obsessive-compulsive disorder in Huntington’s disease. Biol Psychiatry 1992;31:263–270. Eidelberg D, Moeller JR, Antonini A, et al: The metabolic anatomy of Tourette’s syndrome. Neurology 1997;48:927–934. Saba PR, Dastur K, Keshavan MS, Katerji MA: Obsessive-compulsive disorder, Tourette’s syndrome, and basal ganglia pathology on MRI (letter). J Neuropsychiatry Clin Neurosci 1998;10:116–117. Rauch SL, Savage CR: Neuroimaging and neuropsychology of the striatum. Bridging basic science and clinical practice. Psychiatr Clin North Am 1997;20:741–768. Aziz TZ, Peggs D, Sambrook MA, Crossman AR: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 1991;6:288–292. Scoditti U, Rustichelli P, Calzetti S: Spontaneous hemiballism and disappearance of parkinsonism following contralateral lenticular lacunar infarct. Ital J Neurol Sci 1989;10:575–577. Sellal F, Lisovoski F, Hirsch E, Mutschler V, Collard M, Marescaux C: Contralateral disappearance of parkinsonian signs after subthalamic hematoma. Neurology 1992;42:255.

Pathophysiology of Movement Disorders

53

132 133 134 135 136

137 138 139 140 141 142 143 144 145

146 147

148

149

150 151

152

153 154

155

Gill SS, Heywood P: Bilateral dorsolateral subthalamotomy for advanced Parkinson’s disease (letter). Lancet 1997;350:1224. Gill SS, Heywood P: Bilateral subthalamic nucleotomy can be accomplished safely. Mov Disord 1998;13(suppl 2):201. Laitinen LV: Pallidotomy for Parkinson’s diesease. Neurosurg Clin North Am 1995;6:105–112. Lang A, Lozano A, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:1036–1042. Grafton AT, Waters C, Sutton J, Lew MF, Couldwell WC: Pallidotomy increases activity of motor association cortex in Parkinson’s disease: A positron emission tomographic study. Ann Neurol 1995; 37:776–783. Speelman JD: Parkinson’s Disease and Stereotaxic Surgery. Amsterdam, Rodorpi, 1991. Sterio D, Beric A, Dogali M, Fazzini E, Alfaro G, Devinsky O: Neurophysiological properties of pallidal neurons in Parkinson’s disease. Ann Neurol 1994;35:586–591. Ceballos-Bauman AO, Obeso JA, Vitek JL, et al: Restoration of thalamocortical activity after posteroventrolateral pallidotomy in Parkinson’s disease. Lancet 1994;344:814. Eidelberg D, Moeller JR, Ishikawa T: Regional metabolic correlates of surgical outcome following unilateral pallidotomy for Parkinson’s disease. Ann Neurol 1996;39:450–459. Limousin P, Krack P, Pollack P, et al: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339:1105–1111. DeLong MR, Crutcher MD, Georgopoulos AP: Relations between movement and single cell discharge in the substantia nigra of the behaving monkey. J Neurosci 1983;3:1599–1606. Hedreen JC, DeLong MR: Organization of striatopallidal, striatonigral and nigrostriatal projections in the macaque. J Comp Neurol 1991;304:569–595. Schultz W: Activity of pars reticulata neurons of monkey substantia nigra in relation to motor, sensory, and complex events. J Neurophysiol 1986;4:660–677. Francois C, Yelnik J, Percheron G: Golgi study of the primate substantia nigra. II. Spatial organization of dendritic arboriations in relation to the cytoarchitectonic boundaries and to the striatonigral bundle. J Comp Neurol 1987;265:473–493. Lynd-Balta E, Haber SN: Primate striatonigral projections: A comparison of the sensorimotorrelated striatum and the ventral striatum. J Comp Neurol 1994;345:562–578. Ilinsky IA, Tourtellotte WG, Kultas-Ilinsky K: Anatomical distinctions between the two basal ganglia afferent territories in the primate motor thalamus. Stereotact Funct Neurosurg 1993;60: 62–69. Wichmann T, Bergman H, Starr PA, Subramanian T, Watts RL, DeLong MR: Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates. Exp Brain Res 1999;125:397–409. Palombo E, Porrino LJ, Bankiewicz KS, Crane AM, Sokoloff L, Kopin IJ: Local cerebral glucose utilization in monkeys with hemiparkinsonism induced by intracarotid infusion of the neurotoxin MPTP. J Neurosci 1990;10:860–869. Burchiel KJ: Thalamotomy for movement disorders. Neurosurg Clin North Am 1995;6:55–71. Gross C, Rougier A, Guehl D, Boraud T, Julien J, Bioulac B: High-frequency stimulation of the globus pallidus internalis in Parkinson’s disease: A study of seven cases. J Neurosurg 1997;87: 491–498. Tasker RR, Yamashiro K, Lenz F, Dostrovsky JO: Thalamotomy in Parkinson’s disease: Microelectrode techniques; in Lundsford D (ed): Modern Stereotactic Surgery. Norwell, Academic Press, 1988, pp 297–313. Selby G: Stereotactic surgery for the relief of Parkinson’s disease. I. A critical review. J Neurol Sci 1967;5:315–342. Narabayashi H, Maeda T, Yokochi F: Long-term follow-up study of nucleus ventralis intermedius and ventrolateralis thalamotomy using a microelectrode technique in parkinsonism. Appl Neurophysiol 1987;50:330–337. Miyamoto T, Bekku H, Moriyama E, Tsuchida S: Present role of stereotactic thalamotomy for parkinsonism: Retrospective analysis of operative results and thalamic lesions in computed tomograms. Appl Neurophysiol 1985;48:294–304.

Wichmann/DeLong/Vitek

54

156 157

158

159 160 161

162 163 164 165 166 167 168

169 170

171 172 173 174 175 176 177

178 179

Struppler A, Gurfinkel V, Mathis J, Max T: Motor performance in parkinsonism following stereotactic thalamotomy. Adv Neurol 1993;60:403–407. Giller CA, Dewey RB, Ginsburg MI, Mendelsohn DB, Berk AM: Stereotactic pallidotomy and thalamotomy using individual variations of anatomic landmarks for localization. Neurosurg 1998; 42:56–62. Osenbach RK, Burchiel KJ: Thalamotomy: Indications, techniques, and results; in Germano IM (ed): Neurosurgical Treatment of Movement Disorders. Neurosurgical Topics, Park Ridge, AANS, 1998, pp 107–130. Tasker RR, Lang AE, Lozano AM: Pallidal and thalamic surgery for Parkinson’s disease. Exp Neurol 1997;144:35–40. Brophy BP, Kimber TJ, Thompson PD: Thalamotomy for parkinsonian tremor. Stereotact Funct Neurosurg 1997;69:1–4. Page RD, Sambrook MA, Crossman AR: Thalamotomy for the alleviation of levodopa-induced dyskinesia: Experimental studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated parkinsonian monkey. Neuroscience 1993;55:147–165. Canavan AG, Nixon PD, Passingham RE: Motor learning in monkeys (Macaca fascicularis) with lesions in motor thalamus. Exp Brain Res 1989;77:113–126. Vitek JL, Ashe J, Kaneoke Y: Spontaneous neuronal activity in the motor thalamus: Alteration in pattern and rate in parkinsonism. Neuroscience 1994;20:1:561. Pahwa R, Wilkinson S, Smith D, Lyons K, Miyawaki E, Koller W: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997;49:249–253. Benabid AL, Pollak P, Gervason C, et al: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406. Pollak P, Benabid AL, Limousin P, Hoffman D, Le Bas JF, Perret J: Subthalamic nucleus stimulation alleviates akinesia and rigidity in parkinsonian patients. Adv Neurol 1996;69:591–594. Limousin P, Pollak B, Benazzouz A, et al: Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–674. Benazzouz A, Boraud T, Feger J, Burbaud P, Bioulac B, Gross C: Alleviation of experimental hemiparkinsonism by high-frequency stimulation of the subthalamic nucleus in primates: A comparison with L-dopa treatment. Mov Disord 1996;11:627–632. Obeso JA, Rodriguez MC, Gorospe A, Guridi J, Alvarez L, Macias R: Surgical treatment of Parkinson’s disease. Baillie`res Clin Neurol 1997;6:125–145. Siegfried J, Taub E, Wellis G: Chronic electrostimulation of ventroposterolateral pallidum. XIIth Meeting of the World Society for Stereotactic and Functional Neurosurgery. Abstracts of Workshop on Parkinson’s Disease, 1997, pp 2–3. Vitek JL, Chockkan V, Zhang JY, et al: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22–35. Lee MS, Marsden CD: Movement disorders following lesions of the thalamus or subthalamic region. Mov Disord 1994;9:493–507. Perlmutter J, Stambuk M, Markham J, et al: Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia. J Neurosci 1997;17:843–850. Benabid AL, Pollak P, Gao D, et al: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–214. Crossman AR, Sambrook MA, Jackson A: Experimental hemichorea/hemiballismus in the monkey. Study on the intracerebral site of action in a drug-induced dyskinesia. Brain 1984;107:579–596. Hammond C, Feger J, Bioulac B, Souteyrand JP: Experimental hemiballism in the monkey produced by unilateral kainic acid lesion in corpus luysii. Brain Res 1979;171:577–580. Whittier JR, Mettler FA: Studies of the subthalamus of the rhesus monkey. II. Hyperkinesia and other physiologic effects of subthalamic lesions with special references to the subthalamic nucleus of Luys. J Comp Neurol 1949;90:319–372. Kase CS, Maulsby GO, deJuan E, Mohr JP: Hemi-chorea-hemiballism and lacunar infarction in the basal ganglia. Neurology 1981;31:452–455. Hamada I, DeLong MR: Excitotoxic acid lesions of the primate subthalamic nucleus result in transient dyskinesias of the contralateral limbs. J Neurophysiol 1992;68:1850–1858.

Pathophysiology of Movement Disorders

55

180

181 182 183 184 185 186 187

188 189 190

191 192 193

194 195 196 197

198 199 200 201

202 203

Carpenter MB, Whittier JR, Mettler FA: Analysis of choreoid hyperkinesia in the rhesus monkey: Surgical and pharmacological analysis of hyperkinesia resulting from lesions in the subthalamic nucleus of Luys. J Comp Neurol 1950;92:293–332. Carpenter MB, Carpenter CS: Analysis of somatotopic relations of the corpus luysi in man and monkey. J Comp Neurol 1951;95:125–158. Hamada I, DeLong MR: Excitotoxic acid lesions of the primate subthalamic nucleus result in reduced pallidal neuronal activity during active holding. J Neurophysiol 1992;68:1859–1866. Vitek J, Evatt M, Zhang J, et al: Pallidotomy as a treatment for medically intractable dystonia. Ann Neurol 1997;42:409. Group HsDCR: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971–983. Mazurek MF, Garside S, Beal MF: Cortical peptide changes in Huntington’s disease may be independent of striatal degeneration. Ann Neurol 1997;41:540–547. Heinsen H, Rub U, Gangnus D, et al: Nerve cell loss in the thalamic centromedian-parafascicular complex in patients with Huntington’s disease. Acta Neuropathol 1996;91:161–168. Gutekunst CA, Levey AI, Heilman CJ, et al: Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci USA 1995;92:8710–8714. Sapp E, Schwarz C, Chase K, et al: Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 1997;42:604–612. Furtado S, Suchowersky O: Huntington’s disease: Recent advances in diagnosis and management. Can J Neurol Sci 1995;22:5–12. Albin RL, Reiner A, Anderson KD, Penney JB, Young AB: Striatal and nigral neuron subpopulations in rigid Huntington’s disease: Implications for the functional anatomy of chorea and rigidity akinesia. Ann Neurol 1990;27:357–365. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB: Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA 1988;85:5733–5737. Blanchet PJ, Boucher R, Bedard PJ: Excitotoxic lateral pallidotomy does not relieve L-dopa-induced dyskinesia in MPTP parkinsonian monkeys. Brain Res 1994;650:32–39. Blanchet PJ, Grondin R, Bedard PJ: Dyskinesia and wearing-off following dopamine D1 agonist treatment in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates. Mov Disord 1996;11:91–94. Blanchet PJ, Gomez-Mancilla B, Di Paolo T, Bedard PJ: Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia? Fundam Clin Pharmacol 1995;9:434–442. Agid Y, Chase T, Marsden D: Adverse reactions to levodopa: Drug toxicity or progression of disease? Lancet 1998;351:851–852. Chase TN: The significance of continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Drugs 1998;55(suppl 1):1–9. Blanchet PJ, Papa SM, Metman LV, Mouradian MM, Chase TN: Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson’s disease. Neurosci Biobehav Rev 1997;21:447–453. Gille M, Jacquemin C, Kiame G, Delbecq J, Guilmot D, Depre A: Myelinolyse centropontine avec ataxie cerebelleuse et dystonie. Rev Neurol 1993;149:344–346. Tranchant C, Maquet J, Eber AM, Dietemann JL, Franck P, Warter JM: Angiome caverneux cerebelleux, dystonie cervicale et diaschisis cortical croise´. Rev Neurol 1991;147:599–602. Janati A, Metzer WS, Archer RL, Nickols J, Raval J: Blepharospasm associated with olivopontocerebellar atrophy. J Clin Neuroophthalmol 1989;9:281–284. Krauss JK, Mohadjer M, Braus DF, Wakhloo AK, Nobbe F, Mundinger F: Dystonia following head trauma: A report of nine patients and review of the literature. Mov Disord 1992;7:263– 272. Ozelius LJ, Hewett J, Kramer P, et al: Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium. Genome Res 1997;7:483–494. Risch N, deLeon D, Ozelius L, et al: Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 1995;9:152–159.

Wichmann/DeLong/Vitek

56

204 205 206 207 208 209

210

211

212 213 214 215 216 217 218 219 220 221 222 223 224 225

Hutchison WD, Lozano AM, Davis K, Saint-Cyr JA, Lang AE, Dostrovsky JO: Differential neuronal activity in segments of globus pallidus in Parkinson’s disease patients. Neuroreport 1994;5:1533–1537. Patel K, Roskrow T, Davis JS, Heckmatt JZ: Dopa-responsive dystonia. Arch Dis Child 1995;73: 256–257. Nygaard TG: Dopa-responsive dystonia. Curr Opin Neurol 1995;8:310–313. Ichinose H, Ohye T, Takayashi E, et al: Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994;8:236–242. Vitek JL, Bakay RA, Hashimoto T, et al: Microelectrode-guided pallidotomy: Technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998;88:1027–1043. Mitchell IJ, Luquin R, Boyce S, et al: Neural mechanisms of dystonia: Evidence from a 2-deoxyglucose uptake study in a primate model of dopamine agonist-induced dystonia. Mov Disord 1990;5: 49–54. Hantraye P, Riche D, Maziere M, Isacson O: A primate model of Huntington’s disease: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp Neurol 1990;108:91–104. Tasker RR, Doorly T, Yamashiro K: Thalamotomy in generalized dystonia; in Fahn S, Marsden C, Calne D (eds): Advances in Neurology: Dystonia. 2. New York, Raven Press, 1988, vol 50, pp 615–631. Cardoso F, Jankovic J, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for dystonia and hemiballismus. Neurosurg 1995;36:501–508. Andrew J, Fowler CJ, Harrison MJG: Stereotaxic thalamotomy in 55 cases of dystonia. Brain 1983; 106:981–1000. Kistrup K, Gerlach J: Selective D1 and D2 receptor manipulation in Cebus monkeys: Relevance for dystonia and dyskinesia in humans. Pharmacol Toxicol 1987;61:157–161. Casey DE: Dopamine D1 (SCH23390) and D2 (haloperidol) antagonists in drug-naive monkeys. Psychopharmacology 1992;107:18–22. Peacock L, Lublin H, Gerlach J: The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment. Eur J Pharmacol 1990;186:49–59. Gerlach J, Hansen L: Clozapine and D1 /D2 antagonism in extrapyramidal functions. Br J Psychiatry 1997;17(suppl):34–37. Ondo W, Desaloms J, Jankovic J, Grossman R: Pallidotomy for generalized dystonia. Mov Disord 1998;13:693–698. Vitek J, Giroux M: The physiology of hypokinetic and hyperkinetic movement disorders: A model for the dyskinesias. Ann Neurol 2000; in press. Jallo GI, Dogali M: Ventral intermediate thalamotomy for hemiballismus. Stereotact Funct Neurosurg 1995;65:23–25. Krauss JK, Mundinger F: Functional stereotactic surgery for hemiballismus. J Neurosurg 1996;85: 278–286. Lozano AM, Kumar R, Gross RE, et al: Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997;12:865–870. Lenz FA, Suarez JI, Metman LV, et al: Pallidal activity during dystonia: Somatosensory reorganisation and changes with severity: J Neurol Neurosurg Psychiatry 1998;65:767–770. Iacono RP, Kuniyoshi SM, Lonser RR, Maeda G, Inae AM, Ashwal S: Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans. Pediatr Neurol 1996;14:145–148. Blount JP, Kondoh T, Ebner TJ, Low WC, Maxwell RE: Pallidotomy for the treatment of dystonia. Abstr Am Assoc Neurol Surg 1996;64:190. Jerrold L. Vitek, MD, PhD, Department of Neurology, Emory University School of Medicine, Suite 6000, WMRB, P.O. Drawer V, Atlanta, GA 30322 (USA) Tel. +1 404 727 7177, Fax +1 404 727 3157, E-Mail [email protected]

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Functional Models of the Basal Ganglia: Where Are We? J.A. Obeso a, J. Guridi b, M.C. Rodriguez-Oroz a, R. Macias c, M. Rodriguez d, L. Alvarez c, G. Lopez c a

Movement Disorders and Basal Ganglia Group, Department of Neurology and Neurosurgery, Area of Neuroscience, Clinica Universitaria and Medical School, University of Navarra, Pamplona; b Service of Neurosurgery, Hospital de Navarra, Pamplona, Spain; c Centro Internacional de Restauracio´n Neurologica (CIREN), La Habana, Cuba; d Experimental Neurology and Neurobiology Laboratory, Department of Physiology, University of La Laguna, Tenerife, Spain

The current model of basal ganglia pathophysiology was developed in the late 1980s [1–4] mainly on the basis of experimental work undertaken in monkeys in whom either chorea-ballism or parkinsonism was induced by pharmacological blockade of the pallido-subthalamic connection and administration of the neurotoxin MPTP to lesion the substantia nigra pars compacta (SNpc). The model was created to serve as a framework for understanding the physiological origin of movement disorders but never pretended to provide a comprehensive account of the normal functions of the basal ganglia [2, 5]. In recent years the model has received considerable attention and has fueled the generation of numerous experiments and clinical observations. Inevitably, many of these newer findings are not easily explained by the classic model. This in turn has led to some to consider the model is very imperfect and limited [6, 7]. We have adopted a critical but more positive attitude [8]. Indeed, the model has been instrumental in the recent resurgence of surgery for Parkinson’s disease (PD) and other movement disorders [9, 10].

The Current Model Among the several circuits which form the corticobasal ganglia-thalamocortical loops, the ‘motor circuit’ is the most relevant for understanding the

typical clinical manifestations of PD. In the monkey, the motor circuit is somatotopically organized according with a general order. Both anatomical and physiological studies have shown that neurons corresponding to the leg are located dorsally and medially, the face ventrally and the arm in-between with a more lateral distribution [11, 12]. This circuit connects the motor areas (supplementary motor area, area 6 and area 4) as well as the primary somatosensory areas (areas 3, 2, 1) with the dorsolateral putamen. Cortical excitatory (glutamatergic) afferents make synapse with medium spiny GABA neurons and also with the large aspiny cholinergic neurons. The former are striatopallidal projection neurons and the latter are interneurons. The nigrostriatal dopaminergic projection is mainly directed to the GABA output neurons modulating the excitation exerted by the cortical projection. The putamen may modulate the output of the basal ganglia by means of the ‘direct’ striatoglobus pallidus pars interna (GPi)-substantia nigra pars reticulata (SNpr) circuit which is inhibitory and through the ‘indirect’ striato-globus pallidus pars externa (GPe)-subthalamic nucleus (STN)-globus pallidus pars interna (GPi) projection (1, 2, 8) (fig. 1A). The net result of activating the ‘indirect’ circuit is excitation of the GPi/SNpr which is associated with movement arrest, while activation of the ‘direct’ circuit provokes phasic neuronal inhibition of the GPi/SNpr which is associated with movement facilitation [13]. The ‘direct’ and ‘indirect’ circuits are therefore capable of exerting opposite effects on the output structures of the basal ganglia. Extensive work in the rat and monkey has shown that dopamine exerts a dual action on striatal GABA efferent neurons [14–16]. It activates those GABA-Substance P-dynorphin neurons in the origin of the ‘direct’ circuit and inhibits GABA-enkephalin neurons giving rise to the ‘indirect’ circuit. Parkinsonian State Dopamine deficiency leads to a series of functional changes (fig. 1B) in the striatopallidal circuits. The main features consist in increased activity in the STN and reduced inhibition in the ‘direct’ circuit [1, 2, 8]. The major pathophysiological modifications contained in the model regarding the parkinsonian state may be summarized as follows (table 1): Loss of nigrostriatal dopaminergic activity reduces the normal inhibition that dopamine exerts on the GABA-enkephalin neurons, which increases their activity, overinhibiting the GPe. The inhibitory tone of GPe on the STN is reduced leading to increased neuronal activity of the STN (fig. 1B) which drives GPi and SNpr neurons to fire at high rates and to respond excessively to peripheral sensory input [17–19]. In the parkinsonian state therefore, the GPi and SNpr are overexcited through the ‘indirect’ circuit and disinhibited as a consequence of reduced activity in the ‘direct’ circuit (fig. 1B). The end result is an augmented inhibitory

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A

B, C Fig. 1. Diagramatic summary of the model. A In the normal state the ‘direct’ and ‘indirect’ pathways of the motor circuit control with opposite effect the output structures of the basal ganglia (GPi and SNr). B Functional changes in the basal ganglia circuitries in the parkinsonian state. Disinhibition of the ‘indirect’ striatal neurons (D2) leads to a decrease in the GPe activity that induces an overexcitation of the STN and consequently of the GPi and SNr. Decreased activation of D1 GABA striatal neurons giving rise to the ‘direct’ circuit leads to disinhibition of the GPi and SNr and reinforce hyperactivity. Hyperactivity of the nuclei is represented in black (STN, GPi and SNr). C Functional changes associated with dyskinesias. A reduction in the inhibitory tone exerted by the striatal neurons in the origin of the ‘indirect’ pathway (D2) provokes an increment in GPe activity that overinhibits the STN. This leads to a reduction in the excitation exerted over the GPi and SNr. The thickness of the arrows intends to represent the degree of functional activity of the different projections. Black arrows: inhibitory projections; white arrows: excitatory projections.

output towards the motor thalamus, rendering the cortical motor areas and brainstem hypoactive. Dyskinesias The work of Crossman’s group [2, 3, 20–23] has made the largest contribution to define the pathophysiological basis of dyskinesias (chorea-ballism). According to the model in figure 1C, reducing STN activity either by pharmacological blockade or lesioning, diminishes neuronal activity in the GPi and therefore provokes a reduction of the normal inhibition of the thalamocortical motor projection resulting in the release of dyskinetic movements. They also demonstrated that the STN may be functionally overinhibited by the GPe

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Table 1. Main pathophysiological changes associated with the parkinsonian state Method

STN

GPi

Cortex

Firing activity 1 PET activation 2 Metabolic activity 3 Effect of surgery 2

CCC – CCC +++

CCC CC CC +++

BB BB – –

1

Neuronal recording obtained in both monkeys and PD patients. 2 Studies undertaken in humans only. 3 Assessed by ‘in situ’ hybridization of mRNA for CO-I and 2-DG uptake studies.

when the inhibitory tone from the striatum is decreased (fig. 1C). This may occur as a result of focal striatal lesions, neurodegeneration of the GABAenkephalin neurons as in Huntington’s disease [24] or induced pharmacologically as in tardive dyskinesias. The notion of dyskinesia being mediated by a reduction in GPi output was supported by the work of Fillion et al. [25] who recorded neuronal firing activity in MPTP monkeys before and during drug-induced dyskinesias. In a different study they also assessed GPi/GPe activity after inducing dyskinesias in normal monkeys by infusing bicuculline in the GPe [26]. Both experiments showed a reduction in neuronal firing rate of GPi coinciding with the dyskinesias. However, the changes were not uniform. This will be analyzed from a different perspective later in this chapter.

Predictions from the Model Parkinsonism A large number of studies (table 2) have confirmed the overall adequacy of the model to explain the parkinsonian state. Thus, markers of metabolic activity such as 2-deoxyglucose (2-DG) uptake, mRNA expression of glutamic acid decarboxylase (GAD) and mitochondrial cytochrome oxidase I (CO-I) have all consistently shown augmented activity in the STN, GPi and SNpr [8]. Recording neuronal activity in these nuclei before and after MPTP administration has also shown an increment in mean firing frequency and number of cells discharging with an oscillatory pattern [27]. Recent observations during surgery in patients with PD have essentially confirmed the data obtained in

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Table 2. Predictions from the model for PD Reducing neuronal overactivity in the STN/GPi projection improves the parkinsonian state as shown by the effect of : Subthalamotomy in MPTP monkeys Pallidotomy in patients with PD DBS of the STN or GPi in patients with PD Reducing neuronal overactivity in the STN/GPi projection activates cortical motor areas as revealed by: Enhanced oxygen consumption in the SMA and DLPFC after pallidotomy and DBS of the STN or GPi Increased amplitude of the ‘Bereitschaft’ potential Improved simple and choice reaction time

monkeys in the sense of both the somatotopic arrangement and the abnormal neuronal activity which characterize the parkinsonian state [28–30]. The adequacy of the model to explain the pathophysiology of PD was given by the demonstration that lesion of the STN in MPTP monkeys induced marked motor improvement [31–33]. This was accompanied by a reduction of the increased neuronal firing and metabolic hyperactivity in the GPi and SNpr [33, 34]. Such observations provided the scientific basis for the present revitalization of surgery in PD. Both pallidotomy and deep brain stimulation of the STN and GPi have been shown to convey very significant amelioration of the cardinal features of PD [see Bakay and Vitek, Bowen et al., Gross, and Benabid et al., in this volume]. Such marked clinical benefit is associated with an improvement in cortical activation of premotor areas as shown by positron emission tomography (PET) activation studies [35, 36], and a number of kinematic parameters such as reaction and movement time, pegboard, peak force production, etc. [37, 38]. Thus, functional and objective assessment have confirmed that reducing excessive inhibitory output from the basal ganglia leads to substantial improvement of motor control mechanisms in PD as predicted by the model [1, 2]. Dyskinesias The model predicts that lesion of the GPi in the normal state would induce dyskinesias by disinhibition of the thalamocortical projection. However, reversible blockade of the GPi in monkeys by infusing muscimol or cooling were associated with mild dystonic features and slowness of movement initiation but chorea-ballism has not been described. Equally, excitotoxic lesion of the GPi with kainic acid in both normal and MPTP monkeys is not

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Table 3. Problems with the model Experimental parkinsonism In situ hybridization of GAD mRNA and CO-I mRNA is not reduced in the GPe of animals (monkey and rat) with DA depletion Variable effect of GP lesion in the rat on neuronal firing in the STN (+19 to 64%) Levodopa-induced dyskinesias are not associated with reduction below normal levels of metabolic markers (GAD mRNA, CO-I mRNA) in GPi and STN 2-DG uptake does not change in the GPe of monkeys with LID respect to the parkinsonian state in the MPTP model Parkinson’s disease Pallidotomy has a profound antidyskinesia effect Thalamotomy, pallidotomy or DBS do not aggravate motor function Offers no comprehensive explanation for rigidity and tremor

accompanied by dyskinesias. In humans, unilateral lesion of the GPi are extremely rare but when encountered are often asymptomatic. In patients with PD, pallidotomy has a profound antidyskinetic effect. This is the most obvious conflict between the model and reality.

Problems with the Model and Parkinson’s Disease (table 3) The problems of the classic model to explain PD may be divided for the purpose of this discussion in two categories: (1) those related with experimental findings and (2) those related with clinical observations relevant to understand the origin of the cardinal features of PD such as resting tremor, rigidity and the various manifestations of akinesia and bradykinesia. Experimental Findings How dopamine deficiency leads to abnormal neuronal activity in the STN and GPi is not as clearly defined as the model anticipated. The ‘direct’ striatal projection is supposedly hypoactive in the parkinsonian state. Accordingly, administration of GABA or a GABA agonist like muscimol into the GPi should restore part of the inhibitory input and improve motor features. This experiment, to the best of our knowledge, has not been undertaken or published. In fact, there is no definitive evidence as to the physiological state of the ‘direct’ circuit following dopaminergic depletion. All what is known is that in the rat with a lesion by 6-OHDA the binding for GABA receptors in GPi was augmented, which was explained as secondary to functional denervation [1]. At present, the definition of the functional state of a projection based

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Fig. 2. Recordings from neurons in the SNpr connected with the striatum as indicated by antidromic responses. The top response is an example of a cell showing inhibition following striatal stimulation. In the bottom is an example of a cell responding with excitation to the same type of striatal stimulation.

solely on changes in binding is unacceptable. In the particular case of the GPi, this is more overt in view of the currently known increase of GABA activity in the neurons of the GPi in MPTP monkeys. Moreover, we have recently found evidence in the rat indicating that the ‘direct’ circuit is not homogeneously inhibitory [39]. Thus, using a careful electrophysiological technique it was encountered that 15% of cells projecting with a short latency from the striatum to the SNpr were excitatory (fig. 2). The physiological status of the GPe in the parkinsonian state is also ill defined at present and a matter of debate [7]. The model suggests that the

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GPe is hypoactive as a result of increased inhibition from the GABA-enkephalinergic striatal cells which give rise to the ‘indirect’ circuit. However, some biochemical data have been discordant with this assumption. Thus, the expression of GAD mRNA assessed by the technique of in situ hybridization showed above normal levels, indicating an upregulation of GAD and therefore, increased GABA synthesis in the rat with unilateral 6-OHDA lesion. A similar study in monkeys intoxicated with MPTP revealed normal levels of expression. Expression of CO-I mRNA was increased well above control values in MPTP monkeys [40]. All these studies suggest that GPe activity is not reduced in the parkinsonian state and not in keeping with the model. The role of the GPe in leading to STN hyperactivity has also been recently challenged by a study of Hassani et al. [41]. They described in the rat that a lesion of the GPe caused a 19.5% increment in firing rate of the STN compared with a 105.7% provoked by 6-OHDA lesion. Vila et al. [42] found that increased firing and metabolic activity (CO-I mRNA expression) in the STN preceded changes in the striatum and GPe suggesting alternative pathways for the control of STN neuronal activity. Arguments against the role of GPe in the origin of parkinsonism have to be weighted against a very important body of evidence on the contrary. Thus, neuronal recording of GPe and GPi activity in parkinsonian monkeys has consistently showed reciprocal changes in both structures, so that firing frequency in the GPe is decreased with regard to the GPi in the parkinsonian state and increased after levodopa administration [18, 25]. A few studies in patients with PD have also shown slower firing rate in the GPe than in the GPi (fig. 3). Thus, the ratio of neuronal firing rate for GPe/GPi is similar in MPTP monkeys and parkinsonian patients. That the GPe is likely to play a role in the origin of STN increased activity and, consequently, in the origin of parkinsonism is suggested by the existence of a very tight physiological relationship between these two nuclei. There are several pieces of experimental evidence in this regard [8]. For example, inhibition of the GPe with bicuculline activates the STN [43] while stimulation of the STN produces increased firing in the GPe [44]. Lesions of the STN induce a reduction in firing frequency in both GPe and GPi [45]. Recently, Plenz and Kitai [46] have elegantly shown using organotypic cultures a very strict and direct correlation between neuronal burst firing at slow frequencies between the GPe and STN. Interestingly, interrupting the GPe projection provoked a net increment in tonic firing in the STN. All these findings strongly indicate that changes in any one of these two nuclei are readily reflected in the other. The crucial point regarding the pathophysiological origin of PD is to decipher whether GPe inhibition following dopamine depletion leads to STN hyperactivity and parkinsonism or the contrary. The existence of a direct

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dopaminergic innervation of the STN in the primate is accepted at present [47] but the role of dopamine on STN neuronal activity is not well understood [48]. It is conceivable that degeneration of SNpc neurons in PD leads to STN hyperactivity through more than one pathway and that what is found at postmortem is only one aspect, i.e. the end result, of a series of dynamic changes which occurred earlier. Thus, what may be abnormal in the GPe of the parkinsonian brain when the clinical picture is fully established is not the mean value of neuronal discharge but the ratio of activity in relation with that of the STN. Physiologically, the STN excitatory activity prevails over the GPe [46]. Dopamine depletion may provoke several modifications in the basal ganglia which modify and alter the normal relationship between the STN and GPe. These may include a further shift towards STN predominance. The reduced inhibitory capacity of the GPe perpetuates the abnormal firing activity in the STN and perhaps also contributes to the increased activity in the GPi. Clinical Observations Increased inhibition from the basal ganglia output nuclei and the consequent hypoactivity of cortical motor areas provides a reasonable explanation of the slowness of movement initiation and execution which characterize bradykinesia in PD. Pallidotomy and DBS of the STN or GPi have shown an improvement in movement speed in parallel with increased activation of premotor areas demonstrated by PET [36, 49]. However, the movement manifestations of PD are far more plural and complex (table 4). These comprise features as heterogeneous as reduced blinking rate, decreased amplitude and rate of arm swinging, shuffling gait, micrographia and hypophonia among many others. Bradykinesia involves not only the slowness of movement execution but also the difficulty or impossibility to perform simultaneous and sequential movements, the characteristic ‘fatigue’ or neurasthenia of repetitive movements leading to freezing of the task, reduced peak frequency to perform rapid repetitive movements at certain frequencies, etc. Eye movements are also slow, hypometric and decomposed in several steps mimicking the findings of the upper limb during a fast ballistic movement. The latency of postural reflexes elicited by a perturbation of the center of gravity are delayed in PD [50], partially explaining their desequilibrium and propensity to fall even in nonadvanced states. The excitability of the blink reflex is increased perhaps explaining the Meyerson’s sign but the startle reflex is reduced suggesting overinhibition of reticulospinal neurons. Thus, regarding motor features associated with Fig. 3. Digitized action potentials of 3 neurons of the GPe (a) and GPi (b) from a patient with PD submitted to pallidotomy. Histogram (c) of the interspike intervals showing a lower firing rate for neurons in the GPe than in the GPi.

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Table 4. Spectrum of clinical and neurophysiological characteristics of PD Hypokinesia BB Blinking and arm-swinging rate Micrographia Short stepping of gait Hypophonia

Bradykinesia CC Reaction time and movement time Delayed sequential movements Inhibition of simultaneous movements Neuroasthenia during repetitive movement

Rigidity CC Tone during palpation at rest CC Tonic and phasic stretch reflex BB Distensibility ‘Cogwheeling’ phenomenon Tremor Independent firing of different body segments

movement alone, a simple clinical analysis reveals a complex and heterogeneous picture. It is unlikely that all of them can be simply explained as the result of increased inhibitory activity over the motor thalamus and brainstem target neurons. The origin of tremor and rigidity are even less well explained by the model. Tremor at rest (4–6 Hz) is known to be related with neuronal burst firing at the same frequency in the basal ganglia (STN, GPe, GPi) and in the ventralis intermedialis (Vim) nucleus of the thalamus which receives spindle afferents and projects to the motor cortex. Which basal ganglia nuclei (if any in particular) is responsible for the origin of the oscillatory-bursting activity associated with tremor is not known at present. We have suggested that the close interaction between the GPe and STN and the opposite excitatoryinhibitory effects of their respective synaptic activity could be the basis for the creation of an oscillatory loop [51], which can give rise to rhythmical signaling to the motor cortex. This suggestion has been strongly supported by the recent experimental work of Plenz and Kitai [46] who showed that both the STN and GPi tend to fire in phase and produce rhythmical slow frequencies of discharge. It is currently believed that the intrinsic oscillatory membrane properties of STN neurons account primarily for their tendency to fire rhythmically. A slightly different view proposed that the increased neuronal activity in the STN/GPi leading to overinhibition of the motor thalamus and the membrane characteristics of thalamic neurons provides the basis for transforming a rather tonic neuronal firing into a bursting pattern [52].

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This putative role of the STN/GPe in the generation of tremor has the caveat of the lack of evidence showing ‘tremor-related’ activity in the motor thalamus, while neurons in the Vim do not receive afferents from the basal ganglia. An interesting recent observation is that different body segments seem to produce tremor frequency which are not correlated among them [53]. Thus, cross-correlation analysis between the tremor of the upper and lower limbs for example showed no statistical correlation. Similarly it was recently reported that rhythmical neuronal firing in the GPi only correlated with tremor in one specific segment of the limbs [54]. These findings suggest the existence of specific sub-circuits mediating the tremor of different body parts. The pathophysiology of rigidity has fascinated neuroscientists for at least half a century. Rigidity in PD is also composed of several features. At rest, there is increased muscular activity, associated with, and perhaps explaining, the difficulty to relax exhibited by many patients and the augmented muscular tension to palpation. The compliance to passive manipulation is reduced. This may be related to the increased tension at rest and/or to the enhanced stretch reflexes. The tonic component of the latter is responsible for the resistance to slow elongation typically noticed by the examiner. The ‘cogwheel’ phenomenon has classically been attributed to the superimposition of a postural tremor during stretching but it is more likely related with changes in neuronal firing in the basal ganglia. Indeed, we may understand the ‘cogwheeling’ sign as the consequence of discharges in an excitatory-inhibitory loop like the STN/GPe/GPi. How can increased activity in the STN/GPi/SNpr give rise to such plethora of motor manifestations? In this regard, the study of the Toronto group is illustrative. They show that the location of the lesions made during pallidotomy had a significant effect in the outcome [55]. For example, the antidyskinetic effect of pallidotomy was mainly associated with more rostrally placed lesions while the antitremor efficacy was related to ventrally placed lesions. These observations suggest the existence of multiple basal ganglia circuits mediating different manifestations of PD. This is indeed supported by recent anatomical data showing that the motor circuit is actually segregated into various somatotopically arranged regions according to the cortical projection area [56, 57]. Thus, the GPi neurons corresponding to the arm and projecting to the SMA lie dorsolaterally, those projecting to area 4 are medioventral and the ones connecting with area 6 are in-between. For the STN, neurons receiving cortical efferents from area 4 are dorsolateral while those connected to the SMA are dorsomedially placed. It is likely that this discrete anatomical organization is related to the variety of motor manifestations seen in PD. How this occurs precisely has not been defined yet. Finally, the model also has to take into account the apparent paradox represented by the observation that surgery of the basal ganglia in parkinsonian

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patients seems to carry no defect in motor performance [58]. One striking example is a patient of us with advanced PD in whom a subthalamotomy was performed with immediate excellent results. Five days later he developed a hemichorea and a repeated CT scan showed a large infarction of the subthalamic region extending dorsally towards the anterior thalamus and ventrally into the SNpr. A year later, the patient’s motor improvement had continued but the dyskinesia in the leg had not abated. Thus, a pallidotomy was performed resulting in complete abolition of the dyskinesia. This person was, therefore, practically left without output structures in the basal ganglia of the left hemisphere in addition to his severe dopamine depletion. Remarkably, when examined 3 years later he showed no obvious motor deficit on the right limbs, there was no impairment of cognition and there was only a mild dysarthria which benefited from levodopa treatment. The large capacity of the basal ganglia to compensate for focal lesions must have a fundamental albeit hitherto undeciphered relationship with its normal functions and clinical manifestations.

Problems with the Model and Levodopa-Induced Dyskinesias (table 3) Pallidotomy may abolish levodopa-induced dyskinesias (LIDs). This is the single and most consistent effect of pallidotomy in PD [59, 60]. The radical antidyskinetic effect of pallidotomy is the most overt dissociation between the theoretical predictions of the model and credited observations. Experimental Findings Analysis of the experimental data suggest a picture more complex than what has been emphasized until now by the model. Crossman’s group pioneered a number of experiments using 2-DG to characterize the metabolic state of the basal ganglia in parkinsonian monkeys who developed dyskinesias after chronic administration of levodopa or a dopamine agonist [21–23]. The amount of measured 2-DG uptake mainly reflects afferent synaptic activity. These studies showed increased 2-DG uptake in the STN and in GPi in the dyskinetic animals. The former observation was interpreted as secondary to increased inhibition from the GPe and the latter as the result of restoring inhibitory transmission in the direct striato-GPi projection. Thus, LID were thought to use a similar mechanism than chorea-ballism secondary to inhibition or lesion of the STN [23]. However, that the GPe and STN are hyperand hypoactive respectively in monkeys who developed LID is not so firmly established as it has been assumed until now. Mitchell et al. [22] found a 46% increment in 2-DG uptake in the STN and also a mild increment in the GPi. GPe uptake was significantly reduced with respect to parkinsonian animals

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but remained only slightly above normal levels. The latter finding is not in keeping with the model since in order to have increased GPe inhibition to the STN, the activity in the striatopallidal (GPe) enkephalinergic projection should have been reduced (fig. 1C), thus disinhibiting the GPe. However, the 2-DG data does not indicate reduced (i.e. below normal) uptake in the GPe in the dyskinetic animals. Moreover, several studies have consistently found that enkephalin expression in the striatum is increased in the parkinsonian state and is further elevated after chronic treatment with levodopa or dopamine agonists [16, 61]. According with these findings, the increased 2-DG uptake in the STN may reflect increased afferent activity from other sources. The major limitation of the 2-DG technique is that it cannot distinguish between the excitatory and inhibitory nature of afferent activity to a given nucleus. More direct evaluation of cellular metabolism is provided by in situ hybridization studies. Expression of CO-I mRNA activity reflects the level of mitochondrial activity and has been shown to be highly correlated with the generation of neuronal action potentials. Expression of GAD mRNA is a good index of GABA synthesis, thus indirectly indicating the degree of inhibitory activity. In the GPe of parkinsonian monkeys with LID, mRNA expression of GAD is not different from controls and CO-I expression is actually reduced with respect to MPTP (drug-free) animals although still above normal values [40, 62]. Similarly, STN metabolism as judged by CO-I mRNA expression is reduced with respect to the parkinsonian state but elevated when compared with controls [40]. In fact, the metabolic picture for the STN, GPe, GPi and SNpr is strikingly homogeneous. It seems as if the functional status of the GPe, GPi and SNpr would vary in relation with the level of STN activity. Overall, these findings suggest that in monkeys with LID the GPe is only moderately overactive and the STN/GPi are not hypoactive with regard to normal levels of neuronal metabolic activity. In keeping with this is the observation that in MPTP monkeys with LID [63] an excitotoxic lesion of the GPe, theoretically abolishing the excessive inhibition of the STN, actually caused an aggravation of both LID and parkinsonism. These metabolic studies clearly have the advantage a priori of analyzing ample areas of each nuclei, reducing the risk of spurious sampling. On the other hand, they all have several limitations. First of all, the significance of changes in the mRNA expression for a certain protein in relation with the overall metabolism of a given cell and certainly, with its capacity to generate action potentials is not known. In other words, the functional meaning of these subcellular modifications are not completely understood. Secondly, monkeys developed dyskinesias after chronic treatment with dopaminergic drugs but had been a variable time (a few hours to a few days) without receiving drugs before death. At such time monkeys were parkinsonian and although the

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central kinetic of the expression of these molecules is not known, it is feasible that the findings actually reflect a mixed state of parkinsonism plus the changes induced by chronic dopaminergic drugs. The most direct information about the functional state of a nucleus is given by electrophysiological assessment. Unfortunately, recording and isolating neuronal action potentials while animals are dyskinetic is an extremely difficult task which limits the validity of the few available studies. Fillion et al. [25] conducted the first study of the effect of dopaminergic drugs on neuronal firing activity in the GPi and GPe of MPTP monkeys. They observed that the behavioral effect of apomorphine (i.v.), i.e. improving parkinsonism and eliciting dyskinesias, was paralleled by a 15–50% reduction in firing frequency in 24 out of 30 neurons recorded in the GPi and a reciprocal increment in 30 out of 34 neurons from the GPe [55]. More recently, Papa et al. [64] managed to keep recording the same units (n>14) in the GPi in the ‘off ’ state and before (‘on’) and during (‘on with dyskinesias’) the induction of dyskinesias by administration of levodopa. Firing frequency decreased radically (by 71%). Mean firing rate during the dyskinesia period was 7.6 Hz and a few neurons almost stopped firing. Similar, albeit no so dramatic, reductions have been reported for patients with PD in whom changes in neuronal activity after subcutaneous apomorphine administration were recorded intraoperatively before pallidotomy [65–67]. In monkeys with hemichorea induced by focal injection of ibotenic acid into the STN [45] and in 2 patients with hemiballism submitted to surgery [68, 69], mean neuronal firing frequency in the GPi was also reduced with respect to control values (monkeys) and the parkinsonian state (patients). The problem of these single unit studies is the limitation given by sampling biased, reduced number of neurons and impossibility to simultaneously assess possible changes in nearby cells and in intimately related nuclei (i.e. STN/GPe and GPi/GPe). Nevertheless, the overall evidence points to a clear association between slow firing rate in the GPi and the dyskinetic state. In summary, the functional status of the GPe, GPi and STN in dyskinetic monkeys is a matter of some controversy. Dopaminergic drugs reduce neuronal firing and the expression of CO-I mRNA and GAD mRNA in the STN and GPi. However, the degree of such changes in metabolic activity is relative since the values remained higher than normal. The GPe activity is moderately increased over control levels but still below the parkinsonian values. Lesion of the GPe aggravates and lesion of the GPi eliminates LID respectively. Altogether, the available data does not sustain the model’s prediction that LID are mediated by enhanced inhibition from the GPe over the STN rendering the GPi hypoactive and causing disinhibition of the thalamocortical projection.

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Clinical Observations (table 3) A large number of trials have now shown that pallidotomy has a very profound therapeutic effect against LID [70, 71]. These comprise both ‘peak of dose chorea’ and ‘diphasic dyskinesias’ as well as ‘off’ dystonic postures. Interestingly, this effect is present even when there is no improvement in motor cardinal features. Pallidotomy also eliminates hemiballism in humans [68, 69]. The same antidyskinetic effect was described many years ago in monkeys by Carpenter et al. [72] who showed how pallidotomy eliminated the hemiballism induced by a prior STN lesion. Lesion of the motor thalamus (i.e. ventralis lateralis) also has a definite effect against LID [73]. The effect of lesioning the STN in PD are also of interest in the setting of the present discussion. In MPTP monkeys, lesion of the STN was not always accompanied by dyskinesias and when they occurred these were almost always of mild intensity. A review of the literature indicates that hemichoreaballism was a very rare complication of lesions of the thalamus and subthalamic region [74]. There are even examples of patients with hemiballism following stereotactic surgery in whom the STN appeared intact. Our recent and ongoing experience clearly indicates that it is possible to produce a therapeutically valid lesion of the sensorimotor region of STN without causing dyskinesias [75]. It may be concluded therefore, that the model does not account for the main established observations regarding dyskinesias in PD. In fact, the effects of pallidotomy and subthalamotomy are the opposite of what the model predicts, i.e. pallidotomy should induce dyskinesias but it actually abolishes while subthalamotomy is not necessarily accompanied by dyskinesias.

Conclusions The model has provided a conceptual framework for the pathophysiology of the basal ganglia which has fueled intense research and led to refined therapeutic strategies for PD. However, it is difficult to understand the parkinsonian state simply as the result of increased inhibitory output from the basal ganglia and the dyskinetic state as the consequence of reduced output. The view of parkinsonism and dyskinesias as opposite poles of basal ganglia motor manifestations cannot be sustained. We believe dyskinesias represent the disruption of an essential function of the normal basal ganglia, which is to ensure the routine, ‘automatic’ selection and execution of some motor tasks [76]. Modifications in neuronal pattern of discharges (i.e. temporal domain) and the role of the exquisite somatotopic arrangement of the basal ganglia

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(i.e. spatial domain) may well account for the diversity of motor manifestations observed in PD. Problems and paradoxes mainly reflect our lack of knowledge and understanding. We like to postulate that further understanding of the subcircuitries [77, 78] which reciprocally links the GPe, STN and GPi and their brainstem projections will lead to a major revision of present concepts.

References 1 2 3 4

5 6 7

8 9 10 11 12

13 14

15

16

17 18

Albin R, Young A, Penney J: The functional anatomy of basal ganglia disorders. J Neurosci 1989; 12:336–374. DeLong MR: Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281–285. Crossman AR: Primate models of dyskinesia: The experimental approach to the study of basal ganglia-related involuntary movement disorders. Neuroscience 1987;21:1–40. Crossman AR, Mitchell IJ, Jackson A, Sambrook MA: Chorea and myoclonus in the monkey induced by gamma-aminobutyric acid antagonism in the lentiform complex: The site of drug action and a hypothesis of the neural mechanisms of chorea. Brain 1988;111:1211–1233. DeLong MR, Crutcher MD, Georgopoulos AP: Primate globus pallidus and subthalamic nucleus: Functional organization. J Neurophysiol 1985;53:530–543. Parent A, Cicchetti F: The current model of basal ganglia organization under scrutiny. Mov Disord 1998;13:199–203. Levy R, Hazrati LN, Herrero MT, Vila M, Hassani OK, Mouroux M, Ruberg M, Asensi H, Agid Y, Fe´ger J, Obeso JA, Parent A, Hirsch EC: Re-evaluation of the functional anatomy of the basal ganglia in normal and parkinsonian states. Neuroscience 1997;76:335–343. Obeso JA, Rodriguez MC, DeLong MR: Pathophysiology of the basal ganglia: A critical review. Adv Neurol 1997;74:3–18. Obeso JA, Guridi J, DeLong MR: Surgery for Parkinson’s disease. J Neurol Neursurg Psychiatry 1997;62:2–8. Lang AE, Lozano A, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:1036–1042. Kunzle H: Projections from the primary somatosensory cortex to basal ganglia and thalamus in the monkey. Exp Brain Res 1977;30:481–492. DeLong MR, Georgopoulos AP: Motor functions of the basal ganglia; in Brookhart JM, Mountcastle VB, Brooks VB, Geiger SR (eds): Handbook of Physiology. The Nervous System: Motor Control. Bethesda, American Physiological Society, 1981, sect 1, vol 2, part 2, pp 1017–1061. Hikosaka O, Wurtz RH: Visual and oculomotor functions of monkey substantia nigra pars reticulata. IV. Relation to superior colliculus. J Neurophysiol 1983;49;1285–1391. Gerfen RC, McGinty JF, Young WS: Dopamine differentially regulates dynorphin, substance P, and enkephalin in striatal neurons: In situ hybridization histochemical analysis. J Neurosci 1991; 11:1016–1031. Duty S, Henry B, Crossman AR, Brotchie JM: Topographical organization of opioid peptide precursor gene expression following repeated apomorphine treatment in 6-hydroxydopamine-lesioned rat. Exp Neurol 1998;150:223–234. Herrero MT, Augood SJ, Hirsch EC, Javoy-Agid F, Luquin MR, Agid Y, Obeso JA: Effects of L-dopa on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum. Neuroscience 1995;68:1189–1198. Wichmann T, DeLong MR: Functional and pathophysiological models of the basal ganglia. Curr Opin Neurobiol 1996;6:751–758. Fillion M, Tremblay L: Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991;547:142–151.

Obeso/Guridi/Rodriguez-Oroz/Macias/Rodriguez/Alvarez/Lopez

74

19

20

21

22

23 24 25

26

27 28 29

30

31 32 33

34

35

36

37

38

Miller WC, DeLong MR: Altered tonic activity of neurons in the globus pallidus and subthalamic nucleus in the primate MPTP model of parkinsonism; in Carpenter MB, Jayaraman A (eds): The Basal Ganglia II. New York, Plenum Press, 1987, pp 415–427. Mitchell IJ, Jackson A, Sambrook MA, Crossman AR: Common neural mechanisms in experimental chorea and hemiballismus in the macaque monkey: Evidence from 2-deoxyglucose studies. Brain Res 1985;339:346–350. Crossman AR, Mitchell IJ, Jackson A, Sambrook MA: The role of the subthalamic nucleus in experimental chorea: Evidence from 2-deoxyglucose metabolic mapping and horseradish peroxidase tracing studies. Brain 1989;112:1533–1548. Mitchell IJ, Boyce S, Sambrook MA, Crossman AR: A 2-deoxyglucose study of the effects of dopamine agonists on the parkinsonian primate brain. Implications for the neural mechanisms that mediate dopamine agonist-induced dyskinesia. Brain 1992;115:809–824. Crossman AR: A hypothesis on the pathophysiological mechanisms that underlie levodopa or dopamine agonist-induced dyskinesia in Parkinson’s disease. Mov Disord 1990;5:100–108. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penny JB, Young AB: Differential loss of striatal projection neurons in Huntington’s disease. Proc Natl Acad Sci USA 1988;85:5733–5737. Fillion M, Tremblay L, Bedard PJ: Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991;547: 152–161. Matsumara M, Tremblay L, Richard H, Fillion M: Activity of pallidal neurons in the monkey during dyskinesia induced by injection of bicucilline in the external pallidum. Neuroscience 1995; 65:59–70. Bergman H, Wichmann T, Karmon B, DeLong MR: The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 1994;72:507–519. Starr PA, Vitek JL, Bakay RAE: Ablative surgery and deep brain stimulation for Parkinson’s disease. J Neurosurg 1998;43:989–1013. Rodriguez MC, Guridi J, Gorospe A, Mozo A, Ramos E, Linazasoro G, Obeso JA: Neurophysiological characteristics of the subthalamic nucleus in Parkinson’s disease. Neurology 1997;48(suppl 1): 433A. Hutchinson WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, Lozano AM: Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998;44:622–628. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1438. Aziz TZ, Peggs D, Sambrook MA, Crossman AR: Lesion of subthalamic nucleus for the alleviation of MPTP-induced parkinsonism in the primate. Mov Disord 1991;6:288–293. Guridi J, Herrero MT, Luquin MR, Guillen J, Ruberg M, Laguna J, Vila M, Javoy-Agid F, Agid Y, Hirsch E, Obeso JA: Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. Brain 1996;119:1717–1727. Wichmann T, Bergman H, DeLong MR: The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of Parkinson’s disease. J Neurophysiol 1994;72:520–527. Eidelberg D, Moeller JR, Ishikawa T, Dhawan V, Spetsieris P, Silbersweig D, Stern E, Woods RP, Fazzini E, Dogali M, Beric A: Regional metabolic correlates of surgical outcome following unilateral pallidotomy for Parkinson’s disease. Ann Neurol 1996;39:450–459. Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R: Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997;42:283–291. Brown RG, Dowsey P, Brown P, Jahanshani M, Pollak P, Benabid AL, Rodriguez-Oroz MC, Obeso JA, Rothwell JC: Impact of deep brain stimulation on upper limb akinesia in Parkinson’s disease. Ann Neurol 1999;45:473–488. Limousin P, Brown RG, Jahanshani M, Assselman P, Quinn NP, Thomas D, Obeso JA, Rothwell JC: The effects of posteroventral pallidotomy on the preparation and execution of voluntary hand and arm movements in Parkinson’s disease. Brain 1999;122:303–314.

Functional Models of the Basal Ganglia

75

39 40

41 42

43 44

45 46 47 48

49

50 51 52 53 54 55

56 57

58 59

60 61

Rodriguez M, Abdala P, Obeso JA: Excitatory responses in the direct nigrostriatal pathway. Effect of nigrostriatal lesion. Mov Disord 2000; in press. Vila M, Levy R, Herrero MT, Ruberg M, Faucheux B, Obeso JA, Agid Y, Hirsch E: Consequences of nigrostriatal denervation on the functioning of the basal ganglia in human and nonhuman primates: An in situ hybridization study of cytochrome oxidase subunit I mRNA. J Neurosci 1997; 17:765–773. Hassani OK, Mouroux M, Feger J: Increased subthalamic activity after nigral dopaminergic lesion is independent of disinhibition via the globus pallidus. Neuroscience 1995;72:105–115. Vila M, Pe´rier C, Fe´ger J, Yelkin J, Faucheux B, Ruberg M, Raisman-Vozani R, Agid Y, Hirsch EC: Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements. Eur J Neurosci 2000;12:1–9. Robledo P, Feger J: Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: Electrophysiological data. Brain Res 1990;518:47–54. Benazzouz A, Piallat B, Pollak P, Benabid AL: Responses of substantia nigra pars reticulata and globus pallidus complex to high-frequency stimulation of the subthalamic nucleus. Neurosci Lett 1995;189:77–80. Hamada I, DeLong MR: Excitotoxic acid lesions of the primate subthalamic nucleus result in reduced pallidal neuronal activity during active holding. J Neurophysiol 1992;68:1859–1866. Plenz D, Kitai ST: A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 1999;400:677–682. Lavoie B, Smith Y, Parent A: Dopaminergic innervation of the basal ganglia in the squirrel monkey as revealed by tyrosine hydroxylase immunohistochemistry. J Comp Neurol 1994;344:210–231. Kreiss DS, Mastropietro CW, Rawji S, Walters JR: The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson’s disease. J Neurosci 1997;17: 6807–6819. Davis KD, Taub E, Houle S, Lang AE, Dostrovsky JO, Tasker RR, Lozano AM: Globus pallidus stimulation activates the cortical motor system during allevation of parkinsonian symptoms. Nat Med 1997;3:671–674. Horak FB, Nutt JG, Nasher LM: Postural inflexibility in parkinsonian subjects. J Neurol Sci 1992; 111:46–58. Rodriguez MC, Guridi J, Alvarez L, Mewes K, Macias R, Vitek J, DeLong MR, Obeso JA: The subthalamic nucleus and tremor in Parkinson’s disease. Mov Disord 1998;13(suppl 3):111–118. Cox ChL, Sherman SM: Glutamate inhibits thalamic reticular neurons. J Neurosci 1999;19:6694–6699. O’Suilleabhain PE, Matsumoto JY: Time frequency analysis of tremors. Brain 1998;121:2127–2134. Hurtado JM, Gray CM, Tamas LB, Sigvardt KA: Dynamic of tremor-related oscillations in the human globus pallidus: A single case study. Proc Natl Acad Sci USA 1999;96:1674–1679. Gross RE, Lombardi WJ, Lang AE, Duff J, Hutchinson WD, Saint Cyr JA, Tasker RR, Lozano AM: Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson’s disease. Brain 1999;122:405–416. Hoover Strick P, Hoover JE, Strick PL: Multiple output channels in the basal ganglia. Science 1993;259:819–821. Nambu A, Takada M, Inase M, Tokuno H: Dual somatotopical representations in the primate subthalamic nucleus: Evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area. J Neurosci 1996;16:2671–2683. Marsden CD, Obeso JA: The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson’s disease. Brain 1994;117:877–897. Baron MS, Vitek JL, Bakay RAE, Green J, Kaneoke Y, Hashimoto T, Turner RS, Woodard JL,Cole SA, McDonald WM, DeLong MR: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355–366. Lang AE, Lozano A: Parkinson’s disease. N Engl J Med 1999;339:1130–1143. Herrero MT, Augood SJ, Hirsch EC, Javoy-Agid F, Luquin MR, Agid Y, Obeso JA, Emson PC: Effects of L-dopa in preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum. Neuroscience 1995;68:1189–1198.

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Levy R, Herrero MT, Ruberg M, Villares J, Faucheaux B, Guridi J, Guillen J, Luquin MR, JavoyAgid F, Obeso JA, Agid Y, Hirsch EC: Effects of nigrostriatal denervation and L-dopa therapy on the GABAergic neurons of the striatum in MPTP-treated monkeys and Parkinson’s disease: An in situ hybridization study of GAD67 mRNA. Eur J Neurosci 1995;7:1199–1209. Blanchet PJ, Boucher R, Bedard PJ: Excitotoxic lateral pallidotomy does not relieve L-dopa-induced dyskinesia in MPTP parkinsonian monkey. Brain Res 1994;650:32–39. Papa SM, Desimone R, Fiorani M, Oldfield EH: Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesia. Ann Neurol 1999;46:732–738. Merello M, Balej J, Delfino M, Cammarota A, Betti O, Leiguarda R: Apomorphine induces changes in GPi spontaneous outflow in patients with Parkinson’s disease. Mov Disord 1999;14:45–49. Hutchison WD, Levy R, Dostrovsky JO, Lozano AM, Lang AE: Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann Neurol 1997;42:767–775. Lozano A: Dyskinesia meeting. Ann Neurol 2000(suppl 1); in press. Vitek JL, Chockkan V, Zhang JY, Kaneoke Y, Evatt M, DeLong MR, Triche S, Mewes K, Hashimoto T, Bakay RAE: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22–35. Suarez JI, Vrehagen-Metman L, Reich SG, Dougherty PM, Hallett M, Lenz FA: Pallidotomy for hemiballismus efficacy and characteristics of neuronal activity. Ann Neurol 1997;42:807–810. Vitek JL, Bakay RAE: The role of pallidotomy in Parkinson’s disease and dystonia. Curr Opin Neurol 1997;10:332–339. Bronstein JM, DeSalles A, DeLong MR: Stereotactic pallidotomy in the treatment of Parkinson’s disease. Arch Neurol 1999;56:1064–1069. Carpenter MB, Whittier JR, Mettler FA: Analysis of choreic hyperkinesia in the rhesus monkey: Surgical and pharmacological analysis of hyperkinesia resulting from lesions in the subthalamic nucleus of Luys. J Comp Neurol 1950;92:293–331. Narabayashi H, Yokochi F, Nakajima Y: Levodopa-induced dyskinesia and thalamotomy. J Neurol Neurosurg Psychiatry 1984;47:831–839. Guridi J, Obeso JA: The subthalamic nucleus, hemiballismus and Parkinson’s disease. Reappraisal of a neurosurgical dogma. In preparation. Alvarez L, Macias R, Guridi J: Dorsal subthalamotomy for Parkinson’s disease. Mov Disord 2000; in press. Marsden CD: The mysterious motor function of the basal ganglia. Neurology 1982;32:514–539. Shink E, Bevan MD, Bolam JP, Smith Y: The subthalamic nucleus and the external pallidus: Two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience 1996;73:335–357. Smith Y, Bevan MD, Shink E, Bolam JP: Microcircuitry of the direct and indirect pathways of the basal ganglia. Neuroscience 1998;86:353–387.

Dr. J.A. Obeso, Departamento de Neurologia, Clinica Universitaria, Apdo 192, E–31080 Pamplona (Spain) Tel. +34 948 25 54 00, Fax +34 948 29 65 00, E-Mail [email protected]

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Patient and Technical Considerations Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 78–90

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Movement Disorder Surgery: Patient Selection and Evaluation of Surgical Results Eng-King Tan, Joseph Jankovic Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Tex., USA

The cornerstone of therapy for Parkinson’s disease (PD) is dopamine replacement with levodopa. The early years of treatment with levodopa are most predictable in obtaining a satisfactory therapeutic response. However, chronic administration can lead to problematic side effects, chiefly motor fluctuations and dyskinesias, in the majority of patients [1]. Surgical therapy can compliment medical treatment in the more advanced cases of PD. There has been an enormous resurgence of interest in functional surgery in PD in recent years as evidenced by the growing number of reported clinical trials in this area. Better understanding of the pathophysiology of basal ganglia dysfunction underlying PD and advancements in neuroradiological, neurosurgical and neurophysiological techniques have contributed to this trend. In this chapter, we will review the general and specific indications in selecting patients for PD surgery as well as the qualitative and quantitative clinical and imaging parameters used to evaluate and monitor the benefits and progress, preoperatively and postoperatively. The potential shortcomings of the various tests and clinical scales will also be discussed.

Selection of Patients Functional stereotactic surgery should be performed in specialized centers where expertise, technology, equipment, and skilled personnel are available to maximize the benefits and minimize the risks of unwanted adverse events. The decision about which specific type of surgery should be recommended must

be based on a balanced review of current knowledge of the indications and surgical outcomes, personal experience by the surgeon, and a consensus opinion by both the neurologist and neurosurgeon, along with active participation of the patient and the family. There are no rigid rules to follow in the selection process, as every case has to be individualized according to symptomatology and specific needs of the patient. A careful selection process however, should increase the likelihood of beneficial response.

Inclusion Criteria In the absence of a specific clinical marker or a diagnostic test, PD can only be confirmed at autopsy. However, several clinical diagnostic criteria have been proposed for diagnosis of PD [2, 3]. There can be up to 8.1–25% inaccuracy in the initial diagnosis even in the hands of PD experts [4]. Since the diagnostic inaccuracy improves with follow-up, it is advisable to consider patients for surgery only when there is a considerable duration of the disease (at least 5 years). This is reasonable considering the fact that most patients develop complications of fluctuations and dyskinesias, the chief indications for surgery, only after 5–6 years of levodopa therapy [1]. Response to levodopa has been shown to be a preoperative indicator of good clinical outcome for stereotaxic pallidotomy [5]. Kazumata et al. [5] found that in their pallidotomy patients, clinical outcome significantly correlated with preoperative CAPIT (Core Assessment Program for Intracerebral Transplantation) [3] score change with levodopa administration and with preoperative 18Ffluorodeoxyglucose positron emission tomography measurements of lentiform glucose metabolism. They suggested that assessment of clinical response to levodopa could provide a measure of the patient’s capacity to reduce baseline pallidal hyperactivity and to modulate the complex cortico-striato-thalamic motor network. The patient’s symptoms (bradykinesia, rigidity, tremor) must be disabling, despite adequate trial of medications. Surgery is also a consideration in those who could not tolerate the adverse effects of the various drugs. Dyskinesias and Motor Fluctuations Most pallidotomy series reported robust effect on levodopa-induced dyskinesias, with improvement in the contralateral dyskinesia ranging from 65 to 100% [6]. Marked improvement in dyskinesias could be achieved during the ‘on’ state following chronic bilateral globus pallidus interna (GPi) [7] and subthalamic nucleus (STN) stimulation [8]. The effect of grafting on dyskinesia is less clear. It has been shown that the percentage ‘on’ time with dyskinesia

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is reduced at up to 24 months after grafting, though dyskinesia is often increased in the early postoperative period [9]. Tremor Thalamotomy [10] and thalamic ventral intermediate nucleus (VIM) stimulation [11] are very effective for the treatment of PD tremor. Good results have also been reported with STN stimulation [8]. Pallidotomy has also been shown to improve contralateral tremor, but perhaps not to the same degree as the other procedures. Bradykinesia Of all the motor symptoms of PD, bradykinesia appears to correlate best with nigrostriatal dopaminergic deficiency [12]. In one study of patients evaluated by a ‘blinded’ review of videotapes, pallidotomy improved ‘off’ motor scores by 13.6%, 3 months after surgery [13]. Other pallidotomy studies also reported significant improvement in ‘off’ disability with little or no improvement in ‘on’ function. As unilateral pallidotomy improves symptoms predominantly on the contralateral side, simultaneous or staged bilateral pallidotomy may lead to even more robust benefit in overall motor function [14]. However, there may be a higher risk of speech and cognitive problems [14]. Bilateral STN and GPi stimulation have also been reported to improve bradykinesia and ‘off’ motor scores [8]. Grafting can reduce the ‘off’ phase, and the severity of the parkinsonian features (rigidity, bradykinesia) during the ‘off’ state [9]. DBS, which is reversible, may be preferred to lesioning in patients who want to preserve other potential options in the future (e.g. grafting). DBS can also reduce the risk of bilateral lesions if performed contralateral to pre-existing lesions in the VIM or GPi. Further, the effects of DBS may be objectively studied by simply turning the stimulator ‘on’ and ‘off’. However, its high cost, risk of infections, need for battery change, and frequent visits for adjustment and re-programming of parameters limit the usefulness of this surgical intervention.

Exclusion Criteria Atypical Parkinsonism Atypical clinical features indicative of multiple system involvement such as absence of tremor, the presence of supranuclear gaze palsy, dysautonomia, dementia, pyramidal signs, and poor response to levodopa suggest the presence of a neurodegenerative disease other than PD, respond poorly to surgical interventions. There are exceptions, however. For example, one patient with

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peripherally induced parkinsonism has been reported to benefit from unilateral pallidotomy [15]. Severe Brain Atrophy or Ischemic Changes on Imaging Studies Although mild cerebral atrophy and ischemic lesions are relatively common in the elderly, severe cerebral atrophy may pose technical difficulties during surgery and the presence of severe ischemic changes greatly increases operative risk. However, we have shown that mild vascular changes on preoperative magnetic resonance imaging (MRI), have little or no effect on benefit from pallidotomy [16]. Depression, Psychiatric Illness, Dementia, and Alcohol Abuse Besides the lack of insight and poor judgement that could impair their full understanding of the relative risks and benefits of surgery, patients with depression, dementia, or other neurobehavioral disorders are poor candidates for surgical intervention because their outcome may be difficult to assess. Patients with dementia have been shown to have less overall benefit. Mild cognitive deficits, frequently associated with advanced PD, may not, however, be an absolute contraindication to surgery. In our experience, there is initial worsening in short and long delay memory, executive functions and verbal fluency during the first 3 months postoperatively, but 12 months after surgery most of these functions return to baseline with the exception of speed of mental processing [17]. However, these changes rarely result in a meaningful decline in cognitive functioning. Our studies have demonstrated that despite initial fears, patients with young-onset PD, prolonged duration of disease, and mildly impaired cognition, memory and learning do not deteriorate 12 months after pallidotomy [17]. Terminal Illness or Systemic Disease with Organ Dysfunction These patients are usually excluded because of the limited life span and higher surgical risk of complications. Severe PD The benefit/risk ratio of surgery in severely debilitated patients is low and such patients should be excluded from the surgical trials. Advanced Age The state of patient’s physical and mental health, rather than age, is the primary consideration in selection of suitable surgical candidates. Uitti et al. [18] in their study, found that the safety and benefits of pallidotomy were similar in the young (=65 years) and the older (?65 years, mean age 71.4 years) group of patients. Other authors have revealed greater improvement of

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the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores in the ‘off’ state with age [19]. Because of high operative risk and low life expectancy, however, most surgeons do not operate on patients above 80 years of age. When candidates are selected for fetal transplantation, there is a tendency to select younger patients as the effects of grafting are often delayed by several months. Preliminary results from a recent fetal transplant-controlled trial suggest significant improvement of bradykinesia and rigidity only in younger patients (=60 years old) [Fahn, pers. commun.].

Methods of Evaluation A multidisciplinary approach, consisting of a neurologist, neuropsychologist, and a neurosurgeon, is generally needed to fully evaluate potential candidates for surgery. The CAPIT, initially developed to evaluate potential candidates for brain grafting, has been adapted for other types of surgeries, including ablative and stimulation procedures. The protocol comprises four clinical rating scales: UPDRS [20], Hoehn & Yahr (H&Y) Staging [21], Dyskinesia Rating Scale, and Self-Reporting Questionnaire, certain timed tests, and number of clinical and imaging evaluations, inclusion and exclusion criteria for patient selection, and definitions of ‘off’, ‘on’ periods and levodopa responsiveness. Some investigators have added other methods of quantitative assessment or refined the protocol to address special questions. For example, we have employed, in addition to the clinical assessments, various quantitative techniques such as reaction and movement time, Pegboard, gait analysis, and tests for balance and postural control [22]. However, the lack of assessment of cognitive functions and quality of life in the CAPIT protocol makes it incomplete. Some investigators have raised concerns regarding certain timed testings and validity of the dyskinesia rating scale. For instance, the ‘pronationsupination test’ and the ‘finger dexterity test’ introduced a subjective component to the assessment. In particular, the ‘finger dexterity test’ may be difficult to perform by a bradykinetic patient and associated dyskinesias can interfere with proper execution of this test. The Obeso Dyskinesia Rating Scale, used in the CAPIT, although a validated instrument, does not include duration of dyskinesia and only evaluates dystonia and chorea as two broad categories of levodopa-related hyperkinesias. Hence, these scales do not accurately capture the duration, severity, topography and phenomenology of levodopa-related dyskinesias. Subsequent revisions and refinements were designed to improve the assessments of levodopa-related dyskinesias. Members of NECTAR (Network for European CNS Transplantation and Restoration) proposed the development of a common evaluation program for all types of PD surgeries in

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1999 [23]. They formulated the CAPSIT-PD (Core Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease). In this protocol, some of the motor evaluations were simplified and included cognitive assessment and quality-of-life scales. Neurophysiological and quantified video evaluations were not included. Preoperative Evaluation The preoperative evaluation generally involves full documentation of the history, demographics, medical and surgical history, detailed history of types and dosages of medications and allergies. General clinical examination, including cardiac and respiratory systems, blood pressure (supine and standing), pulse rate and weight are also carefully recorded. After a decision has been made by the neurological and neurosurgical team that a patient is a suitable candidate for surgery, a fully informed consent should be discussed with the patient and the family. Specific Evaluation Preoperative clinical evaluation should be done over a period of at least 3 months to establish reliable baseline clinical status, ensure stability of condition and optimize dosages of medications. The baseline assessment should be done within 1 week before surgery. Immediate postoperative assessment is recommended to look for any evidence of focal deficit or other surgery-related complication. Patients with DBS should have the placement of their stimulating electrode verified by a CT scan, although some studies have suggested that MRI scans can be performed safely in the setting of DBS. At the 2-week follow-up, the patient should be examined for surgery-related complications (e.g. focal neurological deficits). The deep brain stimulator is often turned ‘on’ at that time and programmed. The assessment at the 3-month follow-up visit is critical because the neurologic status is not usually confounded by the effects of surgery or disease progression. Patients should be evaluated every 3 months thereafter. At each visit, information regarding levodopa dosage, latency and duration of clinical response, location and severity of any dyskinesias and patient’s clinical global impression should be noted. While not always possible, changes to dosages of anti-parkinsonian medications are kept to a minimum so as not to confound the results. In addition, clinical rating scales such as the UPDRS is used to assess patient’s motor and cognitive states in practically defined ‘off’ (at least 12 h after the last dose of levodopa, typically in the morning after omitting the bedtime dose and within 1 h of rising to avoid potentially confounding effects of sleep) and when they are in their best ‘on’ state (typically 30–60 min after their usual dose of levodopa when both physician and patient agree that maximal therapeutic effect is present). If the practi-

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cally defined ‘off’ is not identical to the worst ‘off’, then separate assessment under worst ‘off’ can be carried out. Unified Parkinson’s Disease Rating Scale The UPDRS provides a quantitative assessment of the mental and motor function in PD [20]. It consists of 6 parts. Each item has a rating score of 0 (normal) to 4 (worst) unless otherwise specified. Patients with motor fluctuations should be scored during their ‘off’ and ‘on’. Part I consists of 4 items, provides an overall gross assessment of the mental state, mood, behavior and motivation. In patients who score q2 on any of these items, a Mini-Mental State Test (MMSE) should be performed. The MMSE is a 30-point scale, consisting of orientation questions and various performance tasks. It is easy to use and should be used routinely in all preoperative baseline assessments and postoperatively at 3 months and every 12 months thereafter. Part II includes assessment of performance of Activities of Daily Living (ADL). It comprises 13 items (items 5–17) that are relevant to daily functioning as reported by the patient. Hence the total score can range from 0 (normal) to 52 (worst). There is an inherent degree of subjectivity in this subscale, and accurate ‘on’ and ‘off’ assessment may not be possible, for example if the patient chooses to perform certain tasks only during the ‘on’ state. Part III includes the motor scores and comprises 14 items (items 18–31). Each item allows rating of movements that are commonly affected in PD. The motor scores range from 0 (normal) to 108 (worst). There are several limitations of this part of the UPDRS. First, the patient may not be in practically defined ‘off’ state or in optimal ‘on’ state. Action tremor may be difficult to assess if the patient has a re-emergent tremor during posture holding [24]. The manner of eliciting the action tremor and its type is also not specified. Presence of dyskinesia, dystonia and severe action tremor can affect the evaluation of motor performance. The method of assessment of the various items in the motor section is not clearly explained. For instance, the relative importance of speed and full execution of the movements (e.g. finger-tapping, pronation/ supination) is not emphasized and investigators may differ on their interpretation. The force of the pull for the testing of postural reflexes is also subjective. Nevertheless, the development of a teaching tape for the motor section of the UPDRS is extremely useful for relatively inexperienced investigators, and can serve as a reference for further discussion on the shortcomings and improvements in the section [25]. Gait and Balance Rating Scale is currently being developed [Jankovic, unpubl.]. Part IV documents complications of therapy. Some of its items here are not graded. Part V is a modified version of the H&Y Staging and in Part VI, the Schwab and England Scale measures disability. Specific items in the UPDRS also allow evaluation of cardinal signs such

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as rigidity (item 22), bradykinesia (items 23–25) and tremor (items 20–21) in PD. Despite limitations of some of the subscales in the UPDRS, several studies have demonstrated good inter- and intra-rater reliability [26, 27]. However, certain individual items like facial expression and sensory symptoms have been shown to be less reliable [26]. Louis et al. [27], in their study of inter-rater reliability between physician and patient, administered the historical section of the UPDRS (items 1–17) and reported highest reliability with items such as swallowing and salivation, probably because these two items may be less ambiguous during questioning. Dyskinesia Rating Scale (CAPIT) score is the arithmetic mean of the intensity and duration scores. Subsequently, Goetz et al. [28] modified and validated this scale based on videotaped ratings of performance of motor tasks. While useful, it does not allow proper measurement of site, severity and duration of the dyskinesias or associated symptoms such as pain, which may be relevant in some studies. Also, the utility of this Modified Dyskinesia Scale (version 2.0) is limited because the examination requires the use of props, such as empty cup and a lab coat. H&Y stage divides severity of PD into 5 stages (I–V), starting with stage 1, which indicates unilateral disease to the most severely disabled PD, stage 5 [21]. Modified H&Y scale includes an intermediary stage between I-II and II-III, which allows greater division of the severity. Patients with H&Y stage 3 or 4 and better during the ‘off’ stage are the most typical PD surgery candidates; H&Y stage 5 during ‘off’ and stage 4 during ‘on’ is usually an exclusion criterion for surgery. H&Y staging has good correlation with UPDRS [26] and striatal uptake of 18F-labeled deoxyglucose [29]. Schwab and England Scale measures overall functional status based on activities of daily living, both in the ‘off’ and ‘on’ state. It has a score of 0–100%, with increments of 5–10%. While there is some degree of subjectivity, and similar scores may be reported in patients with different motor disability, this scale is generally easy to use and the scores have close clinical correlation in patients with mild PD. Clinical Global Impression and Self-Reporting Patients and evaluating neurologist are often asked to rate and compare the parkinsonian symptoms before and after surgery. The global outcome is rated on a 5-point scale from 0 (worse), to 4 (markedly improved). While subjective, it does provide an overall measure of surgical effect. The use of a diary by the patient to report periods of ‘off’, ‘on’, ‘on with dyskinesias’ for 1 week per month for 3 months preoperatively and thereafter after surgery is also useful. For instance, patients have reported increased ‘on’ and decreased ‘off’ after STN stimulation. Self-monitoring of physical disturbance in PD has been demonstrated to be a reliable measurement parameter. The overall impact of surgery on the quality of life should be assessed using validated

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scales, such as the Parkinson’s Disease Quality-of-Life Questionnaire (PDQL) [30]. This measure is important to evaluate the overall impact of surgery. Timed Tests Various timed tests are used to assess bradykinesia in PD. In the CAPIT [3] protocol, four timed tests are recommended, which should be performed in both the best ‘on’, practically defined ‘off’, and the worst ‘off’ if this is different from the practically ‘off’ period. These are designed to measure bradykinesia of upper extremities. The four tests include: pronation-supination test, hand-arm movement between two points, finger dexterity and standwalk-sit test. Postural and gait control is also assessed by the stand-sit-walk test. Due to the possible subjectivity of the ‘pronation-supination test’ and ‘finger dexterity test’, the CAPSIT committee [23] recommended two timed tests for motor evaluation. First, a hand-arm movement between two points 30 cm apart and to use a simple device to measure for a fixed time (20 s), rather than a fixed number of movements in order to obtain better quantification and standardization. Second, the ‘stand-sit test’ is simplified to gait only, without stand and sit and involves counting of number of steps. We have found certain timed tests using movement time (MT), simple reaction time (SRT) and the Purdue Pegboard (PP) to be a useful quantitative index of bradykinesia to assess objectively the effects of surgery [31]. Other studies have shown excellent correlation between PP scores and bradykinesia subscale (speech, facial expression, generalized bradykinesia, and six repetitive movements of the limbs) with a reduction in 18F-6-fluorodopa uptake measured by positron emission tomography (PET) [12]. ‘Blinded’ Assessment of Motor Function The reported clinical effects of PD surgery vary between series because of many factors, including different patient populations, differences in surgical techniques (lesion size, location, localization methods), and different methods of assessment including lack of blinded rating. To remove the bias of open assessment, we randomized videos of 34 patients recorded in the ‘off’ state immediately before and 3 months after stereotactic pallidotomy [13]. The video recording included assessments of writing, a standardized passage reading, and the UPDRS motor examination except hand pronation/supination, and postural stability. Subjects wore caps to avoid unblinding the observers. Tapes were edited into randomly sequenced segments and blindly rated by two observers at separate times. Improvement was seen in the ‘off’ time UPDRS score and contralateral tremor, gait, and arising from the chair. Similar results were obtained by others using the same protocol. Blinded review of videotapes can provide an objective way to assess for improvement in motor function of

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patients undergoing PD surgery. However, some of its limitations include inability to assess rigidity, intermittent rest tremor, long duration of levodopa response and cognitive function. Neuropsychological Testing The CAPSIT [23] recommends preoperative and follow-up evaluations of general and behavioral functions, executive functions, explicit and procedural memory. The Minnesota Multiphasic Personality Inventory (MMPI) and the Minnesota Asberg Depression Rating Scale (MADRS) are used to exclude patients with major behavioral or severe psychiatric illness [23]. Studies of cognitive changes following pallidotomy vary in their findings [17]. However, certain variables such as side of surgery, age at onset, duration of PD, and baseline cognitive function may play a role in influencing the outcome [17]. Magnetic Resonance Imaging A preoperative (0–3 months before surgery) MRI is essential to help detect atypical parkinsonism and to establish baseline MRI for interpretation of possible postoperative changes or complications. Hypointensities on T2weighted images extending into the putamen may suggest Parkinson Plus syndromes, such as multiple system atrophy and progressive supranuclear palsy and lead to an exclusion of patient from surgery. A repeat MRI is recommended to be performed within the first week after lesioning surgery to confirm the anatomic location of the lesion and to detect any complications that are clinically asymptomatic and which may influence outcome (e.g. hemorrhage). Further MRIs at 6 months and 1 year are useful since edematous changes seen in the few weeks after surgery may not allow accurate identification of the thermocoagulation site. Although MRI after implantation of the stimulator is not recommended by the manufacturer, a number of investigators have used it to assess placement of DBS implantation [7]. The implanted electrodes are usually positioned as close as possible to the locations of lowest threshold for motor benefit and highest for adverse effects [7]. Positron Emission Tomography PET is the best in vivo method to evaluate the integrity of the nigrostriatal dopaminergic system in humans. Striatal 18F-dopa uptake correlates with dopamine cell loss [32], and clinically with bradykinesia and rigidity in PD patients [12]. PET scanning is particularly useful in assessing patients undergoing fetal nigral transplantation. Various studies have demonstrated its usefulness and importance in the evaluation of survival and function of grafted neuronal cells [9]. The scans are usually performed preoperatively, at 6 months postoperatively, and at 6 monthly or yearly intervals thereafter. However, PET scans

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are expensive and not readily available in many centers. Even in institutions where this technique is available, great experience and expertise are required for accurate analysis and interpretation of the results. Recently developed technique of imaging dopamine transporters using ligands such as 123I-bcarbomethoxy-3b-(4-iodophenyltropane) (CIT) and 123I-fluoropropyl (FP)-bCIT single-photon emission computer tomography (SPECT), is much less costly, and it provides a potential alternative to PET [33] but much more experience needs to be acquired.

Conclusion With improvement and refinement of surgical, neurophysiologic, and neuroimaging techniques, the results of surgical intervention in the treatment of PD and dystonia have markedly improved. In order to make progress in this therapeutic arena, it is critical, however, that only the most suitable candidates are selected. The importance of good clinical judgement in the diagnosis, selection and optimization of treatment of potential surgical candidates, cannot be overemphasized. Although the inclusion of ‘sham’ operations in surgical protocols, such as fetal transplants, raise disturbing ethical questions, it introduces a new standard, previously utilized only in drug trials. Objective, quantitative assessments, using validated clinical scales and timed tests, which are sensitive to detect even subtle changes in parkinsonian symptoms, should improve our ability to select patients who are most suitable for surgery. The common use of standardized, validated assessments, with modifications to suit the individual study objectives, should enable comparison of surgical results.

References 1

2 3 4 5

Jankovic J, Marsden CD: Therapeutic strategies in Parkinson’s disease; in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders, ed 3. Baltimore, Williams & Wilkins, 1998, pp 191–220. Gelb DJ, Oliver E, Gilman S: Diagnostic criteria for Parkinson’s disease. Arch Neurol 1999;56: 33–39. Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, Watts R: Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13. Jankovic J, Rajput AH, McDermott MP, Perl DP: Evolution of diagnosis in early Parkinson’s disease. Arch Neurol 2000 (in press). Kazumata K, Antonini A, Dhawan V, Moeller JR, Alterman RL, Kelly P, Sterio D, Fazzini E, Beric A, Eidelberg D: Preoperative indicators of clinical outcome following stereotaxic pallidotomy. Neurology 1997;49:1083–1090.

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Lai EC, Krauss JK: Indications for pallidal surgery for Parkinson’s disease; in Krauss JK, Grossman RG, Jankovic J (eds): Pallidal Surgery for the Treatment of Parkinson’s Disease and Movement Disorders. Philadelphia, Lippincott-Raven, 1998, pp 113–120. Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Benazzouz A, Benabid AL: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998;121:451–457. Pollak P, Benabid AL, Krack P, Limousin P, Benazzouz A: Deep brain stimulation; in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders, ed 3. Baltimore, Williams & Wilkins, 1998, pp 191–220. Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH, Olanow CW: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol 1999;56: 179–187. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for parkinsonian, essential and other types of tremor. Neurosurgery 1995;45:1743–1746. Ondo WG, Jankovic J, Schwartz K, Almaguer M, Simpson RK: Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology 1998;51: 1063–1069. Vingerhoets FJ, Schulzer M, Calne DB, Snow BJ: What clinical signs of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 1997;41:58–64. Ondo WG, Jankovic J, Lai EC, Sankhla C, Khan M, Ben-Arie L, Schwartz K, Grossman RG, Krauss JK: Assessment of motor function after stereotactic pallidotomy. Neurology 1998;50:434– 438. Scott R, Gregory R, Hines N, Carroll C, Hyman N, Papanasstasiou V, Leather C, Rowe J, Silburn P, Aziz T: Neuropsychological, neurological and functional outcome following pallidotomy for Parkinson’s disease: A consecutive series of eight simultaneous bilateral and twelve unilateral procedures. Brain 1998;121:659–675. Krauss JK, Jankovic J, Lai EC, Rettig GM, Grossman RG: Posteroventral medial pallidotomy in levodopa unresponsive parkinsonism. Arch Neurol 1997;54:1026–1029. Desaloms JM, Krauss JK, Lai EC, Jankovic J, Grossman RG: Posteroventral medial pallidotomy for treatment of Parkinson’s disease: Preoperative magnetic resonance imaging features and clinical outcome. J Neurosurg 1998;89:194–199. Rettig GM, Lai EC, Krauss JK, Grossman RG, Jankovic J: Neuropsychological evaluation of patients with Parkinson’s disease before and after pallidal surgery; in Krauss JK, Grossman RG, Jankovic J (eds): Pallidal Surgery for the Treatment of Parkinson’s Disease and Movement Disorders. Philadelphia, Lippincott-Raven, 1998, pp 211–231. Uitti RJ, Wharen RE Jr, Turk MF, Lucas JA, Finton MJ, Graff-Radford NR, Boylan KB, Goerss SJ, Kall BA, Adler CH, Caviness JN, Atkinson EJ: Unilateral pallidotomy for Parkinson’s disease: Comparison of outcome in younger versus elderly patients. Neurology 1997;49:1072–1077. Kishore A, Turnbull IM, Snow BJ, de la Fuente-Fernandez R, Schulzer M, Mak E, Yardley S, Calne DB: Efficacy, stability and predictors of outcome of pallidotomy for Parkinson’s disease: Sixmonth follow-up with additional 1-year observations. Brain 1997;120:729–737. Fahn S, Elton RL, members of the UPDRS Development Committee: Unified Parkinson’s Disease Rating Scale; in Fahn S, Marsden CD, Calne DB, Goldstein M (eds): Recent Developments in Parkinson’s Disease. Florham Park/NJ, Macmillan Health Care Information, vol 2, 1987, pp 153–164. Hoehn MM, Yahr MD: Parkinsonism: Onset, progression, and mortality. Neurology 1967;17: 427–442. Jankovic J, Lai EC, Ondo WG, Ratkos L, Roberts-Warrior D, Olson S, Krauss JK, Grossman RG: Effects of pallidotomy on gait and balance; in Ruzicka E, Jankovic J, Hallett M (eds): Gait Disorders. Philadelphia, Lippincott/Williams & Wilkins, 2000. Defer GL, Widner H, Marie RM, Remy P, Levivier M: Core Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease. Mov Disord 1999;14:572–584. Jankovic J, Schwartz K, Ondo WG: Re-emergent tremor of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:646–650. Goetz CG, Stebbins GT, Chmura TA, Fahn S, Klawans HL, Marsden CD: Teaching tape for the motor section of the Unified Parkinson’s Disease Rating Scale. Mov Disord 1995;10:263–266.

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Richards M, Marder K, Cote L, Mayeux R: Interrater reliability of the Unified Parkinson’s Disease Rating Scale Motor Examination. Mov Disord 1994;9:89–91. Louis ED, Lynch T, Marder K, Fahn S: Reliability of patient completion of the historical section of the United Parkinson’s Disease Rating Scale. Mov Disord 1996;11:185–192. Goetz CG, Stebbins GT, Shale HM, Lang AE, Chernik DA, Chmura TA, Ahlskog JE, Dorflinger EE: Utility of an objective dyskinesia rating scale for Parkinson’s disease: Inter- and intrarater reliability assessment. Mov Disord 1994;9:390–394. Eidelberg D, Moeller JR, Ishikawa T, Dhawan V, Spetsieris P, Chaly T, Robeson W, Dahl JR, Margouleff D: Assessment of disease severity in parkinsonism with fluorine-18-fluorodeoxyglucose and PET. J Nucl Med 1995;36:378–383. de Boer AGEM, Wijker W, Speelman JD, de Haes JCJM: Quality of life in patients with Parkinson’s disease: Development of a questionnaire. J Neurol Neurosurg Psychiatry 1996;61:70–74. Jankovic J, Ben-Arie L, Schwartz K, Chen K, Khan M, Lai EC, Krauss JK, Grossman R: Movement and reaction times and fine coordination tasks following pallidotomy. Mov Disord 1999;14:57–62. Snow BJ, Tooyama I, McGeer EG, Yamada T, Calne DB, Takahashi H, Kimura H: Human positron tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels. Ann Neurol 1993;34:324–330. Seibyl JP, Marek K, Sheff K, Zoghbi S, Baldwin RM, Charney DS, van Dyck CH, Innis RB: Iodine-123-beta-CIT and iodine-123-FPCIT SPECT measurement of dopamine transporters in healthy subjects and Parkinson’s patients. J Nucl Med 1998;39:1500–1508.

Joseph Jankovic, MD, Professor of Neurology, Director, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, 6550 Fannin, Smith 1801, Houston, TX 77030-3498 (USA) Tel. +1 713 798 5998, Fax +1 713 798 6808, E-Mail [email protected]

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Technical Considerations in Movement Disorder Surgery: Frames, Imaging and Intraoperative Monitoring Todd P. Thompson, L. Dade Lunsford, Douglas Kondziolka University of Pittsburgh School of Medicine and the Center for Image Guided Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pa., USA

The technical success and efficacy of surgery for movement disorders is dependent upon many factors including preoperative patient selection, frame placement, imaging techniques, intraoperative monitoring, intraoperative patient assessment and safe and effective ablation techniques. Error in any one of these areas can predispose the procedure to failure. In this chapter we review the particulars of our technique with reference to each of these factors. This discussion will focus on lesions of the globus pallidus for medically refractory Parkinson’s disease (PD) and the ventrolateral thalamus for tremor amelioration. These concepts are readily transferable to performing stereotactic lesions in other areas of the brain.

Movement Disorder Surgery The complexity of movement disorders makes their treatment both fascinating and demanding for clinicians and researchers, as well as for the estimated 1 million people affected by PD in the United States. The history of the surgical treatment of movement disorders began with Parkinson’s observation that a patient with paralysis agitans had relief of symptoms following a cerebral infarct [1]. Numerous neuroablative techniques were used to alleviate the symptoms of PD, including posterior rhizotomy, cervical sympathectomy, spinal cordotomy, dentatotomy, mesencephalic pedunculotomy, cortical resections and interruption of the internal capsule [1]. Techniques that destroyed components of the corticospinal pathway were successful in relieving tremor

and rigidity proportionate to the resultant weakness. A significant advancement occurred in 1939 when Myers resected the head of the caudate nucleus in one patient, alleviating both tremor and rigidity [2]. He ultimately resected the pallidothalamic fibers in the ansa lenticularis. This was the first time that tremor and rigidity had been relieved by extrapyramidal surgery (without damage to the corticospinal tract or resultant weakness). Cooper [3] relieved tremor and some rigidity, but not bradykinesia when he inadvertently ligated the anterior choroidal artery during aneurysm surgery on a patient who also suffered from PD. Over the ensuing years, numerous surgeons turned their attention to surgical destruction of the basal ganglia. Leksell is credited with choosing the ventral posterolateral pallidum in order to treat bradykinesia and rigidity [4]. After a lapse of over 20 years, Laitinen and coworkers [4, 5] reevaluated and reported the technique renewing interest in posteroventral pallidotomy. The detailed anatomy and physiology of the basal ganglia have been reviewed in prior chapters. The possible targets for ablative surgeries include the globus pallidus interna (GPi), Forel’s field and the ansa lenticularis for diffuse PD symptoms and dystonia, and the ventrolateral nucleus for tremor, and in some cases dystonia.

Patient Selection Appropriate clinical evaluation of the patient is required in order to select those patients who are most likely to benefit from ablative surgery. Eligible patients include those with medically refractory or intolerant PD, essential tremor, and in certain cases, multiple sclerosis, posttraumatic tremor, choreoathetosis and dystonia. The best benefit from pallidotomy for PD is the dramatic and permanent relief of dopa-induced dyskinesias [4, 6]. The benefits both in terms of activities of daily living, relief of rigidity, bradykinesia and tremor are more modest. Ablative surgery has been attempted for other types of movement disorders, but the results have not been favorable. Patients with Parkinson’s plus syndromes (or multiple system atrophy disease) need to be recognized as they respond poorly to current ablative techniques. Such conditions include Shy-Drager syndrome, striatonigral degeneration, progressive supranuclear palsy, olivopontocerebellar degeneration and the ‘multiple system atrophy’ disorders. Clinically, signs of autonomic dysfunction, long tract signs, cerebellar deficits, extraocular movement abnormalities, increased axial tone and a lack of response to L-dopa therapy are indicators that a Parkinson plus disorder exists. In addition to thorough neurological assessment, preoperative computed tomography (CT) and magnetic resonance imaging (MRI) are important to exclude multi-infarct dementia. Positron emission tomography has

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been shown to help detect decreased striatal metabolism of striatonigral degeneration [2]. Other contraindications include coagulopathy, use of antiplatelet agents and uncontrolled hypertension. All aspirin-type products are discontinued 1 week before surgery. Intraoperatively, it is essential to monitor the patients’ systolic blood pressure, as hypertension will significantly increase the risk of an intracerebral hemorrhage. We do not perforate the dura or enter the brain until the systolic pressure is controlled.

Stereotactic Frames The success of modern stereotactic surgery has been fostered by the synergistic advancements in stereotactic and imaging technology. Spiegel and Wycis [7] developed the first human applied stereotactic frame in 1947. Leksell [8] studied in Philadelphia with Wycis at this time. On his return to Stockholm, he reported the development of the first Leksell stereotactic frame in 1949. We currently utilize aluminum Leksell G frames (Elekta Instruments, Tucker, Ga., USA) which are reliable in the MRI field. There are numerous systems available for use, but a survey of members of the American Society of Stereotactic and Functional Neurosurgery reported that the Leksell system was the most frequently utilized during movement disorder surgery [9]. Consistent frame application technique is important to ensure patient comfort, safety, reliable imaging and planing. The frame is applied in approximately 5 min in the stereotactic suite using local anesthesia, occasionally supplemented by intravenous sedation (midazolam and fentanyl). The rare pediatric patient (e.g. dystonia) generally undergoes general anesthesia for stereotactic procedures, if younger than 12 years old. Patients are positioned supine on the stretcher with the head of the bed elevated 60º. The chest is supported with several pillows to flex the body 90º at the waist, allowing greater access to the head. Ideally, two persons assist with frame placement. A nurse helps to stabilize the head while the surgeon and assistant attach the frame. After the head has been prepared with isopropyl alcohol and the patient is comfortably sedated, ear bars are placed into the external auditory canal with a 1-cm2 foam pad on the end of the ear bar. The foam padding alleviates patient discomfort during frame application. The ear bars are intended to assist with symmetric alignment and do not bear the weight of the frame. The surgeon throughout the application supports the frame. Frame alignment in relation to the skull is important for successful operative planning. The base ring of the frame is aligned parallel with the orbitozygomatic plane to facilitate visualization of the anterior and posterior com-

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missures in the same axial image. Although a frame may be shifted slightly toward the side of the planned lesion, this is not essential. Lidocaine (1%) buffered with sodium bicarbonate to reduce the acidic nature is injected into each pin site. The pin length is chosen to attach the frame bars with fingertight torque and without pin protrusion beyond the frame. The diagonal pins are tightened simultaneously to prevent shifting or rotating the frame.

Imaging Although ventriculography and stereotactic CT have been used successfully for functional procedures, most surgeons use MRI for functional stereotactic procedures [9–13]. MRI has the advantage of being noninvasive and provides superior parenchymal resolution to CT. Initial concerns about geometric distortion caused by gradient field nonlinearities and magnetic field inhomogeneities have not proven to be a practical problem with the Leksell system. Gradient field linearity is primarily a function of hardware quality. Magnetic field inhomogeneities arise from both the patient and the equipment. The main magnetic field requires frequent homogeneity adjustments. Keeping targets in the center of the MRI field and using the fiducial systems near the frame can minimize patient-induced magnetic susceptibility. Software algorithms and image fusion techniques have been described to correct for these problems, but have not been necessary with the Leksell equipment [14]. Clinically, we compared the accuracy of MRI localization to CT and found no significant difference beyond the resolution of the scanners [15]. Once in the radiology suite, the patient is positioned on the MRI table, padding the appropriate pressure points, and elevating the knees for comfort. The frame is docked on a custom-designed frame holder which eliminates Xand Z-axis rotation (fig. 1). This is an improvement over the standard frame holder. Proper positioning within the frame holder is confirmed with a handheld level. The accuracy of MRI planning requires that the images be obtained parallel to the base ring if the software of the General Electric Signa scanner is used. Newer surgical planning systems allow reformatting of the axis planes in the intercommissural plane (fig. 2). A sagittal localizing film is initially obtained. Axial images are acquired with a gadolinium-enhanced spoiled gradient echo technique, dividing the volume into 1-mm slice intervals with minimum TE and TR, matrix 256¶512, and NEX2 (fig. 2). This allows excellent visualization of the AC, PC, basal ganglia, and optic tract. Three-millimeter thick, fast-inversion recovery sequences in the axial or coronal plane allow detailed imaging of the internal capsule and the nuclei of the basal ganglia. The TE is 34, TR 3,000, matrix 256¶256, and NEX2 (fig. 3).

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2 Fig. 1. A custom-designed MRI frame adapter on the left is compared with the commercially available frame adapter (Elekta Instruments) on the right. Fig. 2. An axial MRI image with spoiled Grass gradient recombinant (SPGR) technique reveals the intercommissural plane.

Target Localization Pallidotomy target localization is achieved by defining the line between the anterior and posterior commissures. Ideally, they are located on the same image. If they are on different images, the central slice is used as a starting point for the z coordinate. Planning is facilitated by Surgiplan software (Elekta

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Fig. 3. A coronal image obtained with the inversion recovery signal clearly demarcates the internal, external, and extreme capsules (arrows right to left), the optic tract, putamen and globus pallidus.

Instruments). Images can be reformatted to realign with the AC-PC line. The GPi target is 2–3 mm anterior to the midcommissural point, 18–22 mm lateral to midline and 4–6 mm inferior to the AC-PC line. The x-axis coordinate deviation from midline can be increased slightly to compensate for a dilated third ventricle or decreased slightly in women (fig. 4). Using the axial and coronal images, the trajectory can be adjusted to avoid the internal capsule medially and the optic tract inferiorly (fig. 5). Our goal is to place the electrode in the pallidum but not to penetrate the inferior border of the pallidum and puncture the optic tract. The trajectory is confirmed with the coronal and sagittal images with attention taken to avoid the sulcal arteries. With adjustments in the arc angle, the lateral ventricle can usually be avoided. The X and Y coordinates are most accurate when visualized on axial images. The Z coordinate is most accurate on coronal images. By obtaining a volume acquisition, the error due to slice interval is reduced. Surgiplan software

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Fig. 4. Target localization for a GPi lesion demonstrates the X and Y coordinates in the intercommissural plane. The right image demonstrates the final target in the appropriate Z plane, 2 mm above the right optic tract.

Fig. 5. The electrode trajectory is adjusted in the coronal plane to avoid the sulcus. 24 h postoperatively the electrode tract can be visualized by residual increased intensity on long TR images.

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Fig. 6. A coronal plane MRI using Surgiplan (Elekta Instruments) software demonstrates the planned trajectory in multiple planes.

(Elekta Instruments) allows the entire trajectory to be studied on the images (fig. 6). For thalamotomy target localization of the ventrolateral nucleus, we utilize either Leksell’s target (Y coordinate of 3 mm posterior to the midcommissural point) or a point 3/12 of the distance from the posterior commissure to the anterior commissure, moving 12–15 mm lateral from midline for the X coordinate. The inferior aspect of the lesion is on the AC-PC line. Simultaneous bilateral thalamic or pallidal lesions are avoided due to the increased risk of cognitive or speech complications. For those patients with significant bilateral tremor, a staged procedure separated by 6–12 months is considered.

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Intraoperative Monitoring The primary morbidity of ablative lesioning for PD involves inadvertent injury to the anatomical structures surrounding the target. For the globus pallidus, the optic tract inferiorly and the internal capsule medially must be avoided. Proximity to the internal capsule is determined with both macroelectrode stimulation and test lesioning. Subtle injury to the optic tract is difficult to evaluate. We have shown that the previously reported 14% incidence of optic tract complications can be significantly reduced with the use of intraoperative flash visual evoked potentials (VEPs) [16]. This simple, noninvasive monitoring adds 15 min of total operative time and enhances the safety of the procedure. Preoperative baseline VEPs can be obtained using a light source positioned 100 cm from the patients’ nasion for monocular and binocular stimulation. Currently, we obtain a preoperative baseline in the operating room with flash stimuli delivered through closed eyelids via fiberoptic light sources with attached reflective shields. Ambient light is minimized during the testing and procedure by avoiding direct operating room lights and covering the patients’ eyes and fiberoptic stimulator cells. The baseline VEPs are recorded using 128 trials per epoch with a stimulus frequency of 1.1 Hz, a 200–400 ms observation interval, an amplifier bandwidth of 1–300 Hz, and a gain of 10–50¶103. Recordings are obtained from the left visual cortex to vertex (O1/Cz), midline visual cortex to vertex (Oz/Cz) and right visual cortex to vertex (O2/Cz). For intraoperative recording, monocular stimulation is used, alternating epochs between the ipsilateral and contralateral eyes. Epochs are acquired immediately before and after GPi localization, GPi test thermal lesioning, and permanent GPi lesioning. Patients are continually questioned during the procedure regarding visual phenomena (phosphenes, blurring), sensory disturbances (paresthesias, dysesthesias), or motor effects (weakness, tetanization). For thalamic lesions, we often monitor somatosensory evoked potentials (SSEPs). The risk of thalamotomy is injury to the corticospinal tract. Although microelectrode recording can be used to map the border between the ventrocaudal and the ventral intermediate nuclei, we do not routinely do so. Clinically, patients are at risk for dysphasia (left-sided dominant hemisphere) and hypesthesia, as well as difficulty with gait and balance, or facial and hand weakness.

Target Selection and Electrode Placement We perform intraoperative target localization using a macroelectrode technique which has been shown to be safe and effective [17]. A skin punch and

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twist drill craniostomy are used. This enables the hole in the skin to be closed with a single suture. As the electrode is passed from the pia toward the target, the impedance is monitored. Typically the impedance drops upon entering the white matter and is greater than 600 Xs at the target. Impedance recording is valuable, safe, and simple to use. On occasion, the passage of the electrode to the target will create a temporary ablative effect, with a transient decrease in the patient’s contralateral limb tremor or rigidity. For this reason, the target is approached slowly, evaluating the effect with trial stimulations every 1–3 mm. With the macroelectrode placed at the target using the Radionics RGB3B system (Radionics Inc., Burlington, Mass., USA), stimulation is carried out with 1-ms2 wave pulses at a frequency of 5, 50 and 100 Hz, and voltage ranging from 0.2 to 2.5 V. With adequate targeting, stimulation will increase contralateral limb symptoms at low frequencies and diminish symptoms at higher frequencies. Most patients are in the ‘off ’ state at the time of surgery. For those patients with a primary symptom of dyskinesia, levodopa is administered immediately after imaging in order to assess the development of dyskinesia. Throughout the procedure, the patients’ contralateral arm and leg are exposed in order to allow easy access for continuous physical monitoring. Speech is assessed with complex verbal tasks such as sentence repetition. Tone is monitored by passively moving the limbs. Tremor and dyskinesia are evaluated by performance tasks such as holding a cup of water, drawing concentric circles, and writing. The patient is observed closely for changes in tone, tremor and dyskinesia. Signs of weakness, hypotonia or dysarthria suggest proximity to the internal capsule. Visual scotoma or phosphenes indicate proximity to the optic tract. Current spread into the capsule (below 1 V) may cause increased tone and limb contraction, suggesting that the electrode is too close for lesioning. If an initial stimulation is not conclusive, the preoperative planning is reviewed prior to adjusting the electrode. The first adjustments are made along the same trajectory, utilizing the VEPs when the electrode is passed deeper. If stimulation along the planned trajectory is unsuccessful, without positive or negative stimulation effects, the electrode is moved in accordance with the imaging data.

Methods of Ablation When we are satisfied with the position, heating the tissue surrounding the tip of the electrode to 45 ºC for 30 s makes a reversible test lesion. This allows for assessment of side effects and efficacy. Permanent lesions are produced at 70–80 ºC for 60 s. The electrode is allowed to cool below 37 ºC for

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20 s prior to altering its position for a second or third lesion. Generally, the electrode is withdrawn 3–4 mm to make a second lesion. The final lesion is typically 3–4 mm in diameter and 4–6 mm long. VEPs are obtained prior to creating a permanent lesion. A 1995 census of members of the American Society of Stereotactic and Functional Neurosurgery found that only 25% of those performing functional neurosurgery use microelectrode techniques. The advantages of microelectrode recording and lesioning are well described in the following two chapters. The criticism of macroelectrode stimulation is that it is less precise than the microelectrode technique. In reality, those who use microelectrodes recording make macroelectrode lesions that are often larger than those we create (3¶3¶5 mm). Clinically, the results appear similar. The 1.1-mm diameter probe has a 3.0-mm exposed tip (Radionics Inc.) which creates an elliptical lesion. As an alternative technique for creating a lesion in the ventral intermediolateral nucleus of the thalamus, we have utilized the Gamma knife (Elekta Instruments). The 4-mm collimator creates a focal lesion with image-guided stereotactic placement. As no intraoperative electrophysiology is possible, we have only performed this with patients who have medical contraindications to an electrode thalamotomy or deep brain stimulation. In 3 of the 10 patients who have had radiosurgery, the Gamma knife was used to enlarge electrode lesions that had given excellent but transient improvements. MRI planning allowed accurate visualization and planning.

Experience and Results At the University of Pittsburgh, 58 patients with PD underwent MRIguided pallidotomy using intraoperative macrostimulation without microelectrode recording between 1994 and 1997 [18]. A prospective protocol was used for surgical evaluation. Intraoperative VEPs were also performed. The average surgical time was 2.5 h per patient which included stereotactic head frame application, intraoperative MRI, patient transport, frame setup and electrode placement, macrostimulation, intraoperative evoked potential monitoring, frame removal and immediate postoperative CT imaging. Four patients (6.9%) developed transient neurological morbidity. Four patients developed dysarthria that resolved in 3 patients within one month. No patient developed a visual defect or sustained a brain hemorrhage. All patients were discharged within 24 h. Improvements persisted in dyskinesia and tremor in all 21 patients who were evaluated 1–2 years after pallidotomy. The most obvious improvement was in relief of contralateral dyskinesia. ‘Off ’ period Unified Parkinson’s Dis-

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ease Rating Scale scores improved 22%. In addition, improvements in tremor, rigidity and bradykinesia were noted. Sixty-one percent of patients reported significant functional gains or improvement in symptoms on a self-assessment evaluation.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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Laitinen L, Hariz M: Movement disorders; in Youmans J (ed): Neurological Surgery, ed 5. Philadelphia, Saunders, 1996, vol 5, pp 3575–3609. Kondziolka D, Bonaroti E, Lunsford L. Pallidotomy for Parkinson’s disease. Contemp Neurosurg 1996;18:1–7. Cooper I: Twenty-year follow-up study of the neurosurgical treatment of dystonia musculorum deformans. Adv Neurol 1976;14:423–453. Laitinen L, Bergenheim A, Hariz M: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Laitinen L: Pallidotomy for Parkinson’s disease. Neurosurg Clin North Am 1995;6:105–112. Lozano A, Lang A, Galvez-Jimenez N: GPi pallidotomy improves motor function in patients with Parkinson’s disease. Lancet 1995;346:1383–1386. Spiegel E, Wycis H, Marks M, Lee A: Stereotaxic apparatus for operations of the human brain. Science 1947;106:349–356. Leksell L: A stereotaxic apparatus for intracerebral surgery. Acta Chir Scand 1949;99:229–233. Kondziolka D, Flickinger J: Use of magnetic resonance imaging in stereotactic surgery. Stereotactic Funct Neurosurg 1996;66:193–197. Favre J, Taha J, Nguyen T: Pallidotomy: A survey of current practice in North America. Neurosurgery 1996;39:883–892. Fox M, Ahlskog E, Kelly P: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991;75:723–770. Goldman M, Kelly P: Symptomatic and functional outcome of stereotactic ventralis lateralis thalamotomy for intention tremor. J Neurosurg 1992;77:223–229. Maciunas R, Galoway R, Latimer J: The application accuracy of stereotactic frames. Neurosurgery 1994;35:682–695. Sumanaweera T, Adler J, Napel S: Characterization of spatial distortion in magnetic resonance imaging and its implications for stereotactic surgery. Neurosurgery 1994;35:696–704. Kondziolka D, Dempsey P, Lunsford L, Kestle JRW, Dalan EJ, Kanal E, Tasker RR: A comparison between magnetic resonance imaging and computed tomography for stereotactic coordinate determination. Neurosurgery 1992;30:402–407. Bonaroti E, Rose R, Kondziolka D, Baser S, Lunsford L: Flash visual evoked potential monitoring of optic tract function during microelectrode-based pallidotomy. Neurosurg Focus 1997;2:Article 4. Riordan H, Flashman L, Roberts D: Neurocognitive and psychological correlates of ventroposterolateral pallidotomy surgery in Parkinson’s disease. Neurosurg Focus 1997;2. Kondziolka D, Bonaroti E, Baser S, Brant F, Kim Y, Lunsford L: Outcomes after stereotactically guided pallidotomy for advanced Parkinson’s disease. J Neurosurg 1999;90:197–202.

Todd P. Thompson, MD, University of Pittsburgh Medical Center, Department of Neurosurgery, B-400 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15213 (USA) Tel. +1 412 647 3685, Fax +1 412 647 0989, E-Mail [email protected]

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Microelectrode Recordings in Movement Disorder Surgery William D. Hutchison a–c, Andres M. Lozano a, c a

Department of Surgery, Division of Neurosurgery, The Toronto Western Hospital, Toronto, Ont.; b Department of Physiology, Faculty of Medicine, University of Toronto, Ont., and c Toronto Western Hospital Research Institute, The Toronto Western Hospital, Toronto, Ont., Canada

Single-unit recording techniques were introduced into stereotactic brain surgery some 40 years ago in order to localize subcortical brain structures, mainly for the treatment of movement disorders [1]. Despite the advances in brain imaging over the last decades there is still much interest in the development of microelectrode techniques for both functional localization as well as research into the individual properties and population characteristics of neurons. While this review is limited to our method of sequential recordings of individual spike trains from single neurons in different nuclei, microelectrode techniques are also continuing to evolve to examine simultaneous recordings from neuronal assemblies in the same and different nuclei [2]. These methods will increase our knowledge of functioning and organization of the basal ganglia as well as the alteration in function that leads to movement disorders. Several reports of single-unit microelectrode techniques have been published with a focus on thalamus [3, 4], globus pallidus [5–8], and subthalamic nucleus [9, 10]. The purpose of the present chapter is to review the current methodology in use in our operating room and briefly outline the major neurophysiologic landmarks that need to be identified for target determination in each case.

Microelectrode Assembly Some detail is required in a discussion of microelectrodes, since most problems with recording is due to faulty or damaged electrodes rather than

any failure on the part of the electronic instrumentation used to amplify and filter the neuronal signals. Tungsten or platinum-iridium wire electrodes insulated with Parylene-C are obtained from a commercial source and inserted into Kapton-(polyimide-) insulated stainless steel tubing to extend the length for use in the stereotactic guide tube. Tip sizes of 15–25 lm (height of cone) are the most useful and give good single-unit and occasionally multi-unit recordings. Larger tip sizes pick up potentials from many more neurons in the vicinity of the tip making single-unit discrimination more difficult. Smaller tip sizes may record only single cells with little background input from other cells in the vicinity of the tip. Details of electrode construction, testing for faults and impedance measurements have been previously described [8]. Electrodes are plated with platinum and gold using solutions containing the free metal cations and cathodal current to attract those ions [11]. This is carried out under microscopic control to monitor the amount of plating deposited. The thin coating of Parylene-C on the electrode tip is particularly sensitive to scratching so caution needs to be exercised during handling. Electrodes are best protected by back-loading them into 19-gauge tubing and securing them with adhesive tape. The electrodes are sterilized with ethylene oxide gas while protected in the tubes to avoid damage to the tips during handling. Sometimes the tip can become curled or bent during use and it will be noticeable that few units are picked up in the background or there is background injury discharge before good single-unit spikes can be seen. The other major problem with the electrodes is that with frequent electrical stimulation through the tip, there is erosion of the plating and tip as well leading to an absence of unit recording where one would expect to find neurons. In this instance, impedance measurements may show an increased value from 0.2–0.4 to 1.5 MX or higher indicating that the electrode should be changed.

Instrumentation Several companies have developed systems for microelectrode recording. Basically the systems amplify the neuronal signals and filter the result for display on a touch-sensitive computer screen. The signal is also sent to an audio monitor that can be adjusted to hear a variable amount of the background neuronal activity and the individual spike(s). A millisecond time scale is used to display the spike waveform as well as the spike trace on a time scale in seconds. A software-based spike discrimination algorithm is used to display a real-time histogram of neuronal firing in seconds. A useful feature is a remote stimulation control that triggers the stimulus train and allows adjustment of stimulation intensity while observing the patient for tetanic contractions or visual responses.

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Surgical Technique A stereotactic frame is applied to the head under local anesthesia, and a fiducial box is placed over the frame to obtain references in three dimensions. The target is chosen directly from MRI and/or CT images or alternatively indirectly, estimated as a function of its position relative to AC and PC coordinates using a stereotactic atlas as has been described [12, 13]. When indirect targeting is used, the coordinates of AC and PC are obtained from the MRI console software (GE-Signa 1.5 Tesla magnet), and these are entered into a computer program that modifies any given sagittal map from the Schaltenbrand and Wahren atlas [13]. In this way a customized map is obtained for each patient, which is reformatted to the patient’s individual length of the AC-PC line. Commercially available software can be used to fuse CT and MR images.

Recordings during Pallidal Procedures Several groups have described their methods for pallidotomy recordings [5, 6, 14] and different groups use slightly different techniques and place varying time and emphasis on the recording session. With indirect targeting, the position of the GPi target is estimated in relation to AC and PC. The coordinates of Laitinen et al. [12] in the ventral portion of GPi are, 20 mm lateral to the midline, 3–6 mm inferior to the AC-PC line and 2–3 mm anterior to the midcommissural point. Care should be taken of individual variations attributed to such factors as head size and width of the third ventricle. In our procedure, recording starts about 15 mm from the target in an anterosuperior position and usually the first cells encountered are those of GPe. Although each region of the pallidum has its ‘signature’ cell types (fig. 1), a range of firing rates and patterns is normally found and identifying a subnucleus depends on finding a number of cells with a characteristic pattern of firing that appear in a predicted anatomical location. However, the mean firing rate of many neurons sampled in the various pallidal segments has been demonstrated to differ depending on the disease entity, i.e. Parkinson’s disease (PD) or dystonia [15, 16]. Normally a region is identified only after the electrode track is completed and many well-isolated spikes have been recorded so that a comparison of all the firing rates and patterns can be integrated with the surmised position of the track based on the stereotactic anatomical map. Typically GPe cells have been described as occurring in two major types based on differences in firing rate and pattern as recorded in normal monkeys [17]. These are the LFD-B or low-frequency discharge with bursts, and SFD-P or slow-frequency discharge with pauses. LFD-B neurons are not very common

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Fig. 1. Right: Sagittal section of the globus pallidus from the Schaltenbrand and Wahren atlas 1977, 20 mm from the midline showing the path of the electrode through the structure. AC>Corresponding position of the anterior commissure at midline; PC>midline position of the posterior commissure; Put>putamen; GPe>external segment of the globus pallidus; GPi,e GPi,i>external and internal parts (respectively) of the internal segment of globus pallidus; OT>optic tract. Left: Typical spike examples of cells in segments of globus pallidus during microelectrode exploration. LFD-B>Low-frequency discharge with bursts; SFD-P> slow-frequency discharge with pauses; Bor>Border cell; HFD>high-frequency discharge; TC>tremor cell. Trace below TC is the accelerometer attached to the dorsum of the contralateral hand.

in GPe but are thought to be a characteristic feature of the region. The spontaneous ongoing activity is only about 5–10 Hz (fig. 1) and the short bursts can reach about 300–500 Hz and occur at irregular time intervals. SFD-P neurons have a higher spontaneous firing rate around 20–50 Hz which is sporadically interrupted by pauses in firing of duration about 150–300 ms (see fig. 1). There may also be cell clusters in GPe with higher firing rates 50–70 Hz, and these may receive excitatory input from the hyperactive STN. The firing rate of cells in GPe may be modulated by active and passive movements of limbs.

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Below GPe is a region devoid of cells corresponding to the white matter lamina and border cells are frequently encountered at its margins. Border cells have a wider spike and longer after-hyperpolarization than pallidal cells which imparts a regular firing pattern due to the longer relative refractory period (see fig. 1). These electrophysiological characteristics and the positive immunoreactivity for choline acetyltransferase indicate that the cells are cholinergic and likely displaced from the forebrain nucleus basalis of Meynert [18]. A sample of 17 border cells was found to have a mean firing rate of 35 Hz [15]. After advancement of the electrode tip into GPi there is often an increase in background noise and multi-unit recordings. Cells in GPi have fairly large amplitude spikes, irregular discharge patterns and the highest firing rates of all pallidal cells. An audiovisual example of a recording of a GPi cell firing at 80–100 Hz in a PD patient can be found on the Internet at http://www.axon.com/ pallidotomy/GS3000screen.avi. The firing rates of GPi neurons are in the range of 60–80 Hz and the modal intervals for GPi neurons in the range of 5–7 ms. The sensorimotor territory of GPi is defined as that region populated by neurons which are movement-related. These GPi neurons may show excitatory or inhibitory responses to passive and voluntary movements of limbs, axial and orofacial structures. In a preliminary analyses of the data, there was no clear topographical organization of the body within GPi, which was depicted in early studies by Hassler et al. [19]. In patients that have tremor, cells can be found with periodic oscillations in firing rate at the same frequency as the tremor [20, 21]. These tremor cells show periods of coherent oscillation with limb tremor and appear to be located in ventral and lateral portions of the GPi [22]. Below the GPi the cellular activity becomes sparse and background noise decreases. Upon entering the optic tract there may be some discernible increase in high-frequency noise again due to the ongoing fiber activity in the optic nerve. Stimulation at this site normally evokes phosphenes in the contralateral visual field at low current intensities (5–20 lA). Patients frequently report white or yellow flashes of light, stars, sparkles or lightning-like patterns. This can be in a wedge-shaped portion of the visual field which can be observed to move more ventral as one stimulates more dorsal in the optic tract, consistent with the rotation of the fibers in the tract at this level. In the approximately 10% of cases when patients do not report stimulation-evoked visual sensation (a false negative) it is worthwhile to carry out strobe light-evoked potentials by opening up the highpass (low-cut) filter and averaging the evoked potentials to reveal a peak at about 30–40 ms. In so doing, inadvertent lesioning of the optic tract in patients who fail to report stimulation-induced visual sensation can be avoided. If the sensorimotor GPi and the optic tract have been identified on the first trajectory through the pallidum, what remains is to move posterior to identify the internal capsule. In pallidum the interval between the electrode

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tracts is usually 3 mm at the target site. Recording again begins at 15 mm above the target and cells are usually again found at the top of the tract. In posterior tracks the recordings will go quiet before the target point as the tip of the electrode passes into the internal capsule indicating the posterior aspect of the GPi. Recordings in capsule are usually quiet but the occasional unit or fiber is encountered. Microstimulation (up to 100 lA, 0.2 ms pulse width, 300 Hz, 1 s train) through the electrode may produce tetanic contraction of the contralateral body part or tremor reduction or tremor arrest. A complete map comprises usually two or three electrode trajectories where the optic tract and internal capsule have been unambiguously located. The physiological data should show a good spatial relation to the corresponding anatomical map, incorporating the cell-dense and cell-sparse regions. An estimation of the medial-lateral position through the pallidum can be made by fitting the physiologic data to the anatomical data predicted from stereotactic atlas sagittal maps through the pallidum, by comparing the relative span of GPe and GPi encountered, and by the position and length of the optic tract and of the internal capsule encountered in different sagittal planes. Lesions are made at least 3 mm distant from eloquent structures in a cell-dense area that contains movement-related activity and tremor cells if present. Lesions are created in a stepwise incremental fashion monitoring the temperature at the tip of the lesioning electrode as it increases from 60 ºC up to 90 ºC for 60 s, testing peripheral vision, speech and motor function at each stage. Some groups make several confluent lesions, others, a single lesion. Our group has been placing GPi DBS electrodes at approximately the same target as the lesion, with the deepest contact 1 mm above the optic tract and at least 3 mm anterior to the internal capsule.

Recordings during STN-DBS Procedures The pioneering work of Benabid’s group in Grenoble has shown that there can be remarkable improvement of the motor symptoms in PD with bilateral deep brain stimulation (DBS) of the subthalamic nucleus [23, 24]. This therapeutic advance in the clinic followed closely after work with the MPTP monkey model of PD and the demonstration by several groups that electrolytic and cytotoxic lesions of the STN produced remarkable reversal of parkinsonian symptoms [25]. These beneficial effects could also be seen with delivery of continuous electrical stimulation of the STN in the monkey model of PD [26, 27]. To identify the STN for the purposes of DBS implantation, the major landmarks to identify are: (1) anterior thalamus and its ventral border;

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Fig. 2. Stereotactic trajectory targeting the STN superimposed on a 12-mm sagittal map of the Schaltenbrand and Wahren atlas. The map is reformatted to correspond to the length of this patient’s AC-PC line and is ruled in 5-mm squares based on the Leksell frame coordinates. Rt>Thalamic reticular nucleus; Voa>ventralis oralis anterior; Vop>ventralis oralis posterior; Vim>ventralis intermedius; IC>internal capsule; ZI>zona incerta; H2>fields of Forel; Hpth>hypothalamus; STN>subthalamic nucleus; SNr>substantia nigra pars reticulata; AC, PC>anterior and posterior commissures; mcp>mid-commissural point.

(2) superior and inferior borders of STN; (3) dorsal border of SNr, and the (4) location of medial lemniscus. Although there is considerable variation, an approximate target for the central region of the STN nucleus is usually at about 12 mm lateral to the midline, 2–4 mm posterior to the mid-commissural point and 3 mm below the AC-PC line. In our procedure, recording in microelectrode tracks starts 10 mm above target in the STN (fig. 2). Depending on the trajectory angle in the sagittal plane, recording will usually start in thalamic reticular nucleus or in anterior thalamus Voa, Vop (or Lpo if more lateral). In this region and particularly in the thalamic reticular formation there are cells with spontaneous burst discharges, which have been reported previously [28, 29] and can be considered

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Fig. 3. Typical spike recordings of cell types encountered in trajectories targeting the subthalamic nucleus. Top to bottom: TRN>thalamic reticular nucleus; NB>nonbursting cell; B-bursting cell; STN>subthalamic nucleus; SNr>substantia nigra pars reticulata. Traces are 2 s in duration.

characteristic for the region (fig. 3). The mean firing rates of thalamic bursting and nonbursting cells are given in table 1. Below the thalamus the electrode tip passes into a white matter region which is quieter corresponding to the thalamic and lenticular fasciculi with the zona incerta in-between (fig. 2). The zona incerta is a thin strip of gray matter, and cells with bursting discharges may be found here since it is continuous with the thalamic reticular nucleus at its lateral border. Others have

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Table 1. Characteristic mean firing rates of cellular regions encountered during stereotactic procedures for movement disorders Procedure

Region

Rate SD (n)

Pallidum Parkinson’s

GPe

60×36 (40)

GPi dorsal ventral

53×27 (73) 82×32 (89)

Border cells

35×16 (17)

Anterior thalamus Bursting Nonbursting

15×19 (51) 28×19 (52)

STN

37×17 (248)

SNpr

71×23 (56)

VPLo (Vim)

22×11

VPLc (Vc)

26×8

VLc (Vop)

12×8

VLo (Voa)

13×8

VA

15×8

Subthalamic nucleus Parkinson’s

Normal monkey thalamus

Thalamus Parkinson’s

2

1

Voa/Vop Vim

8×2 (20) 14×3 (17)

1

Data from Vitek et al. [35]. Unpublished observations from nontremor-related cells [Molnar, Dostrovsky and Lozano, 2000]. 2

reported cells in or near zona incerta with properties similar to subthalamic nucleus neurons with responses to limb [30] and also eye movements [31]. The entry into the STN is apparent when high-amplitude spikes with firing rates of 25–45 Hz are found (fig. 3). Neurons in the sensorimotor territory of STN show clear modulation with active and passive movements of the limbs and the responses are usually excitatory. Tremor cells have also been identified in the human STN. STN neurons may only be recorded over a short distance if the electrode does not track through the center of this almond-shaped nucleus where it has the greatest superior/inferior diameter. Typical STN neurons are shown in figure 3 and the firing rate and burst index is found in table 1. Since STN-like cells may be found in the adjacent superiorly located zona incerta,

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the dorsal border of the STN should be defined by a continuous, cell-dense region populated by neurons showing movement-related activity. Below the STN is the substantia nigra, which is divided into the dopaminergic pars compacta (SNpc) and the basal ganglia output portion called the pars reticulata (SNpr). The division between the two structures is not clear and one expects that there is degeneration of the compacta in these PD cases. Based on recordings in monkeys where histological confirmation is possible, there is known to be differences in the firing rates of the SNc and SNpr groups. In normal monkeys, putative dopaminergic pars compacta cells have very low firing rates 1–5 Hz and have inflections on the initial phase of the action potential [32]. We have only rarely encountered this type of neuron, perhaps due to the associated neuropathological changes in PD. The characteristic features of SNpr or reticulata neurons are a high (60–90 Hz) and regular firing rate (see table 1, fig. 3) but there may be another group that have lower rates around 30 Hz, possibly reflecting functional differences within the nucleus [9, 33, 34]. The different firing rates in SNpr may depend on the portion of the reticulata that is explored, since motor regions are more laterally located in this nucleus (about 15 mm from the midline). Microstimulation at parameters of 300 Hz and up to 100 lA for short trains in the region of STN is not as useful for localization as with pallidotomy or thalamotomy cases, but stimulation-induced tremor arrest or reduction from sites within STN has been observed. Paraesthesias have been encountered in more posterior positions and may be due to current spread to the medial lemniscus or the prelemniscal radiation. It is necessary to determine the sites where electrical stimulation evokes paraesthesia and avoid these locations in placing the DBS electrode, since it is a bothersome side effect of STN-DBS therapy. At our center, DBS electrode contacts are placed to span the areas of the STN populated by movement-responsive cells. The ideal target is one where there is clinical benefit and minimal adverse effects with stimulation through the DBS electrodes at 3.5 V or less, 90 ls pulse width, 185 Hz. These parameters mimic those that are usually used clinically. The position of the Medtronic 3387 quadripolar DBS electrode is chosen so that the 4 electrode contacts (with a total separation of 10.5 mm) span the 5–6 mm of the STN nucleus. This means that 1 contact is usually placed in SNpr, 2 contacts within STN and the superior contact in the zona incerta.

Recording and Microstimulation during Thalamotomy Procedures Thalamotomy for tremor (essential, PD, cerebellar tremors) targets the ventral intermediate (Vim) nucleus of the ventral tier thalamic nuclei where

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deep kinesthetic and muscle spindle afferents as well as cerebellar afferents converge. The tentative Vim thalamic target for arm tremor is approximately 15 mm lateral to the midline or 11 mm from the wall of the third ventricle, with a vertical coordinate at 0–2 mm above the AC-PC line and 6–7 mm behind the mid-commissural point. Frequently the ventral caudal somatosensory relay nucleus (Vc) located more posterior is actually the target for the first trajectory since the somatotopy of Vc is an important landmark for orientation (see electrode trajectory 1, fig. 4). The objectives in microelectrode recording-guided thalamic procedures are to identify: (1) movement-responsive cells that populate Vim; (2) the posteriorly located tactile relay nucleus Vc; (3) the thalamic base which represents the ventral border of the thalamus and, most importantly, (4) a thalamic site where stimulation arrests tremor without producing adverse effects. A recent detailed description of thalamic functional procedures has been published [4]. ‘Motor Thalamus’ Voa, Vop, Vim The more anterior nuclei analogous to ventral oral anterior and posterior (Voa and Vop) have firing rates in the range of 12–15 Hz in normal monkeys (table 1) and may respond to voluntary movements of the contralateral limbs or orofacial structures [28]. Microstimulation in the voluntary cell region may produce a focal contraction of muscle groups at threshold that fatigues with repetition and increasing the stimulation intensity involves more muscles. Movement-related activity (kinesthetic responses) may be present and cells may be found that respond to deep pressure or deep tactile stimuli. In patients with tremor, thalamic neurons which fire in clusters of action potentials that are time-locked to tremor (tremor cells) may be recorded in this region, and microstimulation at these sites should produce tremor arrest or tremor reduction (see ‘ TA’ sites in fig. 4). Little systematic data is available for humans and table 1 shows data of normal monkeys from Vitek et al. [35] which suggests also that the anterior thalamic nuclei have lower firing rates on average than the Vim (VPLo) and Vc (VPLc). Vc and Vcpc In passing further down with the electrode, the spontaneous activity will usually increase with entry into the thalamic tactile relay of Vc. Cells in this region have high-amplitude spikes and will respond to light stroke with a brush or cotton swab. The ongoing firing rate of VPLc cells in monkeys was found to be 26×8 Hz, which is likely to be similar to human Vc. The wellknown somatotopic organization within Vc may help to guide the laterality of the procedure and the Vim target chosen for lesions is usually just anterior to the face and hand region of the tactile core. Laterality in Vim is largely

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Fig. 4. Functional localization of thalamic nuclei for deep brain stimulation electrodes implanted for tremor control in a PD patient. Background outlines of the thalamic nuclei are drawn from the Schaltenbrand and Wahren stereotactic atlas 14.5 mm from the midline. Three parallel trajectories along Vop, Vim and Vc separated by 2 mm are shown. The neuronal responses are detected by microelectrode recordings as changes in the baseline rate of action potential discharges in individual neurons. The nature of the stimulus provoking the neuronal responses is indicated by the filled bars. Note that there is a good but not exact fit between the actual physiological data and the atlas derived projected thalamic map. The localization of VC is confirmed by observing tactile neurons which respond to light stroking of the skin in a discrete receptive field. In trajectory 1, the tactile responses were obtained by touching the skin of the fingers and hand with the hairs of a fine paintbrush confirming the location of the somatotopic representation for cutaneous sensation in the upper extremity. Deep tactile neurons responding to muscle or tendon squeezing or tapping in this case biceps and forearm, were encountered in trajectory 2. This class of neurons is usually found in the area of the border of Vim with Vc. Kinesthetic neurons responding to movements of the wrist and elbow joint were observed in the three trajectories. Neurons with voluntary responses to pointing and opening and closing the hand were identified in trajectory 3. The location of thalamic neurons firing in synchrony with tremor in the contralateral arm in this patient is indicated by the asterisk. At sites marked TA, tremor was arrested by electrical stimulation at 25–100 lA and 300 Hz and 100-s pulse width delivered in 1-s trains. Sites with tremorsynchronous neurons or where electrical stimulation abolishes tremor are good potential targets for insertion of the DBS electrode. In this patient, the quadripolar DBS electrode was inserted in tract 3 with the most distal electrode at the base of the thalamus, a position marked by the transition from neurons to axons. The electrode was inserted in tract 3 rather

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determined with reference to Vc somatotopy, leg indicating a more lateral location than face and hand. There may also be ‘spurious tremor cells’ that are rhythmically activated by the skin brushing as the limb oscillates with tremor. Microstimulation at low amplitudes (as low as 1 lA) within Vc produces focal paraesthesia that shows a somatotopic organization roughly corresponding to that obtained by recording the cellular responses to touch. Microstimulation in ventral Vc and below Vc in Vcpc may elicit painful sensation. Ventral to Vc, microstimulation may also elicit hemibody paresthesias due to medial lemniscus fiber activation. Usually several trajectories are made to define the anterior border of Vc and map a large enough segment of the motor thalamus to find the focus and extent of sites of effective tremor suppression from microstimulation. Usually lesions or DBS implantations are made 2–3 mm anterior to the Vc/Vim border (fig. 4). Important attributes of the target area for tremor control include: (1) the presence of kinesthetic cells; (2) tremor-synchronous discharges; (3) microstimulation-induced tremor arrests (300 Hz, 90 ls, 1–5 s trains and up to 100 lA, and (4) the absence of speech or sensory adverse effects with stimulation. As with all DBS procedures, the final target is chosen on the basis of physiologic data and evidence of clinical effectiveness combined with the lack of stimulation-induced adverse effects at clinically relevant stimulation parameters. In Summary: Microelectrode recording is useful to accurately delineate deep brain structures and thalamic subnuclei for various stereotactic targets. In addition it yields much information on the cellular aspects of basal ganglia pathophysiology in movement disorders. Microelectrode recordings obtain direct measures of spontaneous and stimulus-evoked cellular activity and can unequivocally distinguish axonal tracts which are devoid of somatodendritic action potentials from areas populated by neurons. This type of information is important for the refinement of current surgical therapy as well as the rationale development of novel methods for treatment of movement disorders.

Acknowledgments The support both of Parkinson’s Foundation of Canada (W.D.H., A.M.L.) and University of Toronto Connaught Fund (W.D.H.) is gratefully acknowledged. A.M.L. is a Clinician Scientist of the MRC Canada. We thank Drs Dostrovsky and Lang for their ongoing collaboration.

than tract 2 which also had tremor cells and sites where stimulation produced tremor arrest to minimize the possibility of stimulation-induced paresthesia associated with current spread to the nearby sensory (Vc) nucleus. PC>Posterior commissure. [Modified from 36, with permission.]

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References 1

2 3

4

5 6

7 8

9

10 11

12 13 14

15

16

17 18

19 20 21

22

Guiot G, Hardy J, Albe-Fessard D: De´limitation pre´cise des structures sous-corticales et identification de noyaux thalamiques chez l’homme par l’e´lectrophysiologie ste´re´otaxique. Neurochirurgia (Stutt) 1962;51:1–18. Nicolelis MAL (ed): Methods for Neural Ensemble Recordings. Boca Raton, CRC Press, 1998. Lenz FA, Dostrovsky JO, Kwan HC, Tasker RR, Yamashiro K, Murphy JT: Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system. J Neurosurg 1988;68:630–634. Tasker RR, Davis KD, Hutchison WD, Dostrovsky JO: Subcortical and thalamic mapping in functional neurosurgery; in Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, pp 5–31. Sterio D, Beric A, Dogali M, Fazzini E, Alfaro G, Devinsky O: Neurophysiological properties of pallidal neurons in Parkinson’s disease. Ann Neurol 1994;35:586–591. Vitek JL, Bakay RA, Hashimoto T, Kaneoke Y, Mewes K, Zhang JY, Rye D, Starr P, Baron M, Turner R, DeLong MR: Microelectrode-guided pallidotomy: Technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998;88:1027–1043. Lozano AM, Hutchison WD, Kiss ZHT, Davis KD, Dostrovsky JO: Methods for microelectrodeguided posteroventral pallidotomy. J Neurosurg 1996;84:194–202. Hutchison WD: Microelectrode techniques and findings of globus pallidus; in Krauss JK, Grossman RG, Jankovic J (eds): Pallidal Surgery for the Treatment of Parkinson’s Disease and Movement Disorders. Philadelphia, Lippincott-Raven, 1998, pp 135–152. Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, Lozano AM: Neurophysiologic identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998; 44:622–628. Starr PA, Vitek JL, Bakay RAE: Deep brain stimulation for movement disorders. Neurosurg Clin North Am 1998;9:381–402. Millar J, Stamford JA (eds): Monitoring Neuronal Activity: A Practical Approach. 1. Extracellular Single and Multiple Unit Recording with Microelectrodes. New York, IRL Press at Oxford, 1992, pp 1–27. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme, 1977. Taha JM, Favre J, Baumann TK, Burchiel KJ: Characteristics and somatotopic organization of kinesthetic cells in the globus pallidus of patients with Parkinson’s disease. J Neurosurg 1996;85: 1005–1012. Hutchison WD, Lozano CA, Davis KD, Saint-Cyr JA, Lang AE, Dostrovsky JO: Differential neuronal activity in segments of globus pallidus in Parkinson’s disease patients. Neuroreport 1994; 5:1533–1537. Vitek JL, Chockkan V, Zhang JY, Kaneoke Y, Evatt M, DeLong MR, Triche S, Mewes K, Hashimoto T, Bakay RA: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22–35. DeLong MR: Activity of pallidal neurons during movement. J Neurophysiol 1971;34:414–427. Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam MM: Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 1998;121: 2249–2257. Hassler R, Mundinger F, Riechert T: Stereotaxis in Parkinson Syndrome. Berlin, Springer, 1979. Hutchison WD, Lozano AM, Kiss ZHT, Davis KD, Lang AE, Tasker RR, Dostrovsky JO: Tremorrelated activity in globus pallidus of Parkinson’s disease patients. Soc Neurosci Abstr 1994;20:783. Hutchison WD, Lozano AM, Tasker RR, Lang AE, Dostrovsky JO: Identification and characterisation of neurons with tremor-frequency activity in human globus pallidus. Exp Brain Res 1997; 113:557–563. Hutchison WD, Benko R, Dostrovsky JO, Lang AE, Lozano AM: Coherent relation of rest tremor and pallidal tremor cells in Parkinson’s disease patients (abstract). Mov Disord 1998;13:(suppl 2):204.

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23

24

25 26

27

28

29 30 31 32 33 34 35 36

Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret JE: Effets de la stimulation du noyau sousthalamique dans la maladie de Parkinson. Rev Neurol 1993;149:175–176. Limousin P, Pollak P, Hoffmann D, Benazzouz A, Perret JE, Benabid AL: Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients. Mov Disord 1996; 11:231–235. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1438. Benazzouz A, Boraud T, Fe´ger J, Burbaud P, Bioulac B, Gross C: Alleviation of experimental hemiparkinsonism by high-frequency stimulation of the subthalamic nucleus in primates: A comparison with L-dopa treatment. Mov Disord 1996;11:627–632. Benazzouz A, Gross C, Fe´ger J, Boraud T, Bioulac B: Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 1993;5:382–389. Raeva SN, Lukashev A: Unit activity in human thalamic reticularis neurons. II. Activity evoked by significant and non-significant verbal or sensory stimuli. Electroenceph Clin Neurophysiol 1993; 86:110–122. Raeva SN, Lukashev A, Lashin A: Unit activity in human thalamic reticular nucleus. I. Spontaneous activity. Electroenceph Clin Neurophysiol 1991;79:133–140. Fabre M, Rolls ET, Ashton JP, Williams G: Activity of neurons in the ventral tegmental region of the behaving monkey. Behav Brain Res 1983;9:213–235. Ma T: Saccade-related omnivectoral pause neurons in the primate zona incerta. Neuroreport 1996; 7:2713–2716. Schultz W: Responses of midbrain dopamine neurons to behavioural trigger stimuli in the monkey. J Neurophysiol 1986;56:1439–1461. DeLong MR, Crutcher MD, Georgopoulos AP: Primate globus pallidus and subthalamic nucleus: Functional organization. J Neurophysiol 1985;53:530–543. DeLong MR, Crutcher MD, Georgopoulos AP: Relations between movement and single cell discharge in the substantia nigra of the behaving monkey. J Neurosci 1983;3:1599–1606. Vitek JL, Ashe J, DeLong MR, Alexander GE: Physiologic properties and somatotopic organization of the primate motor thalamus. J Neurophysiol 1994;71:1498–1513. Lozano A: Thalamic deep brain stimulation for the control of tremor; in Rengachary S, Wilkins R (eds): Neurosurgical Operative Atlas. Parke Ridge Ill, American Association of Neurological Surgeons, 1998, vol 7, pp 125–134.

William D. Hutchison, Division of Neurosurgery, The Toronto Western Hospital, 399 Bathurst St., East Wing 6-528, Toronto, Ont., M5T 2S8 (Canada) Tel. +1 416 603 5800/ext 2226, Fax +1 416 603 5298, E-Mail [email protected]

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Rational Basis for Pallidotomy in the Treatment of Parkinson’s Disease R.A.E. Bakay a, J.L. Vitek b Departments of a Neurosurgery and Atlanta, Ga., USA

b

Neurology, Emory University,

Functional neurosurgery for movement disorders is actively performed all over the world. The resurgence of functional neurosurgery for the treatment of movement disorders started with pallidotomy for Parkinson’s disease (PD) and has expanded to include all types of movement disorders and a number of other surgical procedures. Movement disorders that may be considered for functional neurosurgery include PD, nonparkinsonian tremor, dystonia, torticollis, hemiballismus, Huntington’s disease and tardive syndromes. The types of surgery that are available in addition to pallidotomy include thalamotomy, subthalamotomy, transplantation, and deep brain stimulation (DBS). The resurgence of interest in pallidotomy as a treatment for PD is due to multiple factors: (1) recognition that long-term medical therapy for PD is often unsatisfactory, with patients eventually suffering from drug-induced dyskinesias, motor fluctuations, and variable responses to medication; (2) greater understanding of the pathophysiology of PD, providing a rational theoretical basis for pallidotomy; (3) the use of newer techniques, including CTand MRI-guided stereotaxis and microelectrode recording, making surgical intervention in the basal ganglia more precise and safe, and (4) the documentation that pallidotomy could relieve all of the cardinal symptoms of PD as well as the drug-induced dyskinesias and dystonias [1]. The Emory pallidotomy program began in 1991 shortly after the publication by Bergman et al. [2] that demonstrated the reversal of MPTP-induced Parkinson-like symptoms in a primate model. Based on the known pathways in the basal ganglia-thalamocortical motor circuit, they lesioned the subthalamic nucleus (STN). Damage to STN resulted in decreased hyperactivity of the basal ganglia output nuclei and a correction of the increased inhibition

A

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Fig. 1. Schematic diagram of the basal ganglia-thalamocortical motor circuit in the normal state and in movement disorders. A>Normal; B>Parkinson’s disease; C>Hemiballismus; D>Dyskinesia. SNc>Substantia nigra, pars compacta; SNr>substantia nigra, pars reticulata; GPe>globus pallidus, external segment; GPi>globus pallidus, internal segment; STN>subthalamic nucleus. Open arrows, excitatory connections; filled arrows, inhibitory connections. Changes in the widths of the arrows between A, B and C indicate changes in the activity of the pathway represented. Wider lines indicate increased activity, narrower lines indicate decreased activity.

of the thalamocortical pathways, which improved all the MPTP-induced Parkinson-like symptoms (fig. 1). There was hesitancy to lesion this nucleus in man as there is a literature that suggested lesions in this area would produce hemiballism. However, by understanding the model, an alternative target presented itself. The basal ganglia-thalamocortical motor circuit plays a key role in regulating motor behavior (fig. 1). The basal ganglia structures that participate in this circuit include portions of the striatum (putamen), the internal and external segments of the globus pallidus (GPi and GPe), STN, the motor thalamus, and the substantia nigra pars compacta (SNc) and pars reticulata (SNr). Loss of dopaminergic cells in the SNc, the fundamental defect in PD, results in abnormalities in neuronal activity in the basal ganglia-thalamocortical motor circuit. Loss of striatal dopamine leads to increased activity in the STN and output nuclei, GPi and SNr, which in turn leads to excessive inhibition of the thalamocortical and brainstem pathways. Therefore, lesioning of GPi could also be effective in reversing PD symptoms.

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Lesioning of the globus pallidus has a long history in the treatment of PD and other movement disorders. In the 1930s, Russell Myers [3] pioneered surgery on the basal ganglia and demonstrated that parkinsonian symptoms could be improved without the need for corticospinal lesioning. However, results were inconsistent and often associated with significant morbidity. In the 1950s, the introduction of stereotactic techniques decreased the morbidity and increased the effectiveness of pallidotomy. Leksell [4] identified the posterior pallidum as a more effective target than the anterior target used by other neurosurgeons. However, following Irving Cooper’s [5] and R. Hassler’s [6] demonstration that lesions in the cerebellar receiving area of the thalamus (Vim) was more effective than pallidotomy in stopping tremor, pallidotomy was largely replaced by thalamotomy. In the 1960s, L-dopa therapy for PD became widespread and was highly successful in treating the motor symptoms. As a result, functional neurosurgical was rarely performed. Unfortunately, medical therapy proved inadequate because the effectiveness of L-dopa therapy typically decline with time and debilitating motor fluctuations and drug-induced dyskinesias often ensue after 3–5 years. The response to medical therapy becomes highly unpredictable overtime and symptoms are poorly controlled. The introduction of multiple new drugs has not solved this problem. As a result of advances in surgical techniques and the theoretical understanding of the rationale for different surgical interventions, there has been a reexploration of surgical techniques for the treatment of movement disorders.

Physiology of Movement Disorders: Basal Ganglia Model The cortex, basal ganglia, and thalamus form multiple segregated circuits controlling motor, limbic, and associative functions [7]. The portions of these nuclei that participate in the motor circuit contain neurons whose discharge rates are modulated by passive joint movements or have cells whose discharge is modulated by active movements, i.e. sensorimotor properties. Sensorimotor regions are anatomically separate from the regions that regulate nonmotor functions. Because of this, it is possible to design surgical interventions that alter function in the motor circuit without directly affecting nonmotor circuits. The current model of the basal ganglia-thalamocortical motor circuit is illustrated schematically in figure 1A. Cortical efferent projections enter the basal ganglia via the putamen. The major basal ganglia output nuclei are GPi and SNr, which project to subdivisions of the motor thalamus and brainstem. Projections from the basal ganglia output nuclei to brainstem nuclei, such as the pedunculopontine nucleus, may be important in the pathophysiology of

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movement disorders, though the function of these projections is less well understood [8]. Within the basal ganglia, motor function is thought to be regulated by two major pathways, both of which are modulated by striatal dopamine. The ‘direct’ pathway is a monosynaptic projection from the putamen to GPi/SNr. In the ‘indirect’ pathway, the putamen projects to GPi/ SNr via intermediate nuclei, GPe and STN. Dopaminergic innervation of the putamen by SNc inhibits transmission over striatopallidal fibers in the indirect pathway, but facilitates transmission over striatopallidal fibers in the direct pathway. The nondopaminergic projections between the basal ganglia nuclei are GABAergic (inhibitory), except for the projection from STN to GPi/SNr, which is glutamatergic (excitatory). Balance between the direct and indirect pathways is considered important for normal motor control. An imbalance between the two pathways results in the abnormal activity in the basal gangliathalamocortical motor circuit which is thought to be responsible for many of the motor abnormalities associated with movement disorders [9]. The deficiency in dopaminergic innervation is manifested by the hypokinetic motor signs of parkinsonism (fig. 1B). This model of PD is supported by metabolic, pharmacological and electrophysiological studies of the basal ganglia in the parkinsonian (MPTP-treated) monkey and in patients with PD. In this model, neuronal activity in GPi and STN are increased compared with normals and inactivation of the STN, whether via lesioning or injections of the GABA agonist muscimol, ameliorates all of the signs of PD in the contralateral limbs. The model also can be used to explain hyperkinetic movement disorders such as hemiballismus or dystonia. Figure 1C illustrates a model of how alterations in the basal ganglia-thalamocortical motor circuit may lead to hyperkinetic movement disorders. Realizing that there is fluctuation in the amount of dopamine presented to the striatum from medical therapy, druginduced disorder can also be explained by excessive suppression and increased synchonization of Gpi neurons. Drug-induced dyskinesias are illustrated as an example of an acute hyperkinetic disorder (fig. 1D). While medically intractable PD is the predominant indication for GPi pallidotomy, the operation has been applied to other movement disorders as well. The first use of stereotactic surgery for a movement disorder by Spiegel and Wycis [10] was for chorea in an HD patient. The procedure was effective for decreasing choreiform movements contralateral to the lesion. It is unclear whether this could provide functional benefit to patients, and the brain atrophy associated with HD increases the risk of postsurgical complications. Isolated case reports indicate that pallidotomy also may be effective for alleviating the involuntary movements associated with hemiballismus. Recently, several centers have reported significant improvement in patients with idiopathic or

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Table 1. Inclusion and exclusion criteria Inclusion a. A clinical diagnosis of idiopathic PD. The diagnosis was based on the presence of at least two of the three cardinal signs of this disorder (bradykinesia, rest tremor and rigidity) and a history of a good response to L-dopa therapy. In addition, patients were evaluated off all antiparkinsonian medication overnight and their response to L-dopa assessed at the time of their initial clinic visit. b. Hoehn and Yahr stage III or greater when ‘off ’. c. Intractable disabling motor fluctuations (severe ‘on-off ’ periods) or dyskinesias. d. Unsatisfactory clinical response to maximal medical management. Exclusion a. Evidence of secondary or atypical parkinsonism as suggested by: i. History of cerebrovascular accidents, encephalitis, exposure to toxins or neuroleptics. ii. Supranuclear gaze palsy or neurologic signs of upper motor neuron or cerebellar involvement. iii. MRI scan with evidence of significant cortical, cerebellar or brainstem atrophy, lacunar infarcts or iron deposits in the putamen. iv. Poor response to L-dopa (by history and by exam). b. Clinically significant medical disease that would increase the risk of developing pre- or postoperative complications (e.g. cardiac or pulmonary disease, uncontrolled hypertension, coagulopathies). c. Significant dementia or untreatable depression.

secondary generalized dystonia [11–15]. Careful clinical follow-up, however, is needed to document long-term effectiveness, before the use of pallidotomy in the treatment of dystonia can be routinely recommended. Currently, the STN is being explored for lesioning [16, 17] and deep brain stimulation is being implemented in the Gpi and STN for the treatment of PD [18–23]. Although preliminary reports are extremely promising, randomized trials are necessary to adequately assess and compare the effect of the different surgical approaches for the treatment of PD. In addition, future studies of surgical therapy will need to identify and control for clinical variables and use standardized methods of patient assessment.

Inclusion and Exclusion Criteria Indications will vary from center to center but the following recommendations are typical of the published series from movement disorder centers (table 1). Candidates for pallidotomy should have a diagnosis of idiopathic

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PD which requires the presence of at least 2 of the 3 cardinal motor signs of PD (bradykinesia, rest tremor and rigidity), and a well-documented beneficial response to L-dopa. The ideal patient has idiopathic PD. Most candidates are moderately disabled, with Hoehn and Yahr scores of 3 or greater when off medication, have disabling drug-induced dyskinesias, and severe motor fluctuations. Although the majority of surgical candidates have rigidity and bradykinesia as predominant symptoms, patients with tremor-dominant PD are also considered good candidates. Patients with tremor-dominant PD are also appropriate candidates for Vim thalamotomy or DBS [21]. Several recent reviews have documented long-term (?3 years) efficacy of 70–90% for alleviation of tremor following the thalamotomy. There are reports that extending the thalamotomy lesion anteriorly into Vop/Voa improves rigidity and may alleviate drug-induced dyskinesias. However, rigidity, bradykinesia, and motor fluctuations appear to be better controlled by pallidotomy. Thus, for PD, pallidotomy is preferable to thalamotomy in all but the minority of PD patients for whom tremor is the dominant feature of the disease because other symptoms will eventually develop. Most centers do not have a specific age cut-off and use the physiological status of the patient to judge surgical candidacy. Contraindications to pallidotomy include dementia, extensive brain atrophy, and ‘Parkinson-plus’ syndromes. These patients generally do not improve and appear to have a higher complication rate, especially cognitive deterioration.

Results of Pallidotomy In considering pallidotomy results, historical perspective is of limited value. It is difficult to compare surgical studies from the pre-L-dopa era with contemporary procedures. In the pre-L-dopa era, standard parkinsonian rating scales to assess clinical outcome were not available, rigorous long-term followup was rarely performed, and documentation of lesion location was possible only by autopsy and infrequently reported. Also, the patient population in the pre-L-dopa era was different in several important aspects. That group included many patients with postencephalitic parkinsonism, which is now rare. Moreover, patients with Parkinson-plus syndromes were not differentiated from idiopathic PD. Finally, PD patients in the pre-L-dopa era did not suffer from drug induced on-off fluctuations or dyskinesias, which are now a major source of contemporary morbidity. Another problem in comparing results is that the major focus of the pre-L-dopa surgery was on tremor rather than akinesia/bradykinesia. Therefore, any discussion of the surgical options for PD must focus on contemporary reports.

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There are numerous contemporary reports on the benefits of pallidotomy for PD [21, 24–55]. Symptomatic responses following pallidotomy appears to vary. Most reported improvement in both tremor and akinesia following pallidal lesions [4, 24, 25, 27, 28, 39–42, 53–55], others reported no effect on bradykinesia but a moderate effect on tremor [34] and there is one report of little effect on tremor but a significant effect on rigidity [45]. Sutton et al. [51] reported no significant clinical benefit in Unified Parkinson’s Disease Rating Scale (UPDRS), Schwab and England, or Hoehn and Yahr scores either ‘on’ or ‘off ’ following pallidotomy, while others found only slight to moderate improvement in some signs and little or no benefit in others [34, 45, 49]. Only one study reported marked and significant improvement in ‘on’ motor scores [32]. The danger underlying the interpretation of these reports is the assumption that the variables which contribute to clinical outcome were controlled across each of these studies. Lesion location is a key factor, which is likely to play a major role in determining clinical outcome and that may also account for much of the variability reported across clinical studies. The reason for this lies in the functional organization of the pallidum and basal ganglia thalamocortical circuits and their relationship to the development of parkinsonian motor signs [9]. Thus, the internal pallidum is a functionally heterogeneous structure with anatomically and physiologically well-defined and nonoverlaping motor, associative and limbic regions. Since the sensorimotor portion of GPi constitutes the caudal most portion of the nucleus with nonmotor areas lying more anteriorly, lesions that lie outside the sensorimotor portion of GPi should have little or no benefit for the motor symptoms of PD [26, 31, 53]. Few of these studies have attempted to correlate lesion location to clinical outcome using high-resolution MRI with standard clinical rating scales [26, 31, 38, 53]. This correlation suggests that lesions, which involve the caudal portion of GPi, are more effective in providing long-term improvement in parkinsonian motor signs than lesions which only partially involve this territory or involve primarily GPe [26, 53]. Furthermore, because the anatomically segregated pallidothalamocortical subcircuits within the larger GPi motor circuit project to different precentral motor areas [56], it is likely that each of these subcircuits may be differentially involved in the development of parkinsonian motor signs. Consistent with this concept is the report that tremor was alleviated to a significantly greater degree with lesions placed more posteriorly in the GPi, while rigidity was alleviated with slightly more anteriorly placed lesions [31]. Conceivably, in those instances where little or no benefit is reported or some motor signs are reported to improve while others do not, lesions may spare a particular motor subcircuit. These observations are consistent with the hypothesis that particular portions of the motor

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circuit are preferentially involved in the development of tremor, rigidity and bradykinesia. In addition to the location of lesions within GPi, it may also be important to avoid lesioning GPe. Based on preliminary data in the monkey [57] and more recent work in humans [26, 53] lesions that involve GPe could limit the benefit of a well-placed lesion in GPi and/or worsen the response to antiparkinsonian medication. In the MPTP monkey model of PD, neurotoxic lesions which selectively ablate GPi and spare the adjacent structures result in dramatic improvement [58] but, in another study, bradykinesia worsened and the benefit from antiparkinsonian medication was reduced following radiofrequency lesions in the GPe [57]. Previous observations that loss of improvement achieved initially by pallidotomy may not occur until a year or more following surgery [45, 53] together with reports of worse clinical outcomes when lesions do not include the posteroventral portions of GPi [26, 53, 54] are difficult to reconcile with the conclusions drawn by Krauss et al. [38]. They concluded lesion location was not related to clinical outcome, however, they reported little variation in the location of their lesions in the GPi and reported only short-term clinical outcome using the global outcome measure. Interestingly in the one patient in their study who had no improvement in clinical outcome, the lesion was confined to the GPe. Thus, it appears that patients who experienced the most improvement in all symptoms without signs of regression had lesions that involved as much of the sensorimotor pallidum as possible without infringing on adjacent structures. These data are important since the targeted portion of the pallidum differed in some studies [32–34, 39, 40, 45] from that targeted by others [24–29, 31, 53, 54] and may account for much of the variability in outcomes and for the loss of benefit over time reported by others [46, 53]. In this regard, the loss of ipsilateral benefit after 6–12 months may also reflect differences in lesion location [41]. Patient assessment, patient selection, incidence of complications associated with the procedure or which occur subsequently during the time of patient assessment, and changes in medications also contributes to differences observed across studies. Age is a factor that must be taken into consideration when comparing the benefits of pallidotomy. Lang et al. [41] reported greater improvement for patients under age 65 versus those over 65. This is in contrast to reports by others in which no age relationship to clinical outcome was observed [27, 52]. Postoperative follow-up time is another factor that may play a significant role in the variability of reported clinical outcome. Since some patients may gradually lose part or all of their clinical benefit over time [41, 46, 49], particularly if the lesion is not well placed in the sensorimotor portion of GPi [26, 53, 54], studies with shorter follow-up are more likely to report better outcomes than those with longer follow-up. In the only study to report significant improvement in ‘on’ motor scores, nonstandardized methods of patient assessment were used to

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evaluate patients [32]. In other studies patients with only particular symptoms have been selected [27, 42]. In a study were the incidence of major complications was exceedingly high (31%, 8/26) there was a high variability in improvement in ‘off ’ motor scores ranging from 38% worsening to as much as 54% improvement [49]. Thus selection bias, the use of nonstandardized methods of clinical evaluation and lesion location make it difficult to compare the results of pallidotomy across studies or to fully assess the effect of pallidotomy on individual symptoms. The present controversies illustrate the need for more well-done randomized clinical outcome studies using standardized assessments by expert movement disorder specialist, high-quality surgical techniques by expert functional neurosurgeons, and postoperative 3-D high-resolution MRI reconstructions to document the lesion location. There has been only one randomized clinical trial comparing the effects of pallidotomy to best medical therapy [55]. The Emory randomized controlled clinical trial compared the effect of pallidotomy to best medical management in 36 patients followed for 6 months as well as the long-term benefit in 20 of these patients followed for 2 years after pallidotomy. Patients with idiopathic PD were randomized to medical therapy (n>18) versus unilateral GPi pallidotomy (n>18). The primary outcome variable was the change in total UPDRS score at 6 months. Secondary outcome variables included subscores and individual parkinsonian symptoms as determined from the UPDRS. At the 6-month follow-up, patients receiving pallidotomy had a statistically significant reduction (32% decrease) in the total UPDRS score compared to those randomized to medical therapy (5% increase). Compared to medical therapy, pallidotomy patients showed improvement in all the cardinal motor signs of PD including tremor, rigidity, bradykinesia, gait and balance. Drug-induced dyskinesias were also markedly improved in the surgical group. Although the greatest improvement occurred on the side contralateral to the lesion, significant ipsilateral improvement was also observed for bradykinesia, rigidity and drug-induced dyskinesias. Twenty of these patients followed for 2 years after pallidotomy showed sustained statistically significant improvement in the total UPDRS, off motor and many subscores. Sustained improvement was seen for tremor, rigidity, bradykinesia, percent on time and drug-induced dyskinesias. Although gait and balance were not significantly improved for the group at the 2-year follow-up, gait and balance remained considerably improved for 10 of the 20 patients. Medication requirements for the group were not significantly changed from baseline 2 years after postpallidotomy, suggesting that there was less need for continued increases in antiparkinsonian medication following pallidotomy. Over half of the patients were able to reduce their antiparkinsonian medications. This study provides class I proof of the efficacy of pallidotomy.

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Complications In one of the first pallidotomy series of the modern era, there was a 14% incidence of visual field deficits due to injury to the optic tract that passes below the target [40]. In a review of 303 nonduplicated patients [24–53] with current techniques, this complication should occur in =2% of patients. Face (7.0%) or limb weakness (2.9%) is usually transient, but permanent paralysis has been reported due to injury to the corticospinal tract that passes medial to the target (2.0%). Involuntary movements after lesioning of GPi are common and should resolve in hours or days and should not be considered complications [44]. Other major complications include symptomatic intraparenchymal hemorrhages along the lesioning tract, subdural empyema, subdural hematomas, seizures and postoperative encephalopathy, especially in elderly patients. Other reported complications of pallidotomy include hypophonia or increased difficulty with speech articulation, which are uncommon following unilateral procedures. Delayed capsular infarctions have been reported following pallidotomy in patients with preexisting cerebrovascular disease [59]. The overall incidence of serious, permanent complications is 1–2%. Death is rare. The neuropsychological and psychiatric findings support the hypothesis that treatment of PD with ventrolateral GPi pallidotomy does not have a significant negative impact on the patient’s affective status or cognitive state [25, 33, 60–62]. Improvement in motor symptoms with significant decline in cognitive function assessed by neuropsychological testing have been reported but those with anatomical correlation suggest lesions that are too anterior and include associative areas [31] or have too short a follow-up time [61]. In the Emory randomized trial, except for slight worsening in tests of letter fluency and visual recognition there was no significant change in neuropsychological function in the surgical group compared to those in best medical therapy at follow-up times ?3 months [55]. Psychiatric assessments revealed an improvement in anxiety and a decreased incidence of depression in the surgical compared to best medical therapy group. The occurrence of a major depressive episode in the 3 months prior to pallidotomy, however, was an important clinical variable since depressed patients tended to rate themselves lower on subjective scales of improvement (e.g. the Hoehn and Yahr and the Schwab and England). Thus, the presence of depression may add significant variability to the clinical data set and may significantly influence the reported results. Although part of the decreased incidence of depression in the surgical group could be accounted for by the associated improvement in motor function, no change in the affective status of patients following pallidotomy was found when there was significant improvement in motor function [Vitek, DeLong and Bakay, unpubl. obs.]. Thus, at least some of the associated improvement in anxiety and depression is independent of the

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effect on motor function and reflects the direct effect of lesioning the GPi. Whether this occurs as a result of infringement of the pallidal lesion on nonmotor portions of the pallidum or reflects a modulatory effect of the motor circuit on nonmotor functions remains to be determined. Following simultaneous or staged bilateral pallidotomy, the efficacy is better but the likelihood of significant speech deterioration has been reported to be as high as 60% [63, 64]. One group has reported that bilateral pallidotomy can produce major cognitive deficits. Even with staged bilateral pallidotomies, the majority of patients are hypophonic, to varying degrees. Others have not observed significant cognitive or speech changes in these patients, although they have not performed formal neuropsychological evaluation or speech testing. The safety of bilateral pallidotomy needs closer scrutiny before it can be routinely recommended and with the coming of DBS, it should be eliminated. In summary: Most contemporary studies cite significant benefit in parkinsonian motor signs following GPi pallidotomy which are sustained over the period of evaluation (varying from 6 months to 4 years). Although acute improvement in gait and postural stability are occasionally reported, the improvement is usually transient. Patients can maintain significant ipsilateral benefit for rigidity, bradykinesia and drug-induced dyskinesias during longterm follow-up. Patients with pallidotomy followed for up to 4 years have shown sustained benefit for all parkinsonian motor signs except gait and postural stability. Consistent with these observations, patients maintained significant improvement in the Schwab and England score of functional independence. Improvements in the motor symptoms of PD are associated with a significant increase in the level of functional independence. Although there are no significant improvements in ‘on’ scores for the motor or ADL subscores of the UPDRS, patients spent less time in the ‘off ’ state, the ‘off ’ is less severe, ‘on’ time is more predictable and the quality of ‘on’ time is improved by the reduction in drug-induced dyskinesia. In subsequent studies, it will be necessary to characterize the relationship between lesion location and other clinical variables to clinical outcome and the differential improvement in particular motor signs. These data may provide important clues to improving our understanding of the contribution of particular motor subcircuits to the development of parkinsonian motor signs. In addition they will further define the optimal target within the pallidum, the relationship between various clinical variables and clinical outcome following pallidotomy and provide a basis for critical comparisons across studies of pallidotomy as well as other surgical therapies for the treatment of PD. There are a number of procedures available to patients with movement disorders. The ablative procedures are most common, but the use of stimulation is rapidly increasing. The future is being explored with transplantation and gene therapy.

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References 1 2 3 4

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9 10

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15 16

17 18

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Vitek JL, Bakay RAE: The role of pallidotomy in Parkinson’s disease and dystonia. Curr Opin Neurol 1997;10:332–339. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1438. Meyers R: Surgical interruption of the pallidofugal fibres: Its effect on the syndrome paralysis agitans and technical considerations in its application. NY State J Med 1942;42:317–325. Svennilson E, Torvik A, Lowe R, Leksell L: Treatment of parkinsonism by stereotactic thermolesions in the pallidal region: A clinical evaluation of 81 cases. Acta Psychiatr Neurol Scand 1960;35: 358–377 Cooper IS, Bergman LL, Caracalos A: Anatomic verification of the lesion which abolishes parkinsonian tremor and rigidity. Neurology 1963;13:779–787. Hassler R, Mundingr F, Reichert T: Correlation between clinical and autoptic findings in stereotaxic operations of parkinsonism. Confin Neurol 1965;26:282–290. Alexander GE, Crutcher MD, DeLong MR: Basal ganglia-thalamocortical circuits: Parallel substrates for motor oculomotor, ‘prefrontal’ and ‘limbic’ functions. Prog Brain Res 1990;85:119–146. Rye DB, Turner RS, Vitek JL, Bakay RAE, Crutcher MD, DeLong MR: Anatomical investigations of the pallidotegmental pathway in monkey and man; in Ohye C (ed): The Basal Ganglia. V. New York, Plenum Press, 1996, vol 5, pp 59–75. DeLong MR, Wichmann T: Basal ganglia-thalamocortical circuits in parkinsonian signs. Clin Neurosci 1993;1:18–26. Spiegel EA, Wycis HT: Pallido-ansotomy: Anatomic-physiological foundation and histopathologic control; in Field WS (ed): Pathogenesis and Treatment of Parkinsonism. Springfield, Thomas, 1958, pp 86–105. Iacono R, Kuniyoshi S, Lonser R, et al: Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans. Pediatr Neurol 1996;14:145–148. Lozano A, Kumar R, Gross R, et al: Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997;12:865–870. Ondo W, Desaloms J, Jankovic J, Grossman R: Pallidotomy for generalized dystonia. Mov Disord 1998;13:693–698. Vitek JL, Zhang J, Evatt ML, Mewes K, DeLong MR, Hashimoto T, Triche S, Bakay RAE: GPi pallidotomy for dystonia: Clinical outcome and neuronal activity. Adv Neurol Dystonia 1998;78: 211–219. Vitek JL, Chockkan V, Zhang J, Kaneoke Y, Evatt M, Delong MR, et al: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22–25. Obeso J, Alvarez L, Macias R, Guridi J, Teijeiro J, Juncos J, Rodriguez M, Ramos E, Linazasoro G, Gorospe A, DeLong M: Lesion of the subthalamic nucleus in Parkinson’s disease (abstract). Neurology 1997;48:138. Gill S, Heywood P: Bilateral subthalamic nucleotomy can be accomplished safely. Mov Disord 1998;13:201. Volkman J, Sturn V, Weiss P, Kappler J, Voges J, Koulousakis A, Lehrke R, Hefter H, Freund HJ: Bilateral high-frequency stimulation of the internal globus pallidus in advanced Parkinson’s disease. Ann Neurol 1998;44:953–961. Siegfried J, Lippitz B: Chronic electrical stimulation of the VL-VPL complex and of the pallidum in the treatment of movement disorders: Personal experience since 1982. Stereotact Funct Neurosurg 1994;62:71–75. Kumar R, Lozano AM, Montgomery E, Lang AE: Pallidotomy and deep brain stimulation of the pallidum and subthalamic nucleus in advanced Parkinson’s disease. Mov Disord 1998;13(suppl 1):73–82. Starr PA, Vitek JL, Bakay RAE: Ablative surgery and deep brain stimulation for Parkinson’s disease. Neurosurgery 1998;43:989–1015. Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R: Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997;42:283–291.

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30

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36 37 38

39 40 41 42 43

44

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Burchiel KJ, Anderson VC, Favre J, Hammerstad JP: Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson’s disease: Results of a randomized, blinded pilot study. Neurosurgery 1995;45:1375–1384. Alterman RL, Kelly PJ: Pallidotomy technique and results: The New York University experience. Neurosurg Clin North Am 1998;9:337–343. Baron MS, Vitek JL, Bakay RA, Green J, Kaneoke Y, Hashimoto T, Turner RS, Woodard JL, Cole SA, McDonald WM, DeLong MR: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355–366. Bronte-Stewart H, Hill B, Molander M, Kaufman R, Pappas C, Fross R, Klingman J: Lesion location predicts clinical outcome of pallidotomy. Mov Disord 1998;13:300. Dogali M, Fazzine E, Kolodny E, et al: Stereotactic ventral pallidotomy for Pakinson’s disease. Neurology 1995;45:753–761. Fazzini E, Dogali M, Stereo D, Eidelberg D, Beric A: Stereotactic pallidotomy for Parkinson’s disease: A long-term follow-up of unilateral pallidotomy. Neurology 1997;48:1273–1277. Giller CA, Dewey RB, Ginsburg MI, Mendelsohn DB, Berk AM: Stereotactic pallidotomy and thalamotomy using individual variations of anatomic landmarks for localization. Neurosurgery 1998;42:56–62. Ghika J, Ghika-Schmid F, Fankhauser H, et al: Bilateral contemporaneous posteroventral pallidotomy for the treatment of Parkinson’s disease: Neuropsychological and neurological side effects. Report of four cases and reveiw of the literature. J Neurosurg 1999;91:313–321. Gross RE, Lombardi WJ, Lang AE, Duff J, Hutchison WD, Saint-Cyr JA, Tasker RR, Lozano AM: Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson’s disease. Brain 1999;122:405–416. Iacono RP, Lonser RR: Reversal of Parkinson’s akinesia by pallidotomy. Lancet 1994;343:418–419. Iacono RP, Shima F, Lonser RR, Kuniyoshi S, Maeda G, Yamada S: The results, indications, and physiology of posteroventral pallidotomy for patients with Parkinson’s disease. Neurosurgery 1995; 36:1118–1127. Johansson F, Malm J, Nordh E, Hariz M: Usefulness of pallidotomy in advanced Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997;62:125–132. Kishore A, Turnbull I, Snow B, de la Fuente-Fernandez Schulzer M, Yardley S, Calne D: Efficacy stability and predictors of outcome of pallidotomy for Parkinson’s disease. Six-month follow-up with additional one-year observations. Brain 1997;120:729–737. Kondziolka D, Bonaroti E, Baser S, Brandt F, et al: Outcomes after stereotactically guided pallidotomy for advanced Parkinson’s disease. J Neurosurg 1999;90:197–202. Kopyov O, Jacques D, Duma C, et al: Microelectrode-guided posteroventral medial radiofrequency pallidotomy for Parkinson’s disease. J Neurosurg 1997;87:52–59. Krauss JK, Desaloms JM, Lai EC, King DE, Jankovic J, Grossman RG: Microelectrode-guided posteroventral pallidotomy for treatment of Parkinson’s disease: Postoperative magnetic resonance imaging analysis. J Neurosurg 1997;87:358–367. Laitinen LV. Pallidotomy for Parkinson’s disease. Neurosurg Clin North Am 1995;6:105–112. Laitinen LV, Bergenheirn AT, Hariz MI: Leksell’s postroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Lang A, Lozano A, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:1036–1042. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Masterman D, DeSalles A, Baloh RW, Frysinger R, Foti D, Behnke E, Cabatan-Awang C, Hoetzel A, Intemann PM, Fairbanks L, Bronstein JM: Motor, cognitive, and behavior performance following unilateral ventroposterior pallidotomy for Parkinson’s disease. Arch Neurol 1998;55:1201–1208. Marello M, Cammarota A, Betti O, Nouzeilles MI, et al: Involuntary movements during thermolesion predict a better outcome after microelectrode-guided posteroventral pallidotomy. J Neurol Neurosurg Psychiatry 1997;63:210–213. Narabayashi H: Pallidotomy revisited. Analysis of posteroventral pallidotomy. Stereotact Funct Neurosurg 1997;69:54–61.

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Samii A, Turnbull IM, Kishore A, Schulzer M, Mak E, Yardley S, Calne DB: Reassessment of unilateral pallidotomy in Parkinson’s disease. A 2-year follow-up study. Brain 1999;122:417–425. Samuel M, Caputo E, Brooks DJ, et al: A study of medial pallidotomy for Parkinson’s disease: Clinical outcome, MRI location and complications. Brain 1998;121:59–75. Shima F, Ishido K, Sun S, Machi T, Kamikaseda K, Fukui M, Kato M: Surgical control of akinesia in Parkinson’s disease. Eur Neurol 1996;36(suppl 1):55–61. Shannon KM, Penn RD, Kroin JS, Adler CH, Janko KA, York M, Cox SJ: Stereotactic pallidotomy for the treatment of Parkinson’s disease. Efficacy and adverse effects at 6 months in 26 patients. Neurology 1998;50:434–438. Scott R, Gregory R, Hines N, Carroll C, Hyman N, Papanasstasiou V, Leather C, Rowe J, Silburn P, Aziz T: Neuropsychological, neurological and functional outcome following pallidotomy for Parkinson’s disease. A consecutive series of eight simultaneous bilateral and twelve unilateral procedures. Brain 1998;121:659–675. Sutton JP, Couldwell W, Lew MF, Mallory L, Grafton S, DeGiorgio C, Welsh M, Apuzzo MLJ, Ahmadi J, Waters CH: Ventroposterior medial pallidotomy in patients with advanced Parkinson’s disease. Neurosurgery 1995;36:1112–1117. Uitti RJ, Wharen RE Jr, Turk MF, Lucas JA, Finton MJ, Graff-Radford NR, Boylan KB, Goerss SJ, Kall BA, Adler CH, Caviness JN, Atkinson EJ: Unilateral pallidotomy for Parkinson’s disease: Comparison of outcome in younger versus elderly patients. Neurology 1997;49:1072–1077. Vitek J, Bakay R, DeLong M: Microelectrode-Guided Pallidotomy for Medically Intractable Parkinson’s Disease. Adv Neurol. Philadelphia, Lippincott-Raven, 1997, pp 183–198. Vitek JL, Bakay RAE, Hashimoto T, Kaneoke Y, Mewes K, Zhang J, Rye D, Starr P, Baron M, Turner R, DeLong MR: Microelectrode-guided pallidotomy: Technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998;88:1027–1043. Vitek JL, Bakay RAE, Freeman A, Evatt ML, Green J, McDonald W, Haber M, Barnhardt H, Triche S, Mewes K, Chockkran V, Zhang J, Wahlay N, Delong MR: Randomized clinical trial of pallidotomy versus medical therapy for Parkinson’s disease. Ann Neurol 2000; in press. Hoover JE, Strick PL: Multiple output channels in the basal ganglia. Science 1993;259:819–821. Zhang J, Mewes K, Chockkan V, Vitek J: The effect of GPe lesions on GPi cell activity and motor behavior in the MPTP-treated monkey. Soc Neurosci Abstr 1997;23:542. Lonser RR, Corthesy ME, Morrison PF, Gogate N, Oldfield EH: Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates. J Neurosurg 1999;91:294–302. Lim JY, De Salles AA, Bronstein J, Masterman DL, Saver JL: Delayed internal capsule infarctions following radiofrequency pallidotomy. Report of three cases. J Neurosurg 1997;87:955–960. Soukup VM, Ingram F, Schiess MC, Bonnen JG, et al: Cognitive sequelae of unilateral posteroventral pallidotomy. Arch Neurol 1997;54:947–950. Junque C, Montse Alegret BA, Nobbe FA, Valldeoriola F, et al: Cognitive and behavioral changes after unilateral posteroventral pallidotomy: Relationship with lesional data from MRI. Mov Disord 1999;14:780–789. Perrine K, Dogali M, Fazzini E, et al: Cognitive functioning after pallidotomy for refractory Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998;65:150–154. Favre J, Taha JM, Kim J, Burchiel KJ: Pallidotomy: A survey of current practice in North America. Neurosurgery 1996;39:883–890. Taha JM, Favre J, Burchiel KJ: Bilateral pallidotomy for the treatment of Parkinson’s disease; in Krauss JK, Grossman RG, Jankovic J (eds): Pallidal Surgery for the Treatment of Parkinson’s Disease and Movement Disorders. Philadelphia, Lippincott-Raven, 1998.

R.A.E. Bakay, MD, Department of Neurosurgery, Emory University, 1365-B Clifton Road N.E., Atlanta, GA 30322 (USA) Tel. +1 404 778 3094, Fax +1 404 778 5121, E-Mail [email protected]

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Non-Microelectrode Recording-Guided Pallidotomy J. Bowen a, L.E. Munro-Davies a, P. Silburn c, R. Gregory a, P. Bain b, R.B. Scott a, C. Joint a, B. Hall c, J. Stein a, T. Aziz a, b a b c

Oxford Movement Disorder Group, Radcliffe Infirmary, Oxford, UK; Charing Cross Hospital, London, UK, and Princess Alexandra Hospital, Brisbane, Qld., Australia

The 1990s have seen a transformation in the clinical management of Parkinson’s disease (PD). The recognition of the limitations of long-term dopamine agonist therapy was accompanied by a phenomenal increase in the understanding of the neural mechanisms underlying parkinsonism from studies in the MPTP-exposed parkinsonian primate model [Mitchell et al., 1989]. At the same time, the study by Latinen et al. [1992] confirmed that a posteroventral pallidotomy could significantly alleviate the cardinal symptoms of the condition and drug-induced dyskinesias. The same study also underscored the need for a techique that could accurately target the medial pallidum to avoid complications such as visual field deficits and hemiplegia. Historically, histological studies have shown that even with ventriculography, localization of deep brain nuclei was hampered by inaccuracies secondary to individual anatomical variability by as much as 5.0 mm in the basal ganglia [Van Buren and McCubbin, 1962]. Computer tomography (CT) scan stereotaxy is only as good as ventriculography because it can only define the anterior and posterior commissures, not the nuclei directly. That being the case, it is critical to use the most accurate form of localization possible to minimize complications in a patient group that is disabled even prior to surgery. If CT or ventriculography is used, physiological confirmation with the use of microelectrode recording is critical. Magnetic resonance imaging (MRI) stereotaxy is seductive because the images obtained show the relevant structures clearly, however field distortions can result in localization inaccuracies of up to 5 mm, too much error in this form of surgery.

Ideally a stereotactic technique that combines the clarity of MRI images with the linear accuracies of CT scanning would be ideal to directly target these critical regions. If so, it would also be possible to eliminate the need for prolonged microelectrode recording as the effects of macrostimulation in an accurately predetermined region could be studied effectively and quickly. Time is important as this patient cohort is one that tires very quickly and they are ‘off’ medication for the procedure. In 1993, two developments led the Oxford group to consider MRI and CT fusion techniques to functional surgery. The work of Alexander and coworkers [Alexander et al., 1996; Kooy et al., 1994] describing the methodology of volumetrically fusing MRI scans to CT scans in acquisition of targets for radiosurgery and eliminating thereby MRI field distortions led to the ImageFusionTM programme. This, in combination with a stereotactic planning system, StereoPlanÔ (both prototypes developed by Radionics) allowed for direct and accurate targeting of the medial pallidum. As a result, anatomical localization combined with careful intraoperative examination of the patient would allow for accurate lesion placement. Furthermore, in collaboration with Radionics, the Schaltenbrand and Wahren [1977] functional atlas was incorporated in the software with the ability to alter the proportions in a manner to make it applicable to the patient’s anatomy. We describe our technique using ImageFusion and StereoPlan in performing PVP without microelectrode guidance. We aimed from the beginning to answer several questions: Is PVP effective for alleviation of PD and in which type of patient? Does the neurological improvement correlate with improved quality of life? Are there any cognitive trade-offs and a general complication rate? The surgeon was to remain independent of the assessments. Functional surgery is a multidisciplinary speciality [Aziz and Bain, 1996] and the group comprises a neurosurgeon, neurologist, neuropsychologist, neuroanaesthetist, neurophysiologist, and a specialist nurse.

Patient Selection Patients with PD were selected from those referred to movement disorder clinics staffed by a neurologist and neurosurgeon in each centre. All patients satisfied United Kingdom PD Society brain bank diagnostic criteria for idiopathic PD [Gibb and Lees, 1988] and most had intractable drug-induced dyskinesias and had failed optimum medical therapy. Any general medical, surgical or neuropsychological contraindications were identified, including for example, significant dysarthria, dysphagia, excessive salivation/drooling, ‘on’ gait freezing, dementia or major psychiatric disorder. Patients had to be

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Table 1. Demographic features of patients UPVP – L>23, R>12 (n>35)

BPVP – sequential 5, simultaneous 35 (n>40)

Number by centre, Oxford/Brisbane

27/11

18/22

Sex, m/f

20/16

24/16

Age, mean (range)

59 (44–79)

62 (43–79)

PD duration, years, mean (range)

13 (4–23)

15 (5–26)

Hoehn & Yahr, mean (95% CI) ‘On’ state ‘Off’ state

2.9 (2.5–3.2) 3.5 (3.1–3.8)

3.2 (2.9–3.4) 4.2 (3.8–4.6)

Daily L-dopa, g, mean (range)

1.0 (0.3–2.5)

1.2 (0.3–2.5)

Follow-up, months, mean (range)

7 (3–22)

6 (2–22)

L-dopa responsive and show that even for a brief period during the day they had windows of quality time. On average, approximately 1 in 3 of all patients seen in clinic were considered appropriate for a PVP. The demographic features of our series are shown in table 1. Outcome was assessed in a total of 75 parkinsonian patients from Radcliffe Infirmary, Oxford, UK, Charing Cross Hospital, London, UK and Princess Alexandra Hospital, Brisbane, Australia, who had unilateral (left n>23, right n>12) or bilateral (n>40) pallidotomies (UPVP and BPVP). Sequential BPVP was reserved for patients in whom UPVP resulted in inadequate symptomatic relief (n>5). Simultaneous BPVP (n>35) was performed in cases where there were essentially symmetrical bilateral symptoms. All patients underwent identical preoperative and 3- to 6-month follow-up neurological assessments at each of the three participating centres; further follow-up has continued annually thereafter (average follow-up 6.5 months, range 3–22). Changes in medication were minimized during this period.

Patient Assessment Patients completed a multidisciplinary assessment protocol in the 4 weeks preceding surgery and 3–6 months postoperatively. The latter time frame was considered long enough for postoperative recovery and patient re-engagement

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in everyday routines, but short enough to minimize the likelihood of interference effects from disease progression. Neurological Assessments Neurological assessments were completed independently of the surgeon. The assessment protocol comprised the Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn & Yahr (H&Y) grade and Schwab & England (S&E) scores. Confrontational visual fields were plotted using a Humphrey field analyser. The last recorded assessments are reported in this series. For patients undergoing staged bilateral procedures, only the final assessment is included. Neuropsychological and Functional Assessments Patients were evaluated in the ‘on’ state in the 4 weeks preceding surgery and 3–6 months postoperatively. The assessment protocol typically included a semistructured interview to screen for any Axis I DSM-IV diagnoses, questionnaire measures of functional disability, quality of life and psychological symptomatology and a comprehensive battery of cognitive tests [Scott et al., 1998]. The current protocol has however evolved with the benefit of clinical experience since 1994; therefore, not all data sets are available for all patients in the neuropsychological series.

Surgical Technique First a preoperative T1-weighted MRI scan using a 3-D Turbo-Flash sequence (TE 7 ms, TR 15 ms) and a Siemens 1.5 T Magnetom Vision Scanner is acquired. Just before the operation and under general anaesthesia the Cosman-Roberts-Wells (CRWTM) head ring is fixed to the patient’s head low enough to acquire a CT scan of the entire skull. We prefer to use a general anaesthetic for this stage to avoid patient movement and for patient comfort. A stereotactic CT scan of the entire skull is acquired using 3-mm contiguous slices. Next the MRI and stereotactic CT are transferred to the StereoPlan workstation. Using the ImageFusion software, the MRI is aligned to the stereotactic CT with at least three anatomic landmarks (fig. 1); we use the lenses of the eyes and the pineal gland. Once alignment is complete the ImageFusion software volumetrically correlates the MRI image set to the stereotactic CT, independently scaling X, Y, Z and all rotational axes. Upon completion of the entire correlation of the MRI to the stereotactic CT, the StereoPlan software is employed to preoperatively plan a surgical trajectory for electrode placement. The spatially corrected and volumetrically correlated MRI is used for anatomic localization of the Gpi that is clearly seen on the Turbo-Flash MRI images (fig. 2). Further anatomic verification is performed with the AtlasPlan module of StereoPlan. The Schaltenbrand and Wahren Atlas (used in the software with permission from Thieme) is co-registered with patient anatomy by the AC and PC points as well as a known lateral landmark (we compare the putaminopallidal boundary of the patient’s scan to that in the atlas). The AtlasPlan module then shows the placement of the target on the Schaltenbrand and Wahren Atlas images. The planned trajec-

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Fig. 1. Radionics ImageFusionTM display of patient CT and MRI images for landmark selection and alignment.

tory can be evaluated with the StereoPlan software once the arc angles are set to enter from an entry point 1.0 cm anterior to the coronal suture and 5–6.0 cm lateral to the midline with the CRW arc system in place. Whilst planning the procedure the patient is woken up after insertion of an arterial line to monitor blood pressure. The patient’s blood pressure is maintained at 20 mm Hg below their normal systolic pressure using intravenous hydralazine or sublingual labetolol. We do not routinely shave the patient’s hair but clean it on the table with aqueous and alcoholic chlorhexidine and then shave a few hairs at the point of entry. A dermal skin punch is then used to incise the skin and a 4 mm twist drill made along the planned trajectory, the dura is then punctured with a biopsy cannula. This prevents any significant CSF leakage that would cause brain sag. For a PVP, the entry point chosen is 1.0 cm anterior to the coronal suture and 5–6.0 cm lateral to the midline. This approach avoids the internal capsule and allows for lesions to be placed from medial to lateral in a single pass of the electrode. Having determined the coordinates using ImageFusion and StereoPlan, the electrode (2 mm exposed tip, 1.8 mm diameter) is passed to the target. We choose the initial target to

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Fig. 2. Fused MRI image with atlas corrected proportionately for patient, showing medial pallidal borders and target selected (+).

be in the medial pallidum just beyond the Gpe and Gpi border and all lesions are placed ventromedially (fig. 3). This avoids encroaching onto the lateral pallidum which may have untoward effects. Despite the large number of cases published, there is still no precise target as such that one could aim for and obtain reliably good results. We feel that in the anteroposterior direction, the posterior half of the medial pallidum should be the target region. In the coronal plane the lesions are localized to the medial pallidum without a great deal of encroachment into the ansa lenticularis. Impedance using this electrode is 500–700 X in the pallidum. Stimulation at 100 Hz beginning at 2.0 mm above the calculated target is then begun with the attending neurologist examining the patient. The electrode is advanced in 1.0-mm steps and testing repeated. The optimal site is that at which rigidity, bradykinesia and if present, tremor are alleviated at 0.5–1.0 V at 100 Hz. Very occasionally, patients may show exacerbation rather than alleviation of symptoms. We feel that it is important to examine the patient during the first pass of the electrode as impedance is measured since the stun effect of passing the electrode to the anticipated end target may render subsequent neurological examination unhelpful. It may be that this is why many groups do not find macrostimulation and

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Fig. 3. Target location and approach trajectory.

examination helpful. Certainly multiple passes to plot single cell activity will cause a significant stun effect. The electrode is then advanced until the impedance begins to rise to about 800–1,100 X which indicates that the bottom of the medial pallidum has been reached and no further advancement is made. If capsular motor responses are not obtained at less than 2.0 V and 2 Hz, and there are no visual phosphenes on stimulation at 3.5–4.0 V, it is safe to begin lesioning. Another confirmatory sign that we find is one of bobbing of the patient’s tongue at 2 Hz and 2.0 V. The first is a temporary lesion at 45 C for 60 s and if there are no side effects the first lesion is placed at 75 C for 30 s, the electrode is then withdrawn 2.0 mm and a second lesion made at 75 C for 60 s and on withdrawing another 2.0 mm a final lesion is made at 75 C for 60 s if bilateral lesions are made and 90 s if not (fig. 4). It is not unusual to observe what we call release dyskinesias on completing the lesions, these tend to herald a good clinical outcome and vary in duration from a few minutes to a few days. The lesions thus obtained are 100–150 mm3 in volume overall, with BPVP we aim to make the lesions asymmetrical with a smaller lesion (D100 mm3) in the dominant hemisphere and the larger (D150 mm3) in the nondominant side.

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Fig. 4. Postoperative MRI showing bilateral pallidal lesions (2 years postsurgery).

Results Neurological Outcome Statistical Analysis. Median and mean scores with 95% confidence intervals were calculated for all variables described above. Pre- and postoperative scores were analysed with Student’s t-test. In view of the large number of analyses undertaken, significance was assumed at p=0.001; however p values between 0.05 and 0.01 were treated with caution and are annotated accordingly in an attempt to minimize type 1 errors. Mean scores with 95% confidence intervals were calculated for UPDRS subscales and total scores (table 2), and individual parameters of functional significance (e.g. ‘gait’ and ‘falls’). Similar changes in scores of cardinal

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Table 2. Mean UPDRS scores following PVP

Unilateral PVP Total UPDRS max>199 Part 1 max>16 Part 2 ADL max>52 ‘On’ state ‘Off’ state Part 3 motor max>108 ‘On’ state ‘Off’ state Part 4 max>23 Hoehn & Yahr max>5 ‘On’ state ‘Off’ state Schwab & England max>100 ‘On’ state ‘Off’ state Bilateral PVP Total UPDRS max>199 Part 1 max>16 Part 2 ADL max>52 ‘On’ state ‘Off’ state Part 3 motor max>108 ‘On’ state ‘Off’ state Part 4 max>23 Hoehn & Yahr max>5 ‘On’ state ‘Off’ state Schwab & England max>100 ‘On’ state ‘Off’ state Drug therapy, L-dopa, g/day

Preoperative

Postoperative

mean

95% CI

mean

95% CI

78.81 2.30

70.22–87.39 1.71–2.89

56.22 1.87

48.44–64.01 1.26–2.48

=0.0001 =0.040

12.29 22.85

10.06–14.53 19.25–26.46

8.32 16.56

6.49–10.16 13.68–19.44

=0.0007 =0.001

20.18 43.21 10.06

16.86–23.49 37.84–48.59 8.87–11.24

15.41 31.55 6.00

12.87–17.95 26.81–36.28 4.82–7.18

=0.003 =0.0001 =0.0001

2.9 3.5

2.6–3.2 3.2–3.8

2.4 2.9

2.2–2.6 2.6–3.2

p value t-test

=0.008 =0.0001

64 36

58–70 30–42

77 52

72–82 45–59

=0.011 =0.023

93.10 3.69

86.72–99.38 2.97–4.42

59.30 3.05

55.15–63.50 2.38–3.72

=0.0001 =0.049

14.90 26.83

13.15–16.65 24.63–29.02

11.58 17.40

10.02–13.13 15.66–19.14

=0.007 =0.0001

30.10 52.95 9.98

26.74–33.46 48.80–57.10 9.23–10.72

21.78 33.75 3.05

19.58–23.97 32.98–38.52 2.56–3.54

=0.0001 =0.0001 =0.0001

3.2 3.8

3.0–3.4 3.5–4.1

2.7 3.1

2.5–2.9 2.9–3.3

=0.0003 =0.0001

67 43 1.2

62–72 37–49 0.3–2.5

76 57 1.1

71–81 52–62 0.15–2.1

=0.020 =0.0003 =0.24

max>Worst possible score; italicized probability values denote a highly significant result; 95% CI>95% confidence interval.

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parkinsonian features of tremor, rigidity, and bradykinesia were also calculated for UPVP (table 3), with ipsilateral and contralateral subscale analysis, and for patients undergoing BPVP (table 4). H&Y grades and S&E scores were also recorded. Unilateral Pallidotomy UPDRS. Pre- and postoperative scores following UPVP are shown in table 2. Total UPDRS decreased from a preoperative mean of 78.81 to 56.22 (28.8%), the H&Y improved significantly in both the ‘on’ and ‘off’ state. Although there is a significant improvement in activities of daily living, these reflect the benefits that accrue contralaterally. No overall improvement is seen in gait, freezing and speech. Mean H&Y scores were only available for 24 patients. There was no overall change in the S&E scores. Bilateral Pallidotomy UPDRS. Pre- and postoperative scores following BPVP are shown in table 2. Total UPDRS scores decreased from 93.1 to 59.3 (36.3%). Significant improvements were observed in mean scores for total UPDRS, part 2 (Activities of Daily Living), part 3 (Motor Examination), both in ‘on’ and ‘off’ states, and part 4 (Complications of Therapy). Additional nonsignificant improvements were also noted in parts 1 (Mentation, Behaviour and Mood). For the BPVP series as a whole, cardinal parkinsonian features of rest tremor, rigidity, and bradykinesia together with drug-induced dyskinesia and duration of ‘off’ time all improved: p=0.001 (table 4). For drug-induced dyskinesias, all patients improved. ‘Off’ time was reduced significantly, despite no significant change in drug therapy (table 2). No overall improvements were seen in freezing, speech and swallowing and gait improved only in the ‘off’ state. Mean S&E scores for ‘dependence’ improved significantly in the ‘off’ state only. Mean H&Y scores improved significantly in both ‘on’ and ‘off’ states. Drug Therapy. All patients were taking levodopa/dopa-decarboxylase inhibitors preoperatively. Mean daily levodopa dose fell nonsignificantly from 1.2 to 1.1 g (table 2). Neuropsychological and Functional Outcome Patient Characteristics. The sample of patients on whom neuropsychological and functional outcome can be reliably reported differs from those with neurological outcomes. It includes 37 PD patients who had UPVP (left UPVP>21; right PVP 16) and 37 who had BPVP; 5 patients were treated at

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Table 3. Mean scores following UPVP Preoperative

Postoperative

p value t-test

mean

95% CI

mean

95% CI

Tremor max>8 Ipsilateral Contralateral

1.58 2.53

1.05–2.12 1.78–3.28

1.29 1.03

0.80–1.77 0.54–1.51

0.31 =0.002

Rigidity max>8 Ipsilateral Contralateral

3.07 4.7

2.51–3.63 4.22–5.18

2.59 2.5

1.97–3.20 1.99–3.01

0.15 =0.0001

Bradykinesia max>16 Ipsilateral Contralateral

6.6 8.27

5.37–7.83 7.23–9.31

5.84 5.40

4.77–6.91 4.62–6.18

0.17 =0.0001

‘Off’ state max>4 Duration

1.5

1.29–1.71

1.06

0.87–1.25

=0.003

Dyskinesia max>4 Duration Disability Pain

1.76 1.62 0.97

1.43–2.10 1.26–1.97 0.59–1.35

1.21 0.68 0.21

0.83–1.58 0.36–0.99 0.00–0.41

=0.008 =0.0001 =0.007

Falls max>4 ‘On’ state ‘Off’ state

1.06 1.37

0.68–1.44 0.88–1.87

0.62 0.91

0.35–0.88 0.60–1.23

=0.007 0.055

Freezing ‘On’ state ‘Off’ state

0.62 1.71

0.31–0.92 1.24–2.19

0.53 1.4

0.26–0.79 1.04–1.76

0.59 0.10

Gait max>4 ‘On’ state ‘Off’ state

1.12 1.83

0.85–1.39 1.48–2.17

0.79 0.91

0.59–1.00 1.48–2.17

0.026 0.031

Speech (subject) max>4 ‘On’ state ‘Off’ state

0.91 1.61

0.57–1.24 1.26–1.96

0.79 1.45

0.50–1.09 1.11–1.80

0.54 0.32

Speech (object) max>4 ‘On’ state ‘Off’ state

0.88 1.77

0.52–1.24 1.42–2.12

0.88 1.61

0.61–1.14 1.24–1.96

1 0.33

max>Worst possible score; italicized probability values denote a highly significant result; 95% CI>95% confidence interval.

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Table 4. Mean scores following BPVP Preoperative

Postoperative

mean

mean

95% CI

95% CI

p value t-test

Tremor max>16

4.55

3.03–6.07

1.93

1.17–2.67

=0.0003

Rigidity max>16

10.05

8.85–11.25

5.5

4.38–6.62

=0.0001

Bradykinesia max>36

22.56

20.23–24.87

16.25

14.80–17.70

=0.0001

‘Off’ state max>4 Duration

1.53

1.30–1.75

1.00

0.85–1.15

=0.0004

Dyskinesia max>4 Duration Disability Pain

2.03 1.78 0.80

1.71–2.34 1.49–2.12 0.46–1.14

0.40 0.10 0.13

0.19–0.61 0.01–0.19 0.00–0.30

=0.0001 =0.0001 =0.0006

Falls max>4 ‘On’ state ‘Off’ state

1.18 1.65

0.85–1.50 1.20–2.10

0.85 1.18

0.54–1.16 0.84–1.51

0.046 0.040

Freezing max>4 ‘On’ state ‘Off’ state

1.08 2.08

0.77–1.38 1.66–2.49

1.18 1.88

0.80–1.55 1.53–2.22

0.70 0.41

Gait max>4 ‘On’ state ‘Off’ state

1.49 2.64

1.24–1.74 2.34–2.93

1.13 1.83

0.88–1.37 1.55–2.10

0.025 =0.0001

Speech (subject) max>4 ‘On’ state ‘Off’ state

1.28 1.90

1.03–1.52 1.55–2.52

1.9 1.68

1.55–2.25 1.39–1.96

0.10 0.09

Speech (object) max>4 ‘On’ state ‘Off’ state

1.33 1.89

1.07–1.58 1.58–2.19

1.31 1.71

1.10–1.53 1.45–1.98

0.92 0.21

Swallowing max>4 ‘On’ state ‘Off’ state

0.35 0.83

0.15–0.55 0.53–1.12

0.25 0.45

0.08–0.42 0.24–0.66

0.44 0.017

Stability max>4 ‘On’ state ‘Off’ state

1.44 2.08

1.16–1.71 1.76–2.39

0.91 1.70

0.66–1.16 1.42–1.97

=0.0008 0.018

max>Worst possible score; italicized probability values denote a highly significant result; 95% CI>95% confidence interval.

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Charing Cross Hospital, London, 42 at Radcliffe Infirmary, Oxford and 27 at Princess Alexandra Hospital, Brisbane. There was no significant difference between the UK and Brisbane series in terms of patients’ presenting total UPDRS scores (UK mean>88; Brisbane mean>81), age (UK mean>58, Brisbane mean>62) or IQ (both groups>100). Brisbane patients however scored somewhat higher on self-rated FLP total % disability (UK>25%, Brisbane>29%) and had significantly higher (p=0.01) scores above caseness on the HADS (UK anxiety 7, depression 6; Brisbane 11 and 9, respectively). All but 2 of the patients studied were right-handed. There were 42 men and 32 women. Patients acted as their own controls and a paired sample t-test was employed to test the null hypothesis of no difference between baseline follow-up scores on questionnaire measures and psychometric tests. Given the large number of t-tests applied in these analyses, an a of 0.01 was chosen to reduce the chances of a type 1 error. For nonparametric data the Wilcoxon signed rank test was employed. UPVP Outcomes. Total UPDRS scores fell by 28% from 75 to 54 (p=0.001). Although scores on almost all questionnaire subscales moved towards improved ‘quality of life’ (and reduced functional disability/psychological symptomatology), only the physical functioning, energy-vitality, and bodily pain subscales of the SF-36, and the mobility and ADL subscales of the Parkinson’s Disease Questionnaire-39 (PDQ-39) improved significantly (p=0.001). Following a left UPVP there has been some evidence to suggest ‘ipsilateral’ cognitive deficits that mirror other large, well-studied series [Trepanier et al., 1998]. There was a trend toward improved (10%) speech articulation rates, but some language functions deteriorated. Following a right UPVP there was a similar (10%) trend toward improved speech articulation but no significant changes in language function. Rather, a deterioration of scores in the visuospatial domains were observed. There were no other significant cognitive changes following UPVP, and no subjective reports of any cognitive or emotional difficulties. BPVP Outcomes. Total UPDRS fell significantly by 35% from a mean of 94 to 61 (p=0.001). Similarly there was a 31% significant fall in total % disability scores on the Functional Limitations Profile from 29 to 20% (p=0.001). In addition to those subscales that were found to change toward improved quality of life following a UPVP, significant improvement was also observed in the anxiety subscale of the Hospital Anxiety and Depression Scale (p=0.001), the bodily discomfort, stigma and emotional well-being subscales of the PDQ-39, and the general mental health and social functioning subscales of the SF-36.

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Cognitive outcome following BPVP included the language deficits observed following a left UPVP but not those visuospatial deficits observed following a right UPVP. This was not an unexpected finding given that lesions in BPVP were intentionally asymmetrical. However, there were additional changes including a 26% fall in phonemic verbal fluency, and a 30% increase in visual scanning time on a test of visual neglect (p=0.001). There was also a trend toward postoperative deterioration in performance on various selective tests of attention and organization. These changes are suggestive of an emerging and relatively selective constellation of executive (i.e. ‘frontal-striatal’) deficits. Interestingly, Trepanier et al. [1998] have also reported a deterioration in ‘frontal-executive’ functioning in 25–30% of their series of 42 patients following UPVP, and deteriorating performance on similar cognitive measures, although the frequency and extent of these changes was much greater than we have observed following either UPVP or BPVP. There were seven subjective reports of cognitive or emotional changes following BPVP. In 1 of these cases there was evidence of relatively global cognitive difficulties and lowered arousal, that were later found to be associated with a misplaced lesion. In the remaining 6 cases (16%) there were reports of some flattening of affect or initiation. There were no new individual instances of HADS caseness or neuropsychiatric sequelae following either UPVP or BPVP. Complications There were no visual field deficits and no deaths, 1 patient developed a frontal haematoma that required surgical evacuation and left her dysphasic; there were 3 subdurals of which 1 required burr hole evacuation 34 days postoperatively, 3 hemipareses of which 1 persisted long term and 4 dysarthrias.

Discussion In the overall management of end-stage PD, PVP will probably retain a useful role. There are some questions as to whom to offer the procedure, whether neuromodulation is a safer alternative, whether surgery is safe to perform bilaterally, whether one needs microelectrode recording to perform the procedure, and how big a lesion to make. In the present literature there is active debate about the future of PVP as a procedure. We feel that pallidal lesions are safe and effective in improving the functional and neurological status of those patients who have remained usefully L-dopa responsive but are limited by the complications of therapy. They are also selected on the basis of good bulbar function (speech and

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swallowing), no on medication freezing or falls, nor psychiatric diagnoses or dementia. Interestingly, these patients are probably those of late onset parkinsonism, quite different to those for whom subthalamic surgery is encouraged, the young onset parkinsonian patients. There has been reluctance in many centres to lesion the pallidum with a preference to implant neuromodulation devices. The literature has not borne out any intrinsic advantages of the latter and a randomized trial comparing lesioning the pallidum to neuromodulation could not demonstrate any advantages of the latter nor were the complications less [Merello et al., 1999]. This has quite profound financial implications for any health-care provider in that whilst successful lesions are maintenance free, neuromodulation will add GBP 5,000 per side to the price of surgery with yearly running costs that are probably of the order of GBP 3,000 (based on a week of inpatient adjustment of the device costing GBP 1,000). Lesioning the pallidum unilaterally can be achieved safely with no perceived adverse effects by the patient or carer but with minor cognitive changes on careful testing. Some series do quote major deficits after unilateral lesions but this probably reflects either the volume lesioned or location within the medial pallidum. This may also explain the rather poor overall results of BPVP in the literature. A very important question that arises from our experience is that of whether there is a place for performing bilateral pallidotomies. A UPVP will improve the total UPDRS scores by 28% but performing a lesion on the other side results in a total UPDRS reduction of 36%. It would appear that the neurological benefits that accrue from a second side may be outweighed by risks intrinsic to surgery. The risk:benefit ratio looks more favourable if the results of self-rated functional outcome measures are examined. After a unilateral procedure there are significant improvements in limited domains even though the neurological benefits are clearly significant. After a bilateral procedure, improvements in quality-of-life questionnaire scores reach significance in many more domains. However, cognitive-personality side effects of the order of 16–20% in BPVP do mean that caution must be exerted in offering it as a simultaneous/staged procedure. We no longer routinely perform simultaneous or staged BPVP unless ipsilateral symptoms are markedly disabling. Finally, the heated debate about whether microelectrode recording is essential to perform a PVP has lost impetus. Published series of well-studied patients demonstrate that equivalent results can be obtained whether or not microelectrode recording is used [Starr et al., 1998]. An important point to make is that it does appear that overall the complication rates are higher when microelectrode recording is used and may reflect the need for multiple electrode passes [Carroll et al., 1998].

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References Alexander E 3rd, Kooy HM, van Herk M, et al: Magnetic resonance image directed stereotactic neurosurgery: Use of image fusion with CT to enhance spatial accuracy. J Neurosurg 1995;83:271–276. Aziz TZ , Bain PG: A multi-disciplinary approach to the management of tremor (editorial). Br J Neurosurg 1996;10:435–437. Carroll C, Scott R, Davies LE, et al: The pallidotomy debate. Br J Neurosurg 1998;12:146–150. Gibb WR, Lees AJ: The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease (review). J Neurol Neurosurg Psychiatry 1988;51:745–752. Kooy HM, van Herk M, Barnes PD, et al: Image fusion for stereotactic radiotherapy and radiosurgery treatment planning. Int J Radiat Oncol Biol Phys 1994;28:1229–12234. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Merello M, Nouzeilles MI, Kuzis G, et al: Unilateral radiofrequency lesion versus electrostimulation of posteroventral pallidum: A prospective randomized comparison. Mov Disord 1999;14:50–56. Mitchell IJ, Clarke CE, Luquin R, et al: Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to MPTP. Neuroscience 1989;32: 213–226. Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme, 1977. Scott R, Gregory R, Hines N, et al: Neuropsychological, neurological and functional outcome following pallidotomy for Parkinson’s disease. Brain 1998;121:659–675. Starr PA, Vitek JL, Bakay RAE: Ablative surgery and deep brain stimulation for Parkinson’s disease. Neurosurgery 1998;43:989–1015. Trepanier LL, Saint-Cyr JA, Lozano AM, Lang AE: Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson’s disease. Neurology 1998;51:207–215 Van Buren J, McCubbin D: An outline atlas of the human basal ganglia with stimation of anatomical variants. J Neurosurg 1962;19:811–839.

J. Bowen, MD, Oxford Movement Disorder Group, Radcliffe Infirmary, Oxford OX2 6HE (UK) Tel. +44 1865 228425, Fax +44 1865 224898, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 148–155

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Stimulation of the Globus pallidus internus Christian E. Gross Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Universite´ de Bordeaux II, France

The pharmacological treatment of Parkinson’s disease (PD) by the administration of levodopa [1] or dopaminergic agonists [2] has brought relief to an incalculable number of patients but still carries with it the long-term problem of therapeutic escape, a state of inurement requiring an increase in drug dosage and often accompanied by the appearance of dyskinesia and ‘on-off ’ phenomena [3, 4] which inevitably intervenes after a certain length of treatment, usually 3–10 years [5]. At the same time the development of high-quality imaging technology and the adoption of standardized stereotactic techniques using precision micromanipulators have vastly improved the efficacy of brain surgery by allowing the accurate and reproducible determination of surgical targets. Unsurprisingly, the conjunction of these two situations has led to a renewed interest in the surgical approach as an effective treatment for the later stage of this pathology. It has been known for some years that lesion of the subthalamic nucleus (STN) alleviates parkinsonian motor abnormalities in 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-treated primates [6] and that high-frequency deep brain stimulation (DBS) of the thalamus ventralis intermedius (Vim) dramatically attenuates all types of tremor [7]. In consequence we have already used high-frequency stimulation to cause functional impairment of STN neuronal activity in MPTP-treated monkeys [8]. The reversal of rigidity and the improvement of motor performance observed in this animal study were so spectacular that we decided in conjunction with the surgical team in Grenoble (France) to use the same technique to treat a human parkinsonian patient a few months later [9]. Numerous other cases of successful treatment by DBS of the STN have followed.

Since (i) the globus pallidus pars internalis (GPi), the main output structure of the basal ganglia network, is hyperactive in PD as a result of STN hyperactivity, (ii) lesion of the basal lateral zone of the GPi (ventroposterolateral pallidotomy) has been shown to give long-lasting relief from akinesia and rigidity [10–12] and (iii) high-frequency DBS appears to have the same inhibitory effect as lesion, it was then proposed that stimulation of the posteroventral part of the GPi, i.e. the target used in pallidotomy, should likewise have a beneficial effect on parkinsonian symptomatology. This report summarizes the long-term follow-up (1–3 years) of 20 patients presenting severe parkinsonian symptoms and levodopa-induced dyskinesia who have undergone either unilateral or bilateral implantation of a stimulating electrode in the posteroventral part of the GPi.

Material and Methods Patients and Clinical Assessment The patients taking part in this study gave informed consent and the protocol was approved by the French National Board of Ethics. All the 20 patients (12 male/8 female, mean age 58.3×6.7 years) to whom this surgery was proposed presented severe parkinsonian symptomatology including rigidity, akinesia, gait and speech disturbances and marked levodopa-induced dyskinesia. Mean duration of the disease was 13.3×5.6 years. Nine patients underwent bilateral implantation, 11 unilateral implantation (6 left, 5 right). Disability and motor performance were assessed on part III of the Unified Parkinson’s Disease Rating Scale [13] (UPDRS; items 18–31 graded from 0 to 4). Dyskinesia was assessed on a dyskinesia rating scale validated by Goetz et al. [14] which rates 7 items graded from 0 to 4 (maximum score 28). Assessment was carried out, preceding surgery, in two situations and, following surgery, in four (fig. 1): (1) after at least 12 h without any treatment (‘off ’ period); (2) during the ‘best on’ period after the administration of approximately1.5 times the usual dose of levodopa; (3) with DBS but without levodopa; (4) with combined DBS and levodopa therapy. Symptoms were evaluated before surgery and at 1, 6, 12, 24 and 36 months after surgery. The present report presents the postoperative clinical assessments at 12 months (n>20 patients), 24 months (n>16 patients) and 36 months (n>9 patients). Mann-Whitney nonparametric U test was used to compare results. A probability level of 5% (p=0.05) was considered significant. Surgical Procedure After the induction of brief general anesthesia using intravenous propofol (2.5 mg/kg), patients were placed in Talairach’s stereotactic frame. A frontal burr hole of 14 mm diameter was first drilled and subcutaneous tunnelling effected. We used the technique of orthogonal teleradiography applied to stereotactic contrast ventriculography to obtain anteroposterior and lateral X-rays of the operative zone. These were then compared with films previously obtained by magnetic resonance imaging. This made it possible to define with precision our target area in the posteroventral GPi. A

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A

B

Fig. 1. A Patients’ UPDRS part III score in both the ‘off ’ and the levodopa situation before surgery (n>20) and in the four clinical situations 12 (n>20), 24 (n>16) and 36 (n>9) months after surgery. * Compared to the ‘off ’ situation; + compared to the levodopa situation; ¶ compared to the levodopa situation and to the DBS situation. B Patients’ dyskinesia score in the levodopa situation before surgery (n>20) and in the levodopa situation and the combined DBS + levodopa situation at 12 (n>20), 24 (n>16) and 36 (n>9) months after surgery.

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microelectrode was then introduced to locate the GPi according to the recording method described by Lozano et al. [15] based on the contrast that can be monitored between GPi unit activity and the electrical silence of the fibers of the internal capsule. When no recording modifications were observed during introduction of the electrode, a new track was performed either on the lateral or the anteroposterior axis. The mean (×SD) stereotactic coordinates of the tip of the contact 0 of the permanent quadripolar electrode (model DBS 3387; Medtronic) were: 7.6×0.9 mm in front of the midcommissural line, 5.2×1.1 mm below the intercommissural line and 19.6×1.9 mm lateral to the midline. Electrical stimulation was first applied through an external stimulator to assess the effect on rigidity and akinesia, evaluated by a brief double-blind clinical quantification, and to detect any side effects. The permanent electrode was then secured within the burr hole and connected to a programmable pulse generator (Itrel II; Medtronic) implanted in the subclavicular region. Stimulators were programmed according to patients’ needs. Mean (×SD) voltage was 4.8×1.6 V, mean pulse duration 90×0 ls and mean frequency of 163×14 Hz. Stimulation parameters were tested over a period of several days to determine optimum levels for each patient. After stimulation it was possible to maintain levodopa therapy at the dosage used before surgery or even increase the dosage without inducing any side effects.

Results Since surgery, all our patients have reported improvement in movement accuracy which has been confirmed by clinical examination. The specificity of the action of DBS on axial or distal symptoms was not investigated in the present study but the scores obtained on part III of the UPDRS show that long-term DBS of the ventroposterolateral GPi has improved the general condition of all those concerned (fig. 1A). It is to be noted that our results show no statistically significant difference between the ‘off ’ scores at each stage of assessment (fig. 1A). This may well be due to differences in the size of each population; it is quite possible that scores, in fact, increased slightly but that the small size of the populations taken into account obscured any variation. There is likewise a slight statistical decrease over the same period in the clinical score for the levodopa situation (p>0.06) despite the fact that dosage increased, and obvious indication that patients’ condition worsened (fig. 1A). The general tendency remains, however, clear. Whatever the stage of assessment (12, 24 or 36 months), the scores of patients in either the levodopa, the DBS or the combined DBS and levodopa situation are always significantly lower than their ‘off ’ scores (p=0.05) (fig. 1A). If we compare results obtained using DBS alone versus levodopa alone, we note no significant difference (p?0.05) at 12 months but the clinical improvement afforded by DBS is significantly better at 24 and 36 months (p=0.05) (fig. 1A). The improvement is even more marked in the case of

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combined DBS and levodopa therapy. Comparison of the results of combined therapy with the results of DBS alone or levodopa alone shows that combined therapy alleviates both parkinsonian symptoms and dyskinesia more satisfactorily than either single therapy at every stage, 12, 24 and 36 months (p=0.05) (fig. 1A). No dyskinesia was observed at any stage (12, 24 or 36 months) in either the ‘off ’ situation or the DBS alone situation. Combined therapy reduced the dyskinesia score at every stage in comparison with the levodopa situation (p=0.05; fig. 1B), even without any reduction in levodopa dosage.

Discussion Long-term DBS of the ventroposterolateral GPi has proved beneficial to all the patients included in this study. Whatever the stage of assessment, clinical scores on part III of the UPDRS were significantly lower for the DBS situation than for the ‘off ’ situation. No significant difference was observed over the short term (12 months) between DBS alone and levodopa alone but a difference became clearly apparent over the long term (24 and 36 months). Combined DBS and levodopa therapy was clearly superior at every stage, 12, 24 and 36 months, to treatment with DBS alone or levodopa alone. The results we present show that DBS retained its efficacy over the entire period of 3 years and we have unpublished data extending this period to 4 years for our first patients. The efficacy of levodopa therapy, on the other hand, decreased progressively despite an increase in dosage. DBS considerably alleviated rigidity, tremor and, particularly, dyskinesia. Gait and speech also improved. For akinesia, the improvement afforded by DBS of the GPi would appear less important than that afforded by DBS of the STN [16; also see chapter 15 of the current issue]. In all our patients, rigidity and akinesia were more often alleviated in the upper limb than in the lower. This may well be due to the position of the tip of the electrode in the GPi. In 1 of our patients the original monopolar electrode has been changed for a quadripolar electrode, positioned slightly differently. Whereas DBS previously had more effect on the lower limbs, it is now upper limb movement that is improved but the patient does not walk as well as before. It has been shown that the ‘arm and leg neurons’ that respond to passive movements have a clear somatotopic organization in the human GPi. Using microrecording techniques, Taha et al. [17] have now established that ‘arm cells’ are located in the rostral segment, 5–5.5 mm above the base of the pallidum, and in the caudal segment, 1.5–3 mm above the same base. ‘Leg cells’ are located centrally, 3–4.5 mm above the pallidal base. This has

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allowed us to chart the correlation between clinical and anatomical data for patients. The position of the tip of the electrode in our procedure (depth 5.2×1.1 mm, lateral 19.6×1.9 mm, anterior 7.6×0.9 mm in front of the midcommissural line) corresponds to the pool of ‘arm neurons’ in the rostral segment of the basal pallidum. DBS considerably attenuated parkinsonian tremor in 8 of the 11 patients presenting this symptom. Similar results were reported a few years ago by Siegfried and Lippitz [18]. At the same time, Bergman et al. [19] proposed from results obtained in MPTP-treated monkeys that tremor could be generated by periodic bursting activity in the corticosubthalamic-GPi-thalamic loop. Taha et al. [20] have since shown that 9% of pallidal cells discharge synchronously with the patient’s tremor. The alleviation of tremor observed in our patients after DBS of the GPi could therefore be, at least in part, explained by an inhibition of the rhythmic bursts that arise in the GPi-thalamic pathway. Analysis of the alleviation of dyskinesia induced by DBS of the GPi is more complex since we have little knowledge of either the basic physiopathology of dyskinesia or the mechanism of action of DBS. It has often been suggested that levodopa-induced dyskinesia is the result of fluctuations in STN activity and subsequent repercussions (via the STN-GPi pathway) on GPi activity. These fluctuations could be linked to levodopa levels in the blood and central nervous system. A high level of levodopa would produce a decrease in subthalamic activity and thereby a downregulation of pallidal neuronal activity [21]. The thalamic nuclei disinhibited by the underfunctioning GPi would in turn send abnormal messages to the motor cortex area. Since our results show that DBS alleviated dyskinesia not only in the absence of any diminution of levodopa dosage but even after an increase, it would seem that DBS of the GPi has a specific action of its own, impeding the emergence of levodopa-induced dyskinesia by blocking an eventual irregular or ‘chequered’ functioning of the network constituted by the STN-GPi-VL. It would thus interrupt this continuous dysfunction as do pallidotomy or thalamotomy of the VIM. DBS of the GPi is at the moment being tested in several centers around the world. Some studies have emphasized its efficiency in reducing levodopainduced dyskinesia but have found it has little effect on symptoms other than rigidity [22, 23]. Others have reported a dramatic attenuation of most of the main symptoms [24, 25]. These disparities could well be due to slight differences in target location pinpointed by Bejjani et al. [26]. Stimulation of the posteroventral zone selected by Laitinen and his team for pallidotomy would appear to aggravate akinesia and gait but reduce rigidity and dyskinesia whereas stimulation of a more dorsal and more medial target alleviates most parkinsonian symptoms (akinesia, rigidity and gait) but can induce abnormal involuntary movements.

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If the choice of the target within the GPi can have such varying effects, it is obvious that the choice of the target structure is even more important. The studies so far published tend to show that DBS of the GPi is a particularly effective treatment for dyskinesia and rigidity and that DBS of the STN has more effect on akinesia and tremor [16, 27]. The relative merits of each type of stimulation need to be further investigated. There remains also the fundamental question of how DBS actually works. Comparison of the clinical and electrophysiological effects of DBS on these different structures highlights the different role played by each in the basal ganglia motor loop. DBS of the GPi, for example, appears to alleviate dyskinesia per se whereas the amelioration induced by DBS of the STN would seem to be mainly due to the concomitant decrease in levodopa dosage that this therapy allows. It would be preferable to elucidate the basic mechanisms of high-frequency stimulation of the subcortical nuclei before developing this surgical approach on a wide scale.

References 1 2 3 4 5

6 7

8

9

10 11 12 13

Yahr MD, Duvoisin RC, Hoehn M, Schear MJ, Barrett RE: L-dopa: Its clinical effects in parkinsonism. Trans Am Neurol Assoc 1968;93:56–63. Lieberman AN, Goldstein M: Bromocriptine in Parkinson’s disease. Pharmacol Rev 1985;37:217– 227. Lesser RP, Fahn S, Snider SR, Cote LJ, Isgreen WP, Barrett RE: Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 1979;19:1253–1260. Marsden CD, Parkes JD, Quinn N: Fluctuations of disability in Parkinson’s disease – Clinical aspects; in Marsden CD, Fahn S (eds): Movement Disorders. London, Butterworth, 1982, pp 96–122 Miyawaki E, Lyons K, Pahwa R, Tro¨ster AI, Hubble J, Smith D, Busenbark K, McGuire D, Michalek D, Koller WC: Motor complications of chronic levodopa therapy in Parkinson’s disease. Clin Neuropharmacol 1997;20:523–530. Bergman H, Wichmann T, Delong MR: Reversal of experimental parkinsonism by lesion of the subthalamic nucleus. Science 1990;249:1436–1438. Benabid AL, Pollak P, Louveau A, Henry S, DeRougemont J: Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson’s disease. Appl Neurophysiol 1987;50:344–346. Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B: Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 1993;5:382–389. Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret J: Effets de la stimulation du noyau sous-thalamique dans la maladie de Parkinson. Rev Neurol 1993;149:175–176. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchison WD, Dostrovsky JO: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Vitek JL, Bakay RAE: The role of pallidotomy in Parkinson’s disease and dystonia. Curr Opin Neurol 1997;10:332–339. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Fahn S, Elton RL and Committee MotUD: Unified Parkinson’s Disease Rating Scale; in Fahn S, Marsden CD (eds): Recent Developments in Parkinson’s Disease. Florham Park, Macmillan Health Care, 1987, vol 2, pp 153–164.

Gross

154

14

15 16 17

18 19 20 21

22 23

24 25 26

27

Goetz CG, Stebbins GT, Shale HM, Lang AE, Chernik DA, Chmura TA, Ahlskog JE, Dorflinger EE: Utility of an objective dyskinesia rating scale for Parkinson’s disease: Inter- and intrarater reliability assessment. Mov Disord 1994;9:390–394. Lozano A, Hutchison W, Kiss Z, Tasker R, Davis K, Dostrovsky J: Methods for microelectrodeguided posteroventral pallidotomy. J Neurosurg 1996;84:194–202. Limousin P, Pollak P, Benazzouz A, Hofmann D, Broussole E, Perret JE, Benabid AL: Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–674. Taha JM, Favre J, Baumann TK, Burchiel KJ: Characteristics and somatotopic organization of kinesthetic cells in the globus pallidus of patients with Parkinson’s disease. J Neurosurg 1996;85: 1005–1012. Siegfried J, Lippitz B: Bilateral chronic electrostimulation of ventroposterolateral pallidum: A new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994;35:1126–1130. Bergman H, Wichmann T, Karmon B, Delong MR: The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 1994;72:507–520. Taha JM, Favre J, Baumann TK, Burchiel KJ: Functional anatomy of the pallidal base in Parkinson’s disease. Neurosurgery 1996;39:1164–1168. Levy R, Hazrati LN, Herrero MT, Vila M, Hassani OK, Mouroux M, Ruberg M, Asensi H, Agid Y, Fe´ger J, Obeso JA, Parent A, Hirsch EC: Re-evaluation of the functional anatomy of the basal ganglia in normal and parkinsonian states. Neuroscience 1997;76:335–343. Siegfried J, Wellis G: Chronic electrostimulation of ventroposterolateral pallidum: Follow up. Acta Neurochir 1997;68:11–13. Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R: Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997;42:283–291. Pahwa R, Wilkinson S, Smith D, Lyons K, Miyawaki E, Koller WC: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997;49:249–253. Gross C, Rougier A, Guehl D, Boraud T, Julien J, Bioulac B: High-frequency stimulation of the globus pallidus internalis in Parkinson’s disease: A 7 case study. J Neurosurg 1997;87:491–498. Bejjani BP, Damier P, Papadopoulos S, Bonnet AM, Vidailhet M, Agid Y, Pidoux B, Cornu P, Dormont D, Marsault C: Deep brain stimulation in Parkinson’s disease: Opposite effects of stimulation in the pallidum. Mov Disord 1998;13:969–970. Pollak P, Benabid AL, Limousin P, Benazzouz A, Hoffmann D, Le Bas JF, Perret J: Subthalamic nucleus stimulation alleviates akinesia and rigidity in parkinsonian patients; in Battistin L, Scarlato G, Caraceni T, Ruggieri (eds): Advances in Neurology. Philadelphia, Lippincott-Raven, 1996, vol 69, pp 591–594.

Dr. C.E. Gross, Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Universite´ de Bordeaux II, 146, rue Leo Saignat, F–33076 Bordeaux Cedex (France) Tel. +33 557 571 687, Fax +33 556 901 421, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 156–171

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Thalamotomy with Microelectrode Recordings Marcelo N. Linhares, Ronald R. Tasker Division of Neurosurgery, The Toronto Hospital Western Division, Department of Surgery, University of Toronto, Ont., Canada

Thalamotomy is one of the main surgical procedures for the palliative treatment of Parkinson’s disease (PD). Though better understanding of basal ganglia pathophysiology restored interest in other surgical targets such as the internal segment of globus pallidus and led to use of new targets such as the subthalamic nucleus, lesioning the posterior ventral oral nucleus (Vop) and ventral intermediate nucleus (Vim) of thalamus still remains a major strategy for the relief of tremor, one of the triad of disabling symptoms of PD. Our objective is to describe and evaluate our technique and outcome data in thalamotomy for PD using microelectrodes for physiological localization.

History Spiegel and Wycis [1] introduced human stereotactic surgery in 1947 by combining radiological localization with the use of a stereotactic frame. After initial experience with pallidotomy, Hassler and Riechert [2] reported that they had successfully treated PD by ventrolateral thalamotomy in 1951, and by 1954 they described two thalamic targets depending on the symptoms: anterior ventral oral nucleus of thalamus (Voa) for rigidity and Vop for tremor. In the early 1960s, Albe-Fessard et al. [3] first described the use of semimicroelectrode recording during thalamotomy, and with this technique, demonstrated that the Vim nucleus, situated just caudal to Vop, contained ‘tremor cells’ that fired in a tremor-synchronous manner [4]. This area gradually became the preferred target for lesions to arrest tremor, regardless of the etiology [5]. The senior author (R.R.T.) began doing thalamotomies in 1961

using macrostimulation for physiological localization, began exploring the use of true microelectrodes in 1976, and has used them routinely since 1984, at first in conjunction with macrostimulation and then with microstimulation with the same electrode at the same sites at which recordings were made. Our reasoning was that, for thalamotomy, some type of physiological corroboration of the target site was necessary since there was no reliable way of recognizing it by imaging. Of the techniques available recording and microstimulation seemed preferable having the following advantages: (1) identification of actual brain cells in the vicinity of the electrode, (2) providing data that are partly objective and not entirely dependent upon patient cooperation, (3) avoidance of current spread of at least 2 mm radius that occurs with macrostimulation, (4) allowing concomitant observations on normal or abnormal brain function. The technique has the following disadvantages compared with macrostimulation: (1) need for complex backup equipment, (2) fragility of electrodes, (3) expense and effort. We also reasoned that the precision of microelectrode studies might allow smaller lesions to be made avoiding lesioninduced complications. In this chapter we review all our thalamotomies for PD done with the microelectrode technique from the first, the results reflecting our growing experience with the technique.

The Toronto Western Hospital Technique Patients and Methods Patients aged up to the late 70s with the diagnosis of PD who were otherwise fit and in whom tremor was the most disabling symptom but who had failed to respond adequately to medical therapy were accepted for thalamotomy if there were no contraindications such as bleeding diatheses, chronic progressive or potentially fatal disease or cognitive impairment, after weighing the advantages to be expected from tremor relief against the risks of the operation. Controlled hypertension and diabetes mellitus were not considered contraindications. Between October 1984 and January 1996, 38 patients (25 males, 13 females) with the diagnosis of PD were submitted to microelectrode-guided thalamotomy at the Toronto Hospital. The relevant records performed were reviewed retrospectively. The mean age at the onset of PD was 52.5 years (range 35–72), and at surgery 58.8 years (range 39–75). Twenty-one patients were operated upon on the left, 13 on the right and 4 patients bilaterally, totalling 42 hemispheres treated. Two patients had had previous thalamotomies performed on the opposite hemisphere using macroelectrode techniques and 1 had previously had a deep brain stimulator (DBS) inserted on the opposite side of the brain. Operative Technique In our experience, imaging with computerized tomography (CT) has proven as accurate as ventriculography [6] and magnetic resonance imaging (MRI) superior to CT because of

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the better definition of brain structures especially anterior commissure (AC). The disadvantages of ventriculography include its more invasive nature, the greater likelihood of brain shift and the rare risk of ventriculitis [7, 8]. Ventriculography was used for radiological localization in the first 5 operations, CT in the next 28, MRI in the last 3. In cases in whom thalamotomy was repeated on the same side, CT was used on one occasion, MRI on the other in 4 patients. With our technique described previously [9–13], a Leksell G-model MRI-compatible stereotactic frame is applied to the patient’s head under local anesthesia.The approximate locations of AC and posterior commissure (PC) are noted in sagittal scout films and their 3-dimensional coordinates determined in axial cuts using the scanner’s computer software. A separate computer software program is then used to construct a set of sagittal brain diagrams encompassing the target structure based on the diagrams from the Schaltenbrand and Wahren atlas [14] but redrawn, shrunk or expanded, to match the patient’s intercommissural distance. These diagrams are ruled in a 1.0 mm grid conforming to the scales on the Leksell frame as it is applied to the patient’s head. Our strategy is to, first, physiologically, identify the tactile relay nucleus for the hand since it is large, relatively easily identified and located immediately caudal to the target for tremor relief. Its approximate location is then identified on the appropriate redrawn sagittal diagram and its 3-dimensional frame coordinates read off and applied to the Leksell frame. A twist drill hole is then made in the vicinity of the coronal suture in the same sagittal plane as the intended target (usually 15 mm from midline) so that all electrode trajectories with the related physiological data can be plotted in a single sagittal diagram thus facilitating their interpretation. Physiological Localization A microelectrode capable of differentiating single neurons is now directed toward the tactile relay nucleus using hydraulic microdrive [9–11, 15–19]. Continual recording is done from about 10 to 15 mm superficial to up to 10 mm deep to the target, identifying types of spontaneous neural activity and neurons encountered. Receptive fields (RF) are mapped. Threshold microstimulation is done every 1.0 mm noting any motor, sensory or other response and the projected fields (PF) outlined. RFs and PFs are then plotted by hand on a magnified 100¶80 cm wall chart of the sagittal plane being explored on which the electrode trajectories are drawn. PFs are displayed at the site where they occurred on one side of each trajectory by shading in the appropriate part of a body outline diagram adding stimulation threshold in microamperes. Quality of response is indicated by suitable alphanumerics such as P for paresthetic, M for tetanizing, etc. If no response is obtained with currents up to 100 lA the site is labelled as unresponsive and marked with a triangle; higher current flows would damage our microelectrodes. RFs are similarly mapped on the other side of the trajectory indicating the effective stimulus. As the microelectrode is introduced parasagittally from anterodorsally toward the tactile nucleus, identifiable cells begin to appear in the lower half of the lateral tier of nuclei. Depending on the location of the trajectory, the first identifiable cells encountered often lie in Vop firing in advance of a particular contralateral voluntary movement. Some may also fire synchronously with tremor and a few may have kinesthetic receptive fields as well. As the electrode advances, cells may be encountered that respond to a specific contralateral passive movement or muscle or joint perturbation (kinesthetic cells); or else these may be the first cells encountered. They will fire synchronously with tremor if the related part of the body is shaking. The trajectory may eventually pass into the lemniscal (tactile) relay

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nucleus (ventrocaudal, Vc) and encounter tactile cells. If not, additional trajectories more posteriorly will do so. Tactile cells respond to specific contralateral deep and, slightly more posteriorly, superficial tactile stimuli such as hair bending or stroking with a wisp of cotton. Voluntary, kinesthetic and especially tactile cells are somatotopographically arranged from medial (for face and head) to lateral (for foot). Microstimulation or macrostimulation of tactile and kinesthetic cells causes paresthesiae in the contralateral side of the body in a similar area to that of their RFs. Microstimulation of voluntary cells may cause a contralateral muscle jerk at the onset of the stimulus train but not tetanization affecting muscles related to the RF. Microstimulation amongst tremor cells may suppress or arrest tremor. We believe the ideal site for making a lesion to control tremor is amongst voluntary and/or kinesthetic tremor cells related to the body part whose tremor is to be arrested where stimulation-induced tremor arrest is most striking. However not every site that meets these criteria is an effective lesion site, which may be better located amongst tremor cells whose synchronous activity is most tightly linked to the EMG pattern of the tremor to be relieved, possibly about 2 mm rostral to the rostral margin of tactile cells and 2–3 mm above the intercommissural line [9–11, 20, 21]. When a suitable target is found based on both the imaging and the physiological studies, a graded radiofrequency (rF) lesion is made, with serial testing of tremor, rigidity and neurological status, using a 1.1 mm electrode insulated along its shaft except for a 3.0 mm bare tip using suitable backup equipment such as the OWL Universal RF System (available from Diros Technology, Toronto, Ont., Canada). Lesioning is begun at 50–60 ºC for 60 s and gradually increased up to 80–90 ºC according to the lesion size desired and the result achieved. Clinical Evaluation Assessments of tremor and rigidity were made pre- and postoperatively by the senior author (R.R.T.), using a semiquantitative protocol during the ‘off ’ period (more than 3 h after the last medication containing L-dopa). Tremor and rigidity were evaluated at each joint in each limb (thumb, fingers, wrist, elbow, shoulder, hip, knee and ankle), on a 0–5 scale, 0 being normal and 5 the worst possible degree of tremor and rigidity. Rigidity was always assessed while the patient patted rapidly with the opposite hand. Dexterity was similarly graded 0–5 in each hand on the basis of performance of repetitive finger-thumb and finger-nose touching, hand-patting at slow to rapid speeds, and rapidly repeated wrist rotation. Speech and gait were also rated on a 0–5 scale using a set protocol. The mean follow-up was 35.8 months (range 1–152). Two patients had less than 3 months’ follow-up; 1 patient was seen for a 1-month follow-up and the other patient was never seen after the hospital discharge, both with good results. Since parkinsonian rest tremor is a continuous or at least a continual problem that disables patients as much by its cosmetic, distracting and psychic effects as by its effect on fine dexterous tasks, the purpose of thalamotomy in PD is, in our opinion, to completely stop upper limb tremor, unlike the situation in essential tremor where the goal is to restore manual dexterity. In order to take these factors into account, as well as the variations of tremor over different joints and at different examinations and to allow for subjective differences in the assessment on each occasion as well as for disease progress, we assessed tremor in various ways. First we averaged tremor scores for each set of joints in upper and lower limbs over the entire follow-up period. Since tremor might be abolished in some joints but not in others,

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tremor was also averaged for all upper limb and lower limb joints taken together over the same period. To take into account possible tremor recurrence over time we also assessed tremor averaged for the whole upper and the whole lower limb at the last follow-up. In order to make these data comparable with other published data, our tremor grading described above was converted to that of the tremor assessment of the Unified Parkinson’s Disease Rating Scale (UPDRS) [22] as absent (grade 0), slight and infrequently present (grade 1), mild in amplitude and persistent, or moderate in amplitude, but only intermittently present (grade 2), moderate in amplitude and present most of the time (grade 3) and marked in amplitude and present most of the time (grade 4). The conversion could be accomplished readily from our database. Finally we calculated percentage average tremor reduction over the follow-up compared with preoperative levels for the entire upper and lower limbs. Complications were assessed from the clinical record and deemed transient if they recovered during the follow-up, permanent if they did not. Assessment of the Surgical Technique We next examined some technical factors that might affect outcome. We assessed the quality of the microelectrode mapping in each case, examining the quality of manual tactile, upper limb kinesthetic, and tremor cell recording, the clarity with which the border between tactile and kinesthetic cells had been identified and how well microstimulation abolished tremor. We also examined lesion size noting how many rF lesions had been made and with what current flow (all lesions were made over 60 s).

Results Tremor Table 1 lists the pre- and postoperative tremor graded on the authors’ 0–5 scale for individual joints averaged throughout the follow-up period after the final procedure performed on the side. This shows that after the final operation, tremor was abolished or nearly so in the manual digits in 83.8%, the wrist in 83.8%, elbow and shoulder in 83.8%, hip and knee in 91.3% and in the ankle in 81.9% of brain sides. The preoperative ratings show the prevalence of distal upper limb tremor compared with proximal upper limb and lower limb tremor. However, rating tremor this way may be misleading in that it may be abolished at one joint and not at another. Table 2 therefore lists residual upper and lower limb tremor taking all joints together averaged over the follow-up period, using the authors’ 0–5 grading scale. Sixty-five percent of brain sides treated had a preoperative tremor grade of ?2.5–5; no patients with slight upper limb tremor were operated on. After the last thalamotomy on the side, 77.5% had their tremor abolished or nearly so in the upper limb; 85.5% in the lower limb (only 21 patient sides were associated with lower limb tremor). Table 3 shows residual tremor at the last follow-up in the upper and lower limbs after completion of all surgery on that side to allow for the maximum

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Table 1. Residual tremor grade for contralateral body parts using the authors’ 0–5 scale (see text) averaged over the entire follow-up after the final thalamotomy on the side Site of tremor

Average grade of tremor

Percentage of brain sides preoperative

postoperative

Thumb, fingers

0 ?0–1 ?1–2.5 ?2.5–5

0 0 51.4 48.6

67.7 16.2 8.1 8.1

Wrist

0 ?0–1 ?1–2.5 ?2.5–5

5.4 0 13.5 81.1

75.7 8.1 8.1 8.1

Elbow, shoulder

0 ?0–1 ?1–2.5 ?2.5–5

37.8 10.8 27.0 24.4

78.4 5.4 8.1 8.1

Hip, knee

0 ?0–1 ?1–2.5 ?2.5–5

70.8 0 16.7 12.5

86.9 4.4 0 8.7

Ankle

0 ?0–1 ?1–2.5 ?2.5–5

41.2 0 35.3 23.5

78.8 3.1 12.6 6.2

H

83.9

H

83.8

H

83.8

H

91.3

H

81.9

chance for tremor recurrence over time, using the tremor assessment of the UPDRS as already described. Seventy-five percent of patient sides assessed had no or virtually no tremor in the upper limb and 73% in the lower limb, while 87.5% had no or only a mild-moderate degree of tremor in the upper and 82% in the lower. To present the data in another way, table 4 shows percentage of tremor reduction in the upper limb for all patient sides, averaged over the entire follow-up. Seventy percent enjoyed more than 75% reduction, and 77.5% over 50% reduction in the upper limb tremor, 77.5% and 82%, respectively in lower limb tremor. Table 5 lists improvements in scores averaged over the entire follow-up after the last operation on the side for rigidity, dexterity, speech and locomotion

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Table 2. Residual tremor averaged through follow-up for upper and lower limbs using the authors’ 0–5 grading scale (see text) Tremor grade

Preoperative

Postoperative

Upper limb 0 ?0–1 ?1–2.5 ?2.5–5

0 0 14 (35%) 26 (65%)

21 10 6 3

(52.5%) (25%) (15%) (7.5%)

Lower limb 1 0 ?0–1 ?1–2.5 ?2.5–5

0 2 (9.5%) 12 (57.2%) 7 (33.3%)

15 3 2 1

(71.5%) (14.3%) (9.5%) (4.7%)

1

H

77.5%

H

85.5%

Only the 21 patient sides with contralateral preoperative tremor were included.

Table 3. Residual contralateral tremor at the last follow-up after thalamotomy using the UPDRS tremor assessment scale (see text) Grade

Upper extremity

0 1 2 3 4

26 4 5 3 2 1

(65%) (10%) (12.5%) (7.5%) (5%)

H

75%

Lower extremity 1 15 1 2 1 3

(68.5%) (4.5%) (9%) (4.5%) (13.5%)

H

73%

Only the 21 patient sides with contralateral preoperative tremor were included.

using the authors’ 0–5 rating scale. All these functions deteriorate over time from progression of PD regardless of any surgery in contradistinction to tremor which, if totally relieved, tends not to recur [6, 23]; partially relieved tremor however may worsen with time. In the case of dexterity, speech and locomotion, postoperative deterioration in score can result not only from disease progression but also as a complication of lesion-making. It can be seen that rigidity was reduced below preoperative levels in 67.5% of patient sides. This percentage would have been greater if the lesions had been directed more rostrally to include Vop. However, since it is our opinion that rigidity alone is not disabling and that larger lesions are more likely to produce the

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Table 4. Percent reduction in tremor averaged over the follow-up after the last surgery on the side Lower extremity 1

Upper extremity Abolished Reduced ?75% Reduced 50–75% Reduced 50% or worse 1

21 7 3 9

(52.5%) (17.5%) (7.5%) (22.5%)

H

15 2 1 4

70

(68.5%) (9%) (4.5%) (18%)

H

77.5%

Only the 21 patient sides with contralateral preoperative tremor were included.

Table 5. Effect of thalamotomy on other features of PD (% of patient sides) Rigidity

Reduced ?50% Reduced =50% Same, worse Data unavailable

22 5 6 7

(55%) (12.5%) (15%) (17.5%)

Dexterity

Improved ?50% Improved =50% Same Worse Data unavailable

10 13 6 4 7

(25%) (32.5%) (15%) (10%) (17.5%)

Speech

Improved ?50% Improved =50% Same Worse Data unavailable

2 6 7 19 6

(5%) (15%) (17.5%) (47.5%) (15%)

Gait

Improved ?50% Improved =50% Same Worse Data unavailable

2 4 12 7 15

(5%) (10%) (30%) (17.5%) (37.5%)

H

67.5%

H

57.5%

complications of hand ataxia, dysarthria and gait disturbance, our lesions were aimed at Vim. Dexterity improved in 57.5% over the entire follow-up, reflecting tremor reduction in those tasks such as rapid wrist rotation that are usually limited by tremor. Speech and gait showed no significant improvement. Complications are presented in table 6. There was no instance of intracerebral hematoma, persistent hemiparesis, dysphasia, epileptic seizures, persistent cognitive or psychiatric abnormalities or persistent dysarthria and those

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Table 6. Complications (percent of patient sides)

Complications

%

Persistent Hand ataxia Gait disturbance Paresthesiae

12.5 7.5 27.5

Transient Emotional lability Parkinsonian crisis Hemiparesis Dysarthria Hand ataxia Paresthesiae Pin site infection

2.5 5 2.5 5 10 12.5 2.5

complications that did persist did not cause significant disability. Paresthesiae were slight and usually confined to the perioral area or the manual digits though 1 patient complained of paresthesiae in his contralateral face, arm and leg. Of the 16 patients with any postoperative paresthesiae, 6 (37.5%) were left with significant residual tremor, more than in those with any postoperative ataxia only 11% of whom did not have their tremor abolished or nearly abolished. This presumably reflects the fact that the target for tremor abolition lies amongst or near kinesthetic but not tactile cells [24]. The 3 patients with persistent gait disturbance displayed equinovarus deformity during walking causing some scuffing of the toes. In 1 of them the deformity was also seen in the unoperated foot to a lesser degree, raising questions as to whether it was an operative complication or a feature of the patient’s PD. Five patients demonstrated permanent hand ataxia of a mild degree that was not significantly disabling, making writing slightly clumsy or interfering with fine manual tasks only under stress. Failure, Repetition of Thalamotomy and Overall Results Forty-two patients were considered for microelectrode-guided thalamotomy. One patient became uncooperative in the operating room, so that the procedure was abandoned at an early stage while another, who had had a previous thalamotomy on the other side of the brain, became dysarthric when we attempted to make a lesion at a current flow of 10 mA. The data from these 2 patients were excluded from our study. Thus 40 patient sides were evaluated of which 75% ended up with no or almost no tremor (grades 0 and 1), 87.5% with abolition of tremor or reduction to a moderate level

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according to the UPDRS scale. However, thalamotomies on 11 patient sides (27.5%) had to be repeated to achieve this result, at first glance a high repetition rate. Five of these 11 repetitions were necessitated by identifiable problems. No lesion was made in 2 cases. In 1 the microelectrode repeatedly fractured against calcium deposits in thalamus, attempts to localize with macrostimulation failed and three repetitions failed to abolish tremor. In the other, attempts to use microelectrodes failed and the procedure was abandoned. In 1 the lesion was retrospectively deemed too small (45 mA) due to our unjustified feeling in earlier cases that, with microelectrodes, we could be precise enough to accomplish tremor abolition with very small lesions. In 1 case lesion size was limited to 40 mA by severe paresthesiae, and in 1, microelectrode recording failed and localization done with macrostimulation was poor. Our resulting uncertainty led to too small a lesion (50 mA) being made. However, in 6 cases (15% of the entire series) no identifiable reasons were found to explain the need for repetition. Of the 11 repeated procedures 9 (81.8%) were successful in abolishing or almost abolishing tremor. Thus repeated thalamotomies failed in 2 cases to abolish or nearly abolish contralateral tremor. One case with repeatedly broken microelectrodes has been mentioned above. In the other an adequate lesion could not be made because of evoking strong paresthesiae at low currents (30–35 mA). A further 8 procedures failed to abolish or nearly abolish tremor but were not repeated, 2 going on to DBS. Of the remaining 6, 4 resulted in moderate tremor reduction with which the patients appeared satisfied, though the results were failures to us. There were 2 patients who lived far away and would not return for further assessment. Five of these 8 failures occurred for technical reasons. In 4, lesion size was restricted to =55 mA by the appearance of dysarthria, bizarre dyskinesias, bizarre behavioral effects and strong paresthesiae, each in 1 case. In 1, recordings were unsatisfactory. In 3 of the 8 no reason could be found to explain failure. Thus of the 19 patient sides on which tremor was not abolished or almost so on the first attempt, 10 were associated with technical problems and 9 were not. We now compared the operative details in successful and failed procedures, as shown in table 7. The number of lesions made regardless of size averaged 2.3 in successful and 1.9 in failed procedures while lesions were larger in successful (mean 59 mA) than in unsuccessful procedures (mean 50 mA). rF lesions made in rat brains with the same equipment as that used for thalamotomy measured under 0.5 mm in diameter with a 60-second 25-mA lesion, 3.5 mm at 35 mA, 4.0 mm at 45 mA, 4.8 mm at 55 mA and 6.2 mm at 65 mA. When we assessed outcomes in our patients in whom a single thalamotomy lesion had been made, only one lesion made at =60 mA abolished or nearly abolished tremor on the first attempt.

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Table 7. Assessment of microelectrode recording and lesion size in successful (tremor abolished or nearly so) and unsuccessful thalamotomy Successful

Unsuccessful

yes Microelectrode recording Kinesthetic cells found Tremor cells found Tactile border clearly marked Good tremor arrest with microstimulation Assessment of lesion Average number Average size, mA

25 20 28 26

(92.6%) (69%) (96.5%) (89.7%)

2.3 59

no

yes

2 9 1 3

17 16 18 16

(7.4%) (31%) (3.5%) (10.3%)

no

(89.5%) (88.9%) (94.7%) (84.2%)

2 2 1 3

(10.5%) (11.1%) (5.3%) (15.8%)

1.95 50

When we reviewed the microelectrode recordings there were, overall, no striking differences between failed and successful procedures. However, recordings were unsatisfactory in 9 patient sides, 6 in failed and 3 in successful procedures. Kinesthetic cells were not found in 3, tremor arrest could not be demonstrated in 3 because of premature cessation of tremor while multiple deficiencies occurred in 3. Finally we compared the data for the first and last 20 patient sides to look for evidence that experience improved our outcome statistics as shown in table 8. Of the first 20, 8 (40%) of the procedures abolished or nearly abolished tremor on the first attempt while in the second 20, 13 (65%) did so. If patient sides with moderate tremor reduction were included, these percentages became 50 and 80%, respectively. These data suggest better outcomes in the second 20. Twelve (60%) of the first operations failed in the first 20 patient sides, 7 (35%) in the second, again suggesting improvement with experience. Amongst the first 20 the first procedure failed in 8 instances for identifiable technical reasons (40%); 2 (10%) in the second, suggesting improvement in the use of the microelectrode technique. Forty-five percent of the first 20, 10% of the second 20 procedures were repeated. The greater difficulty with microelectrode recordings in the first 20 has been mentioned. When we counted the number of lesions made at the first procedure on the side, in the first 20 a single lesion was made in 70% of cases whereas in the second 20 a single lesion was made in only 25%, 3 in 35% and over 3 in 25%, reflecting our recognition of the fact that a larger lesion was needed to be successful despite using microelectrodes.

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Table 8. Comparison of outcomes in thalamotomy in the first and last 20 cases First 20 Tremor abolished or almost so in first operation First operation failed Technical reasons Unknown reasons Procedure repeated Abolition or near abolition of tremor after completion of surgery Unsatisfactory microelectrode recording Number of lesions made, first attempt 0 1 2 3 ?3 ?

Last 20

8 (40%)

13 (65%)

12 (60%) 8 (40%) 4 (20%)

7 (35%) 2 (10%) 5 (25%)

9 (45%)

2 (10%)

15 (75%)

15 (75%)

6 (30%)

3 (15%)

2 14 3 1

(10%) (70%) (15%) (5%)

0 5 2 7 5 1

(25%) (10%) (35%) (25%) (5%)

Nevertheless, the overall outcome was the same in both groups at the completion of all surgery on the side – 75% tremor abolished or nearly so, and 85% with at least moderate reduction in the first 20; 75% abolished or nearly so and 90% at least moderately reduced in the second 20.

Discussion Our microelectrode thalamotomy technique for PD has been reviewed as it evolved from the beginning and our outcome data in the first 40 patient sides presented. Tremor was abolished or nearly so in 84% of the individual joints of the upper limb, data very similar to those obtained by us with macrostimulation-guided thalamotomy [6]. As with macroelectrode-guided thalamotomy, a lesser effect was observed on rigidity (rigidity reduced over 50% in 55% of patient sides), reflecting the fact that lesions were not specifically directed rostrally into Vop to control rigidity, which, in our opinion, is not in itself disabling; moreover, the larger lesions that would be needed to control both tremor and rigidity would increase the risk of the 3 cerebellar complications of thalamotomy: dysarthria, ataxia and gait disturbance [6, 9, 12, 23,

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25, 26]. The same degree of moderate improvement (25% of patient sides improved by 50% or more) is seen in dexterity as with macroelectrode-guided thalamotomy and neither procedure benefits speech or gait. However, tremor may be abolished at one joint and not at another. Therefore we examined tremor reduction for the whole limb as well. 77.5% of patient sides ended up with complete or almost complete tremor abolition averaged over the whole follow-up in the upper limb, 85.8% in the lower limb. In order to make our data more comparable to the result of others, according to the UPDRS scale, 75% of upper and 73% of lower limbs had grade 0–1 tremor at the last followup; 87.5% of upper limbs, 82% of lower limbs grades 0, 1 or 2 tremor. Achieving these results was the result of over 75% tremor reduction in 70% of upper and 77.5% of lower limbs. It is difficult to compare these data with published information because of differing patient selection and outcome evaluation and because of the enormous variation in published results. Perry and Lenz [27], in what is really a consensus statement, found 70–90% good results in tremor suppression from thalamotomy. A literature review by the senior author [9] found 68–100% reported significant reduction of tremor. Osenbach and Burchiel [28] recorded 79% complete, 22% near complete tremor abolition in a group of tremor patients with mixed diagnoses, 56% of whom had PD. Jancovic et al. [25] reported 86% of their patients with complete or moderate to marked reduction in tremor after thalamotomy using macroelectrode techniques. Brophy et al. [29] reported that 67% of their patients had no tremor and 11% marked alleviation of tremor after thalamotomy. Fox et al. [30], in the only recent series guided by microelectrode recording, recorded 85% of their patients free of tremor at 1 year follow-up. Our results reported here are therefore comparable to those in reported series, whether done with microelectrode or macroelectrode guidance but it cannot be established that our results are better. In this study there were no significant complications. The only persistent complications were minimal hand ataxia in 12.5%, minimal gait disturbance in 7.5% and persistent paresthesiae in 27.5%, considerably less than in many published series [9]. These same complications (paresthesiae, dysarthria, ataxia and gait disturbance) occur with thalamic DBS for the control of tremor but, in our experience, after DBS they can be circumvented by changing stimulation parameters. However these results were accomplished at the expense of a 15% repetition rate if cases were excluded in whom technical problems prevented adequate completion of the surgery. Incidence of repeated thalamotomy is often not stated in reported series, though Osenbach and Burchiel [28] reported 2% repetitions, Jancovic et al. [25] 15%.

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In our experience [31, 32], the advantages of DBS over thalamotomy are exemplified by examining repetition rate. If a thalamotomy fails it must be repeated to achieve tremor control, but we found, in a comparison of the two procedures, that if tremor escapes from control after DBS it can usually be abolished again by altering stimulation parameters without repetition of surgery; none of our thalamic DBS procedures in PD had to be repeated [31, 32]. When we searched for risk factors for unsatisfactory outcome, technical problems with microelectrode recording and the making of a too small lesion seemed important. Based on rat studies, lesions are =5 mm in diameter if made at 55 mA or less for 60 s and it would appear that single lesions made with currents below 60 mA are inadequate for successful tremor control in thalamotomy. Lesion size averaged 50 mA in failed, 59 mA in successful cases and only one operation done with a single lesion succeeded if the lesion was below 60 mA. The need for adequately sized lesions is also shown in the fact that an average of 1.95 lesions was made in failed, 2.3 in successful cases. There is a learning curve in most techniques and our study suggests that we did better on the first attempt in our second than in our first 20 patient sides operated upon. Not only initial success, but also repetition rate was less and technical difficulties fewer, though the end result after completion of all surgery on that side was the same. The experience described here shows the difficulty which we have experienced in accomplishing tremor control even with physiological corroboration of the target site using microelectrodes. One of the problems is that we cannot precisely identify the optimum target site. It is not enough to find tremor arrest sites amongst voluntary and/or kinesthetic tremor cells related to the part of the body whose tremor is to be relieved. All of our lesions were made in such areas yet some failed. There is obviously a subsite which must be lesioned for thalamotomy to succeed, but which we cannot easily recognize. Albe-Fessard [20] recognized this in a paper presented long ago showing a smaller volume of thalamus for lesion-making amongst the larger tremor cell region. Lenz et al. [21] have attempted to identify this smaller area within the tremor cell zone. That such a subsite exists is supported by experience with DBS. In 18% of 16 cases of PD treated by DBS, the minimal lesion made by the mere insertion of the electrode completely or significantly abolished tremor sometimes permanently. Presumably a very small lesion in the correct site is all that is necessary but it is unclear how to recognize that site. Though imaging is being continuously improved, it is difficult to understand how radiothalamotomy [33–35], which must be accomplished without physiological guidance, can be both very safe and very effective. Large lesions will certainly produce better tremor control but, based on our experience, at the risk of ‘cerebellar’ complications and we have seen how small lesions

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guided by careful microelectrode studies can fail. Possibly the radiolesion can accomplish tremor control by some effect on neurons other than elimination of their function. Conclusion Microelectrode recording and microstimulation are effective techniques for physiological guidance of thalamotomy for PD. The technique is demanding and requires experience but has the potential to minimize lesion size and, therefore, complications. It is also very useful in studying normal and abnormal brain function, hopefully leading to a better understanding of PD and other movement disorders and greater success in future treatment.

References 1 2 3 4

5 6 7 8

9

10

11

12

13

Spiegel EA, Wycis HT, Marks M, Lee AS: Stereotaxic apparatus for operations on the human brain. Science 1947;106:349–350. Hassler R: Die extrapyramidalen Rindensysteme und die zentrale Regelung der Motorik. Dtsch Z Nervenheilk 1956;175:233–258. Albe-Fessard D, Arfel G, Guiot G: Activite´s e´lectriques caracte´ristiques de quelques structures ce´re´brales chez l’homme. Ann Chir 1963;17:1185–1214. Albe-Fessard D, Guiot G, Hardy J: Electrophysiological localization and identification of subcortical structures in man by recording spontaneous and evoked activities. EEG Clin Neurophysiol 1963; 15:1052–1053. Tasker RR, Siqueira J, Hawrylyshyn P, Organ LW: What happened to Vim thalamotomy for Parkinson’s disease? Appl Neurophysiol 1983;46:68–83. Tasker RR, Dostrovsky JO, Dolan EJ: Computerized tomography is just as accurate as ventriculography for functional stereotactic thalamotomy. Stereotact Funct Neurosurg 1991;57:157–166. Tasker RR: Movement disorders; in Apuzzo MLJ (ed): Brain Surgery. Complication Avoidance and Management. New York, Churchill Livingstone, 1993, pp 1509–1524. Tsukamoto H, Inui K, Taniike M, Nishimoto J, Midorikawa M, Yoshimine T, Kato A, Ikeda T: A case of Hallervorden-Spatz disease: Progressive and intractable dystonia controlled by bilateral thalamotomy. Brain Dev 1992;14:269–272. Tasker RR: Thalamotomy for Parkinson’s disease and other types of tremor. II. The outcome of thalamotomy for tremor; in Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, pp 1179–1198. Tasker RR, Dostrovsky JO: Invasive lesioning of the central nervous system for functional disorders; in Alexander EB, Maciunas RM (eds): Advanced Neurosurgical Navigation. New York, Thieme, 1998, pp 483–506. Tasker RR, Davis KD, Hutchison WD, Dostrovsky JO: Subcortical and thalamic mapping in functional neurosurgery; in Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, pp 883–969. Tasker RR, Yamashiro K, Lenz F, Dostrovsky JO: Thalamotomy for Parkinson’s disease: Microelectrode technique; in Lunsford LD (ed): Modern Stereotactic Neurosurgery. Boston, Nijhoff, 1988, pp 297–314. Tasker RR: The use of microelectrodes in the human brain; in Broom B, Desmedt JE (eds): Pain and the Brain: From Nociception to Cognition. Adv Pain Res The. New York, Raven Press, 1995, vol 22, pp 143–174.

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14 15 16 17

18 19 20 21

22

23

24

25 26 27 28 29 30 31 32 33 34

35

Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme, 1977. Lozano A, Hutchison WD: Pallidotomy: Indications and technique; in Germano IM (ed): Neurosurgical Treatment of Movement Disorders. Park Ridge/Ill, AANS, 1998, pp 131–141. Lozano AM, Hutchison WD, Dostrovsky JO: Microelectrode monitoring of cortical and subcortical structures during stereotactic surgery. Acta Neurochir 1995;(suppl 64):30–34. Lozano A, Hutchison W, Kiss Z, Tasker R, Davis K, Dostrovsky JO: Methods for microelectrodeguided posteroventral pallidotomy. Comments. J Neurosurg 1996;84:194–202. J Neurosurg 1996; 85:986–987, 987–988, discussion 988–990. Hutchison WD, Lozano AM, Davis KD, St-Cyr JA, Lang AE, Dostrovsky JO: Differential neuronal activity in segments of globus pallidus in Parkinson’s disease patients. Neuroreport 1994;5:1533–1537. Lozano AM, Lang AE, Hutchison WD, Dostrovsky JO: Microelectrode recording-guided posteroventral pallidotomy in patients with Parkinson’s disease. Adv Neurol 1997;74:167–174. Albe-Fessard D: Physio-pathologie de Parkinson. Le point sur la maladie de Parkinson. Symposium organized by Merck Sharp & Dohme, Brussels, Oct 13, 1973. Lenz FA, Normand SL, Kwan HC, Andrews D, Rowland LH, Jones MW, Seike M, Lin YC, Tasker RR, Dostrovsky JO, Lenz YE: Statistical prediction of the optimal site for thalamotomy in parkinsonian tremor. Mov Disord 1995;10:318–328. Fahn S, Elton RL, UPDRS Development Commitee: Unified Parkinson’s Disease Rating Scale; in Fahn S, Marsden CD, Calne DB, Goldstein M (eds): Recent Developments in Parkinson’s Disease. Florham Park, Macmillan Health Care Information, 1987, pp 153–164. Tasker RR, de Carvalho GC, Li CS, Kestle JRW: Does thalamotomy alter the course of Parkinson’s disease? in Battistin L, Scarlato G, Caraceni T, Ruggieri S (eds): Advances in Neurology. Philadelphia, Lippincott-Raven, 1996, vol 69, pp 563–583. Jones MW, Tasker RR: The relationship of documented destruction of specific cell types to complications and effectiveness in thalamotomy for tremor in Parkinson’s disease. Stereotact Funct Neurosurg 1990;54/55:207–211. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery 1995;37:680–687. Yasui N, Narabaiashi H, Kondo T, Ohye C: Slight cerebellar signs in stereotactic thalamotomy and subthalamotomy for parkinsonism. Appl Neurophysiol 1976/77;39:315–320. Perry VL, Lenz FA: Ablative therapy for movement disorders. Thalamotomy for Parkinson’s disease. Neurosurg Clin North Am 1998;9:317–324. Osenbach RK, Burchiel RJ: Thalamotomy: Indications, techniques, and results; in Germano IM (ed): Neurosurgical Treatment of Movement Disorders. Park Ridge/Ill, AANS, 1998, pp 107–129. Brophy BP, Kimber TJ, Thompson PD: Thalamotomy for parkinsonian tremor. Stereotact Funct Neurosurg 1997;69:1–4. Fox MW, Ahlskog JE, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991; 75:723–730. Tasker RR, Munz M, Junn CK, Kiss ZHT, Dostrovsky JO, Lozano AM: Deep brain stimulation and thalamotomy for tremor compared. Acta Neurochir 1997;68(suppl):49–53. Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998;49:145–154. Kondziolka D: Functional radiosurgery. Neurosurgery 1999;44:12–20. Young RF, Shumway-Cook A, Vermulen SS, Grimm P, Posewitz A, Burkhart WA, Goiney RC: Gamma knife radiosurgery as a lesioning technique in movement disorder surgery. J Neurosurg 1998;89:183–193. Young RF, Vermulen SS, Grimm P, Posewitz A: Electrophysiological target localization is not required for the treatment of functional disorders. Stereotact Funct Neurosurg 1996;66(suppl 1): 309–319.

Dr. R.R. Tasker, Division of Neurosurgery, Western Division, The Toronto Hospital, 399 Bathurst Street, Suite 2-431 McL, Toronto, Ont. M5T 2S8 (Canada) Tel. +1 416 603 5771, Fax +1 416 603 5298, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 172–180

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Thalamotomy without Microelectrode Recording Konstantin V. Slavin, Kim J. Burchiel Department of Neurosurgery, Oregon Health Science University, Portland, Oreg., USA

Stereotactic surgery is a well-established means of treatment of medically intractable movement disorders. Since its development in the 1950s, the interest in stereotactic surgery of basal ganglia for the control of movement disorders has fluctuated dramatically, primarily due to discovery of therapeutic effect of levodopa and subsequent realization of its side effects and waning efficacy over time [1, 2]. The technique of stereotactic functional procedures and target selection have been gradually refined in order to both decrease attendant morbidity and side effects and to maximize effectiveness. Tremor, both essential and parkinsonian, has been found to be highly responsive to a focal lesion of the thalamus that can be accomplished with relatively few side effects. As a result, stereotactic thalamotomy is currently the treatment of choice for drugrefractory tremor [3]. The thalamotomy target for tremor control is located in the mid-portion of the ventral thalamus, corresponding to the ventralis intermedius nucleus (Vim) in the Hassler nomenclature and posterolateral ventrolateral nucleus (VL) of Anglo-American nomenclature [4]. This nucleus is located in the middle of the ventrolateral thalamic mass rostral to the ventrocaudal nucleus (VC) and caudal to the ventro-oral nucleus. Laterally, it is adjacent to the posterior limb of the internal capsule, and medially it is bordering the centrum medianum (CM) of the thalamus. The nucleus measures 10 mm in lateral and superoinferior dimensions and 3–4 mm in anteroposterior dimension, and is inclined 20º anteriorly. The Vim nucleus receives kinesthetic afferent input from the contralateral body parts and may be concerned with muscle sensation. It contains large neurons that sometimes discharge synchronously with peripheral tremor (‘tremor cells’). Many of these cells are simply somatosensory neurons that respond to

joint movements, but the majority of tremor cells have peak discharges preceding the electromyographic signal. That may indicate that tremor cells are involved in tremor production rather than sensory feedback from tremulous body part [5, 6], and might be thought of as tremor ‘pacemaker’ cells. Detailed studies of physiological activity of Vim neurons have shown presence of somatotopic organization within the nucleus. The contralateral leg area is represented in the dorsolateral part of the nucleus, the face in the most medial part, and the arm area between them and somewhat ventrally [7]. The VC nucleus of the thalamus is also somatotopically organized, with the sensory homunculus that has its face located medially and leg laterally [8]. A constant relationship between somatotopically arranged cells in Vim and VC nuclei allows us to pinpoint targets for tremor-relieving procedures by sensory stimulation of adjacent VC neurons [4].

Patient Selection Stereotactic Vim thalamotomy is indicated for drug-refractory tremor of various etiologies. The two most common pathological conditions that are treated with thalamotomy are Parkinson’s disease (PD) and essential tremor (ET) [9–11]. Tremor of cerebellar and posttraumatic origin and other movement disorders, such as chorea, athetosis, hemiballism of dystonia, comprise another group of diseases that may be successfully treated with Vim thalamotomy, although the results for these latter conditions are much less favorable than PD or ET. The detailed indications for surgical intervention are discussed earlier in this book. We would like to mention, however, that prior to the surgery all patients need to be screened for bleeding disorders, uncontrolled hypertension, and significant cerebral atrophy. These conditions may increase the risk of intracerebral hemorrhage which remains the major source of mortality for thalamotomy. Special considerations are used for selection of patients for second-side thalamotomy in bilateral disease. First of all, the initial operation is usually performed on the more symptomatic side or on the dominant side in cases of equal severity of symptoms. If the first operation is successful and results in complete disappearance of the tremor, the second operation may be deferred because of the high incidence of postoperative complications, particularly hypophonia and other speech disorders. Generally, in these cases we prefer unilateral thalamotomy with contralateral thalamic stimulation to bilateral thalamotomy [12]. If a patient presents with bilateral severe tremor and prefers to proceed with one-time bilateral intervention, then bilateral thalamic stimulation may be the reasonable choice of treatment [13].

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Surgical Technique The procedure of stereotactic thalamotomy starts with a thorough explanation of surgery and its details to the prospective patient. It is hard to overestimate the need for the patient’s cooperation during all stages of the operation. Intravenous sedation is usually avoided because of its interference with patient’s symptoms. In the past, we have used routine premedication with intravenous midazolam and fentanyl, but currently we prefer to reserve it only for patients with high level of anxiety or those who cannot remain immobile during the imaging stage. The stereotactic frame is applied with the patient in sitting position. The local anesthetic mixture, consisting of equal amount of 0.5% bupivacaine and 1% lidocaine and epinephrine 1:200,000, is applied to the sites of screw insertion. Care is taken to align the frame in the axial plane parallel to the intercommissural line so the target coordinate calculation becomes somewhat easier. Standard Series G Leksell frame (Elekta, Atlanta, Ga., USA) may be applied and positioned with relative ease using a pair of plastic ear bars. We have found that covering the tip of each ear bar with a small piece of self-adherent plastic foam greatly reduces the patient’s discomfort, to the point that sedative or analgesic medication is unnecessary. Four screws are advanced symmetrically alternating between pairs of diagonally opposing screws [14]. After the frame is tightly attached to the patient’s head, the ear bars are removed, and the patient is transferred to the imaging suite. Magnetic resonance imaging (MRI) appears to be the most appropriate imaging technique since it allows direct visualization of anatomic landmarks (the third ventricle, anterior (AC) and posterior (PC) commissures) and intracranial structures (the thalamus, internal capsule, basal ganglia) while maintaining high degree of accuracy. Usually, 3 mm thick contiguous T1-weighted axial MRI images obtained above and below the intercommissural plane are sufficient for stereotactic planning. The field of view should be at least 28¶28 cm and centered around the frame center so that all fiducial markers of stereotactic MRI localizer appear on each image. In those patients who cannot undergo MRI because of extreme claustrophobia or presence of pacemakers, other implanted electronic devices, or ferromagnetic objects, computer tomography (CR) may be used instead of MRI. CT images are obtained in similar manner, with 1-mm thick contiguous scans through the vicinity of the intercommissural plane. Both techniques, MRI and CT, have been compared with conventional ventriculography, a technique previously considered to be the ‘gold standard’ imaging modality of functional stereotaxis [15–17]. Both MRI and CT were found to be accurate and reliable for purposes of target calculation. One study analyzed MRI features of the human thalamus and found 4–5 mm variation in the distance from the midline to the thalamocapsular border in patients with the same third ventricular width [18]. This finding could not have been predicted by ventriculography and this supports the value of MRI as a direct intracranial visualization technique. Target Calculation Traditional coordinaates for the thalamotomy target are derived from the classic stereotactic atlases, such as Schaltenbrand and Wahren [19], and these can be adjusted individually based on the intercommissural distance (IC) and size of the third ventricle. Usually, the coordinates of AC and PC are calculated first relative to the geometric center of the frame. Intercommissural distance and the third ventricular width are calculated next. The anteropos-

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Fig. 1. Geometric method of Guiot delineating the quadrilateral space corresponding to the lateral projection of ventralis intermedius nucleus (Vim) of the thalamus. AC>Anterior commissure; HT>thalamic height; PC>posterior commissure; VC>ventralis caudalis nucleus; VOp>ventralis oralis posterior nucleus.

terior (Y) target coordinate is derived by adding one fourth of the IC to the AP coordinate of PC, and the lateral coordinate of the target (X) is calculated at 13.5–15 mm laterally to midline or 11.5 mm from the lateral wall of the third ventricle. Vertically (Z), the target is located in the axial plane of AC and PC (intercommissural plane). This target location corresponds to the ventriculography-based quadrilateral space of Guiot [8]. The quadrilateral space is located between the intercommissural line and more superior line placed parallel to it at the half of the thalamic height (HT/2 line). Anteriorly, this space is limited by a line connecting the point of 3/12 of IC in front of PC on the intercommissural line and 5/12 of IC on HT/2 line. The posterior border of the quadrilateral space is the line between the points of 2/12 of IC in front of PC on the intercommissural line and 4/12 of IC on HT/2 line (fig. 1). Most modern published series use image-based coordinates that fit into this quadrilateral space and physiologically correlate with the position of the Vim nucleus. The usual algorithms describe a point 4 mm behind the midcommissural point, 13 mm lateral to the midline and 1 mm above the intercommissural plane [9], or 5 mm anterior to PC, 15 mm lateral to the midline and at the level of the intercommissural plane [20]. In addition to image-based coordinates we prefer to recalculate target position using two additional methods: a proprietary Leksell digitizer and computer-based stereotactic navigation software. The purpose of this recalculation is to eliminate factor of human calculation error and increase confidence rather than improve accuracy of targeting. However, because of the intersubject variability or anatomy, target determination based on the imaging alone is insufficient. The final position of the thalamotomy target is adjusted based on results of the intraoperative stimulation (see below). Electrode Insertion Once the target coordinates are selected, the patient is taken to the operating room where he or she is placed on the operating table and the head frame is attached to a standard Mayfield headholder via an adapter. Approritate padding and warm blankets are used to

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keep the patient comfortable throughout the procedure. Monitoring is used primarily for blood pressure control and suppression of intraoperative hypertension. A small area of skin in front of the coronal structure at 2–3 cm lateral from the midline is shaved and then sterilely prepped prior to the stereotactic arc attachment. The stereotactic arc of Leksell system is attached to the frame and its angle is adjusted to a trajectory about 5º lateral to the sagittal plane and 60–70º anteriorly relative to the intercommissural axial plane. The skin and periosteum are infiltrated with local anesthetic. A 3 mm hole is made using a hand-held twist drill, and the dura mater is penetrated with a 1.2 mm sharp drill bit. After that, a cannula is inserted into the brain matter along the stereotactic trajectory and its tip is positioned 12 mm above the target point. A standard radiofrequency electrode with a 1.6–1.8 mm diameter and a 2–3 mm bare tip is placed in the desired position throughout the cannula. It is important to monitor the patient’s tremor immediately prior and during the electrode insertion because in some cases the tremor may disappear or significantly decrease from the so-called ‘microthalamotomy effect’ which is related to a local mechanical injury of the Vim nucleus by the inserted electrode [21]. Intraoperative Macrostimulation It is generally agreed that physiological confirmation of the target is essential for surgical success of the functional ablative procedure. In case of thalamotomy, this can be adequately achieved using intraoperative macrostimulation through the radiofrequency electrode. We perform stimulation at three different frequencies with gradually increasing electrical current. First, 2 Hz stimulation is performed with careful observation of evoked motor activity. The operator holds the patient’s contralateral arm while also observing facial movements. A current of 1–2 V usually elicits muscle contraction in the contralateral arm. Lower stimulation threshold indicates proximity of the electrode tip to the pyramidal tract in the posterior limb of the internal capsule and requires more medial placement of the target. Second stimulation trial is aimed at sensory response. It is performed at 50 Hz frequency with 1 ms pulse width, and the patient is asked to report induced sensations (paresthesias), usually described as mild tingling. Adequate position of the electrode is associated with paresthesias in the contralateral corner of the mouth (labial commissure) and the thumb and index finger at about 1.5 V. Lower sensory threshold (=1.0 V) indicates position of the electrode tip inside the VC nucleus, whereas much higher thresholds suggest that the electrode is positioned too far anteriorly. Development of paresthesias in the leg and lower body may be a sign of the lateral electrode placement, which may be more appropriate for patients with predominance of the lower extremity tremor. A goal of the third stimulation trial that is done at 180–200 Hz frequency is to suppress the tremor. In cases of appropriate electrode placement, this stimulation may suppress tremor completely at current intensity at or below 0.5 V. Intraoperative stimulation results require repositioning of the electrode in approximately one-half of the patients [9]. This is similar to results reported by groups using microelectrode recording for physiological confirmation of the target position [22]. Radiofrequency Lesion Destruction of the Vim at the target point is performed using radiofrequency (RF) heating of the tissue. Although other techniques of local tissue ablation were used in the past, RF thermocoagulation is currently accepted as most reliable, reproducible and predict-

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able means of focal tissue lesion production [23]. It must be mentioned, however, that large historical series of thalamotomies utilized chemical destruction with local instillation of absolute alcohol (chemothalamectomy) [24] and cryoablation (freezing) of the target area with a special cannula refrigerated by liquid nitrogen (cryothalamectomy) [25, 26]. The RF lesion is performed at the final target point with continuous testing of the patient’s speech and motor strength. Usually, a series of test lesions are performed first so the procedure may be aborted and target position adjusted before the development of irreversible damage. The initial test lesion is usually made at 45 ºC for 10 s. If the patient tolerates this lesion without new deficits, the probe temperature is raised to 70–72 ºC and maintained at this level for 60 s while the patient is continuously tested for speech and the hand strength. Once the lesion at the target point is completed, the electrode is withdrawn 2 mm and the second lesion is made, and then withdrawn an additional 2 mm (4 mm from the target point) for the third lesion along the same trajectory. These coagulation parameters result in ovoid shape lesion with volume of 40–60 mm3. Such lesion is usually sufficient for tremor control in patients with PD and ET. For posttraumatic and poststroke tremor, a larger lesion measuring 100–200 mm3 may be required. Larger lesions may be achieved by larger electrode tip diameter, higher electrode tip temperature and a longer coagulation period (90–120 s). If the tremor persists after the RF lesion is completed, and the patient tolerated procedure without development of new symptoms, it is recommended to either enlarge lesion in its original position by additional RF heating to a higher temperature or to move the electrode to another target point, usually 1–2 mm posterior and/or ventral to the initial lesion [9]. Macrostimulation mapping should be repeated at each new position of the electrode in order to prevent development of undesired effects and complications.

Results Thalamotomy is a highly effective procedure for control of parkinsonian and nonparkinsonian tremor. It produces immediate relief in up to 95% of patients. Although effectiveness of the procedure decreases over time, most series in the literature report more than 50% overall long-term effect of stereotactic thalamotomy on tremor suppression. It appears that patients with essential tremor and stable PD maintain higher rate of surgical success on long-term follow-up comparing to patients with progressive parkinsonism who lose their functional status because of the ongoing neurological deterioration. It has also been noted that the majority of recurrences take place within first 3 months after surgery [27]. Analysis of the current literature shows that results of stereotactic thalamotomy are quite consistent, and independent of the technique of intraoperative target localization. We performed meta-analysis of 13 large clinical series that were published after 1990 (table 1). Since there is an issue of possible added benefit of intraoperative microrecording and microstimulation, we compared results of reported series that routinely use microelectrodes during stereotactic

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Table 1. Comparison of results of stereotactic Vim thalamotomy with and without intraoperative microelectrode recording in 13 recent clinical series

References Number of patients Percentage of PD Immediate improvement Long-term improvement Length of follow-up Transient complications Permanent complications

Series without microrecording

Series with microrecording

32–38 243 71.5% (136/190) 89% (42/47) 87.2% (212/243) 19.5 months 40% (59/147) 10% (23/226)

9, 27–31 243 35.5% (78/208) 98% (145/148) 70.2% (158/225) 29.3 months 46.5% (113/243) 31% (75/242)

thalamotomies [27–31] with those that confirm imaging-derived coordinates by intraoperative physiological testing using macrostimulation [32–38]. Results of this meta-analysis indicate that initial success rate from these two groups of studies was 89–93%. The long-term success rate at 19.5 months’ follow-up in the group of thalamotomies without microrecording was 87.2%, whereas the microrecording-assisted thalamotomy group achieved 70.2% success rate at 29.3 months’ follow-up. Transient postoperative complications, including neglect, paresthesias, hemiparesis, gait difficulties, cognitive disturbances, etc., in these two groups were encountered in 40% in the group without microrecording and in 46.5% in the microrecording group. Permanent complications, such as hemiparesis, dystonia, gait apraxia, sensory loss and others, occurred in 10 and 31%, respectively.

Rationale for Thalamotomy without Microrecording Although we strongly support use of microrecording in operations on the globus pallidus and the subthalamic nucleus, we think that stereotactic thalamotomy may be safely performed without use of the microelectrodes. The reason for this is that thalamotomy target in the ventrobasal thalamus is relatively ‘forgiving’. First of all, there is a range of locations in this region in which a lesion produced by thalamotomy will result in good outcome [39]. Second, the morbidity of the procedure may be minimal as long as the neurosurgeon avoids damage to the pyramidal tract from too lateral placement of the lesion. Finally, the end point for the procedure is fairly ‘hard’, in that arrest of tremor by test stimulation or test lesions can be readily observed [40].

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Comparison of the literature data suggests that microrecording in stereotactic thalamotomy does not significantly improve results of the procedure. Use of intraoperative stimulation with macroelectrodes provides adequate means of neurophysiological localization of the Vim thalamotomy target.

References 1 2 3 4 5 6

7 8

9 10 11 12 13

14 15 16 17

18

19 20 21

Gabriel EM, Nashold BS Jr: Evolution of neuroablative surgery for involuntary movement disorders: A historical review. Neurosurgery 1998;42:575–591. Guridi J, Lozano AM: A brief history of pallidotomy. Neurosurgery 1997;41:1169–1183. Starr PA, Vitek JL, Bakay RAE: Ablative surgery and deep brain stimulation for Parkinson’s disease. Neurosurgery 1988;43:989–1015. Burchiel KJ: Thalamotomy for movement disorders. Neurosurg Clin North Am 1995;6:55–71. Hua SE, Lenz FA, Zirh TA, Reich SG, Dougherty PM: Thalamic neuronal activity correlated with essential tremor. J Neurol Neurosurg Psychiatry 1998;64:273–276. Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murayama Y, Dostrovsky JO, Murphy JT: Single unit analysis of human ventral thalamic nuclear group: Correlation of thalamic ‘tremor cells’ with the 3–6 Hz component of parkinsonian tremor. J Neurosci 1988;8:754–764. Oyhe C, Shibazaki T, Hirato M, Kawashima Y, Matsumura M: Strategy of selective Vim thalamotomy guided by microrecording. Stereotact Funct Neurosurg 1990;54/55:186–191. Taren J, Guiot G, Derome P, Trigo JC: Hazards of stereotaxic thalamectomy. Added safety factor in corroborating x-ray target localization with neurophysiological methods. J Neurosurg 1968;29: 173–182. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for parkinsonian, essential and other types of tremor. Neurosurgery 1995;37:680–687. Hitchcock E, Flint GA, Gutowski NJ: Thalamotomy for movement disorders: A critical appraisal. Acta Neurochir Suppl 1987;39:61–65. Tasker RR, Siqueria J, Hawrylyshyn P, Organ LW: What happened to Vim thalamotomy for Parkinson’s disease? Appl Neurophysiol 1983;46:68–83. Slavin K, Louw D, Burchiel KJ: Treatment of bilateral tremor with thalamotomy and contralateral thalamic stimulation. J Neurosurg 1999;90:436A. Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin P, Gay E, Payen I, Benazzouz A: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–214. Louw DF, Burchiel KJ: Ablative therapy for movement disorders. Complications in the treatment of movement disorders. Neurosurg Clin North Am 1998;9:367–373. Alterman RL, Kall BA, Cohen H, Kelly PJ: Stereotactic ventrolateral thalamotomy: Is ventriculography necessary? Neurosurgery 1995;37:717–722. Kall BA, Goerss SJ, Kelly PJ: A new multimodality correlative imaging technique for VOp/Vim (VL) thalamotomy procedures. Stereotact Funct Neurosurg 1992;58:45–51. Hariz MI, Bergenheim AT: A comparative study on the ventriculographic and computer tomography-guided determinations of brain targets in functional stereotaxis. J Neurosurg 1990;73:565– 571. Kawashima Y, Chen HJ, Takahashi A, Hirato M, Ohye C: Application of magnetic resonance imaging in functional stereotactic thalamotomy for the evaluation of individual variations of the thalamus. Stereotact Funct Neurosurg 1992;58:33–38. Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme, 1977. Ohyer C, Hirai T, Miyazaki M, Shibazaki T, Nakajima H: Vim thalamotomy for the treatment of various kinds of tremor. Appl Neurophysiol 1982;45:275–280. Andy OJ, Jurko MF: Alteration in Parkinson tremor during electrode insertion. Confin Neurol 1965;26:378–381.

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22 23 24 25 26 27 28 29 30 31 32 33

34 35 36 37 38

39 40

Kelly PJ, Derome P, Guiot G: Thalamic spatial variability and the surgical results of lesions placed with neurophysiologic control. Surg Neurol 1978;9:307–315. Alberts WW, Wright EW Jr, Feinstein B, von Bonin G: Experimental radiofrequency brain lesion size as a function of physical parameters. J Neurosurg 1996;25:421–423. Cooper IS, Bravo G: Chemopallidectomy and chemothalamectomy. J Neurosurg 1958;15:244–250. Waltz JM, Riklan M, Stellar S, Cooper IS: Cryothalamectomy for Parkinson’s disease. A statistical analysis. Neurology 1966;16:944–1002. Stellar S, Cooper IS: Mortality and morbidity in cryothalamectomy for parkinsonism. A statistical study of 2,868 consecutive operations. J Neurosurg 1968;28:459–467. Fox MW, Ahlskog JE, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991;75:723–730. Goldman MS, Ahlskog JE, Kelly PJ: The symptomatic and functional outcome of stereotactic thalamotomy for medically intractable essential tremor. J Neurosurg 1992;76:924–928. Goldman MS, Kelly PJ: Symptomatic and functional outcome of stereotactic ventralis lateralis thalamotomy for intention tremor. J Neurosurg 1992;77:223–229. Shahzadi S, Tasker RR, Lozano A: Thalamotomy for essential and cerebellar tremor. Stereotact Funct Neurosurg 1995;65:11–17. Tasker RR, Munz M, Junn FSCK, Kiss AHT, Davis K, Dostrovsky JO, Lozano AM: Deep brain stimulation and thalamotomy for tremor compared. Acta Neurochir Suppl 1997;68:49–53. Wester K, Hauglie-Hansses E: Stereotaxic thalamotomy – Experiences form the levodopa era. J Neurol Neurosurg Psychiatry 1990;53:427–430. Diederich N, Goetz CG, Stebbins GT, Klawans HL, Nittner K, Koulosakis A, Sanker P, Sturm V: Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy of subthalamotomy on tremor in Parkinson’s disease. Neurology 1992;42:1311–1314. Hariz MI, Bergenheim AT: Clinical evaluation of computed tomography-guided versus ventriculography-guided thalamotomy for movement disorders. Acta Neurochir Suppl 1993;58:53–55. Taira T, Speelman JD, Bosch DA; Trajectory angle in stereotactic thalamotomy. Stereotact Funct Neurosurg 1993;61:23–31. Brophy BP, Kimber TJ, Thomson PD: Thalamotomy for parkinsonian tremor. Stereotact Funct Neurosurg 1997;69:1–4. Osenbach R, Dowling J, Burchiel KJ: MRI-guided thalamotomy for tremor; in Program Book of 47th Annual Meeting of the Congress of Neurological Surgeons, New Orleans, 1997, pp 271–272. Giller CA, Dewey RB, Ginsburg MI, Mendelson DB, Berk AM: Stereotactic pallidotomy and thalamotomy using individual variations of anatomic landmarks for localization. Neurosurgery 1998;42:56–65. Laitinen LV: Brain targets in surgery for Parkinson’s disease: Results of a survey of neurosurgeons. J Neurosurg 1985;62:349–251. Burchiel KJ: Comments on Giller CA, Dewey RB, Ginsburg MI, Mendelson DB, Berk AM: Stereotactic pallidotomy and thalamotomy using individual variations of anatomic landmarks for localization. Neurosurgery 1998;42:64–65.

Konstantin V. Slavin, MD, Fellow in Stereotactic and Functional Neurosurgery, Department of Neurosurgery, Oregon Health Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201–3098 (USA) Tel. +1 503 494 6207, Fax +1 503 494 7161, E-Mail [email protected]

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Thalamic Deep Brain Stimulation for Tremor Steven B. Wilkinson, William C. Koller Kansas University Medical Center, Kansas City, Kans., USA

The surgical treatment of tremor has focused primarily on destructive procedures in the basal ganglia. The development of pallidotomy and thalamotomy led to a safe and effective procedure for the control of at least unilateral tremor. The risks associated with these surgeries are significant and can include permanent neurological dysfunction [1]. Importantly, the cognitive and speech risks associated with bilateral thalamotomies are so great that bilateral surgery is prohibitive [1]. There are still significant numbers of patients with severe tremor and a small number that have ‘tremor-dominant’ Parkinson’s disease (PD) despite adequate medication in which there main limitation is due to the tremor. In essential tremor (ET) the majority of patients are only mildly affected by their tremor or the tremor is abated significantly by medications. There is still a significant minority of patients with ET whose tremor cannot be medically controlled. The tremor in ET is predominately a postural and kinetic tremor greatly effecting the ability to perform any functional tasks in these severe ET patients. In addition to ET and PD, there are other less common tremor states such as posttraumatic and poststroke tremor. These disorders rarely respond to medications. Though there are numerous conditions in which a surgical treatment of tremor may be warranted, there has been in the past a reluctance to recommend surgery because of the possibility of untoward side effects, the high risks of bilateral procedures, and the finality of a destructive procedure [1]. The development of chronic thalamic stimulation (TS) was spurred by the need to address these concerns. Though originally described by Andy [2], Benabid et al. [3, 4] initially promoted TS as an alternative for the other hemisphere in patients who have had a successful thalamotomy. Their results were encouraging enough to begin to recommend TS initially as an alternative to thalamot-

omy. Since these initial reports there have been numerous confirmations of the success of thalamic stimulation in the control of tremor and importantly, in the general safety of the procedures [5–9].

Indications ET and PD have been the major indications for TS. Patients should have functional limitations from the tremor to undertake the risks of surgery. In ET the patient should have a 3 or 4 out of 4 on the tremor rating scale. In PD the best candidates are the tremor-dominant ones with significant dysfunction related to the tremor and minimal if any other parkinsonian symptoms. Rarely there are patients with severe dyskinesias that result from high doses of levodopa given specifically to control tremor who might also be candidates. Though some groups have reported control of dyskinesias, rigidity and bradykinesia with thalamotomy, these benefits are not universally seen and TS would not be recommended in patients with these as the primary problem from their PD [1, 8]. There is some discussion now with the success of subthalamic nucleus stimulation (STNS) in all aspects of PD whether to proceed with this versus TS even in tremor-dominant PD patients. The rationale is that these patients will most likely progress and over time develop the other aspects of PD. So far we have not proceeded with this approach because of the extra time and effort that programming of the STNS requires and that experience with this procedure is not as great as TS so that the long-term usefulness is uncertain. For any other tremor state, TS functions in an equivalent fashion to a thalamotomy so that for any disorder that thalamotomy is considered one could consider TS [1, 3–10]. As with thalamotomy, the patient should be fit enough to tolerate the procedure. Patients with dementia or cognitive dysfunction are poor candidates since patient cooperation is an important aspect in the outcome. As with all stereotactic procedures, coagulopathy or other bleeding tendencies need to be addressed and corrected prior to the surgery. Also since the surgery involves the implantation of a foreign body the patient should be free of any infection and caution should be exercised in patients with diabetes or other disorders that would make them prone to infection. Patients with pacemakers, dorsal column stimulators, are not candidates because of the risks of cross talk between the devices.

Technique An informed patient is as important in this procedure as in any neurosurgical procedure. The patient should be aware of what will take place during the surgery so that they will be

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as cooperative and calm as possible. Usually the antitremor medications are held the morning of the surgery. We usually avoid giving any sedative medications since this may interfere with the tremor. If sedation is needed then either small doses of midazolam or proprofol may be used because of their short duration of action. Patients are usually given antibiotics prior to the procedure; steroids or anticonvulsants are not routinely given. The head frame placement, though routine, is critical. It needs to be tilted in the sagittal plane to approximate the anterior commissure-posterior commissure (AC-PC) plane. Yaw and roll of the frame in reference to the head needs to be minimized. After adequate infiltration with a local anesthetic the pins need to be tightened so that the frame is held securely and will be so for the entire procedure. We have used CT for our localization purposes but other groups have used MR or stereotactic ventriculography. Our protocol involves 10-mm scan slices through the thalamus to insure that the AC and PC will be appropriately imaged. Then 1-mm slices are made through the region of interest and the slice with the best representation of the AC and PC is selected. Since the target is nearer the PC, this is the more critical of the two on the image [11]. The stereotactic target is determined by taking the AC-PC distance and dividing that by 12, this result is multiplied by 2.5 to give the distance anterior to the PC. The lateral coordinate is one-half the width of the third ventricle plus 11.5 mm from the midline. We have found that with microelectrode recording this places us usually in the face area of the homunculus so we usually add 1–2 mm in addition lateral for the final target. The vertical coordinate is the AC-PC plane. In the operating room the patient needs to be positioned on the OR table so that they are comfortable. The patient may need to be in that position for an extended period of time so this is an important key of the procedure. The position of the neck is very critical; we place a piece of foam behind the neck so that there is some support. The position of the skin incision will determine the path of the electrode through the VIM. Typically the angle of the electrode should be about 60º from the AC-PC plane and close to 0º in the sagittal pain. Placing the burr hole anterior to the coronal suture about 2.5 cm from the midline should place the electrode near that trajectory in most patients. Initially we used macroelectrode stimulation to confirm and refine the position of the electrode. This approach involved placing a macroelectrode usually several millimeters above the calculated target and stimulating through the electrode to see the effect. Stimulation was done with a pulse rate of 140/s and 100 ls pulse duration the volts were varied from 0 up to about 5 V. Typically the patient would experience paresthesias in the hand or corner of the mouth and then at a voltage slightly above this the tremor would stop. The electrode was advanced to several different areas above, at, and below the target. The site, which gave the best tremor control at the lowest voltage, was chosen as long as the paresthesias were transitory. The implanted electrode would then be placed in the position that gave the best control and stimulation was done again to confirm the same effect. Tremor was tested in all of the different modes that caused the patient difficulty (i.e. postural, kinetic, etc.). Recreating activities such as writing, holding a cup, bringing a spoon to the mouth were done to assess the functional benefit of the tremor control. Also speech was tested on implants on the dominant hemisphere to insure there were no adverse effects. This approach was successful and straightforward (fig. 1). In at least 70% of our cases the CT target alone or some minor movements of the electrode according to the type of response were enough to be able to successfully implant the electrode with good tremor control. In the remaining it was unclear how to move the electrode to gain tremor control. Though this difficulty was only in the minority of the cases

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Fig. 1. Axial inversion recovery MR after unilateral placement of thalamic DBS electrode.

it was a very frustrating experience and was the main reason we adopted microelectrode recording. With this approach the microelectrode is used to map the cellular responses around the image-calculated target. The VIM was defined by cells that fired in synch with the tremor and cells that responded to deep muscle stimulation. Just posterior to the VIM the ventral caudal nucleus is found and it has cells that respond to light tactile input that is in a very restricted area and does not fatigue. The VC determines the posterior border of the VIM. This was a clearer and more precise way in our experience to determine the physiologic target to give the best tremor control. The downside to this approach is the extra time and effort that is needed to perform microelectrode recording. Also electronic interference from devices in the operating room or adjoining areas can degrade the signal making interpretation difficult. Once the physiologic target has been confirmed the permanent electrode is implanted. This electrode has four individual contacts each 1.5 mm in length separated by 1.5 mm in distance giving a span of 10 mm of working space. Stimulation through the permanent electrode is done to insure tremor control and no side effects. We have used bipolar stimulation between the most inferior and superior electrodes with parameters of 140 Hz, 100 ls pulse width, and vary the volts from 0 to 5. The doubling point of the pulse generator is 5 V so if it takes more than this to control tremor the life of the battery will be significantly shortened. Also this probably means that the lead is too far away from the correct location in the VIM to be effective over time. Typically tremor control occurs between 2 and 3.5 V. Again the position with the lowest voltage that gives tremor control and transitory paresthesias is the point of final placement. To secure the electrode a special flange is placed in the burr hole. This has two slots that allow the lead to be placed once the stylet has been removed. The lead is typically placed in the brain inside of a cannula that ends at least 10 mm above the target. After the desired placement is determined the cannula is withdrawn until the lead can be seen above the burr hole. An assistant then grasps the lead with a protected forceps. Once this is secured

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Fig. 2. Implanted hardware for thalamic stimulation, includes DBS electrode, extension cable, and intermittent pulse generator (Medtronics, Inc.).

the stylet can be removed and all of the introduction apparatus and the arc of the frame moved. The lead is placed in one of the grooves and a special burr hole cap is placed on the flange thus securing the lead in place. The burr hole ring and cap make it quite easy to perform revisions and remove the electrode without any significant scar tissue surrounding the electrode. It has two disadvantages. The minor problem is that it protrudes above the skull (especially important cosmetically in bald patients). The more major problem is that when the cap is applied it may push the electrode inferiorly or unless the electrode is next to one of the grooves in the burr hole it may be displaced anteriorly/posteriorly or medially/ laterally when placing it in the groove. One way of overcoming this problem is to use flouroscopy to insure that the electrode is not deviated when placing the cap. We have begun using a different method to secure the lead this way adopted from techniques used by Burchiel and Grossman. The burr hole is filled with hydroxyapatite bone cement while the introducing cannula is still in place. Once this hardens then the stylet is removed and the electrode is placed flushed on the skull surface and secured with a straight microplate that is bent slightly in the middle to accommodate the electrode (fig. 2). The placement of the rest of the hardware can be done at the same time or the lead can be externalized for a trial of stimulation prior to internalization to confirm the response. We have used general anesthesia to place the stimulating hardware but others have used sedation and local anesthetic with the same success. An incision is made below the clavicle and a subcutaneous pocket created. This should be big enough to just accept the pulse generator and any excess extension cable so that there is not room for the device to migrate or rotate in the pocket. Care should also be taken in making sure there is complete hemostasis because a hematoma in the pocket provides a fertile ground for infection. Placement of the end of the extension that accepts the DBS electrode is also a critical issue. If it is placed too high on the head (above the line of the temporalis muscle insertion) then there is a risk of skin breakdown. However, if the connector is placed in the neck then the DBS electrode tends to fatigue and eventually fracture from the movement of the neck.

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The connector should be placed behind the ear. Some have drilled a trough in the skull so that the connector will be lower profile, others have buried it beneath the temporalis fascia, and others have placed a suture around the connector so that it will not migrate into the neck. Care should also be taken when tunneling the extension because if the tunnel is out of the loose areolar tissue below the galea then the device will lie too close to the skin risking skin breakdown. Usually one or two small relaxing incisions will simplify the passage of the tunneling rod. Bleeding can occur if one of the external jugular veins is damaged above the clavicle. Pressure over this area invariably stops the bleeding after several minutes. We have had one case and have also seen another in referral with a brachial plexus injury secondary to the tunneling.

Results Benabid et al. [3] were the first to present a series of patients treated with thalamic DBS. This and a subsequent paper [14] detailed the experience with 100 patients with predominately PD and ET. Overall there was an approximately 92% success rate in controlling tremor in the target extremity by 3 months [4]. Others have reported similar findings [5–10]. Overall our series have had an 80–85% success rate as defined by a two-point reduction on a four-point tremor rating scale [6–8]. Our case total is now over 150 patients implanted unilaterally in the thalamus with the same outcome. At least in patients with ET there is good evidence that there are functional improvements associated with the tremor control [12]. Immediate complications associated with the surgery are minimal but have included intracranial hemorrhage as the most severe. Side effects from stimulation such as dysarthria, imbalance and weakness all resolve with adjustment or turning off the stimulation. In some rare cases some degree of unwanted side effects has been tolerated by the patient to gain tremor control. Longer term issues relate to the implanted hardware. Infection is always a risk but is usually seen within the first 6 weeks of implantation. There is some evidence though that the neurologic risks are lower with DBS than thalamotomy but the hardware risks and maintenance are not an issue with thalamotomy [13]. One late problem is that of tolerance. Most of the studies published have only followed the patients for approximately 12 months. There is a group of patients who have excellent early success but lose the benefit over time. Fortunately this is a small number of our series (so far). This has occurred in a few patients with severe ET and it is unclear whether this is progression of their disease or a true failure of the therapy. Our approach is to consider reoperation in severe cases and if this is not successful then consideration can be given to performing a thalamotomy. This problem will need continuing monitoring to determine the circumstances and hopefully a therapy for this group of patients.

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References 1 2 3 4 5

6 7 8 9 10 11 12 13

Burchiel KJ: Thalamotomy for movement disorders. Neurosurg Clin North Am 1995;6:55–71. Andy OJ: Thalamic stimulation for control of movement disorders. Appl Neurophysiol 1983;46: 107–111. Benabid AL, Pollak P, Gervason C, et al: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406. Benabid AL, Pollak P, Gao D, et al: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–214. Blond S, Caparros-Lefebvre D, Parker F, et al: Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg 1992;77:62–68. Hubble JP, Busenbark KL, Wilkinson S, et al: Deep brain stimulation for essential tremor. Neurology 1996;46:1150–1153. Hubble JP, Busenbark KL, Wilkinson S, et al: Effects of thalamic deep brain stimulation based on tremor type and diagnosis. Mov Disorder 1997;12:337–341. Koller W, Pahwa R, Busenbark K, et al: High-frequency unilateral thalamic stimulation in the treatment of essential tremor and Parkinsonian tremor. Ann Neurol 1997;42:292–299. Limousin P, Speelman JD, Gielen F, et al: Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry 1999;66:289–296. Ondo W, Jankovic J, Schwartz K, et al: Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology 1998;51:1063–1069. Tasker RR, Kiss ZHT: The role of the thalamus in functional neurosurgery. Neurosurg Clin North Am 1995;6:73–104. Lyons KE, Pahwa R, Busenbark KL, et al: Improvements in daily functioning after deep brain stimulation of the thalamus for intractable tremor. Mov Disord 1998;13:690–692. Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998;49:145–154.

Steven B. Wilkinson, MD, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160 (USA) Tel. +1 913 588 6107, Fax +1 913 588 7570, E-Mail [email protected]

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Subthalamic Nucleus Lesions Steven S. Gill, Peter Heywood Frenchay Hospital, Bristol, UK

Lesions of the subthalamic nucleus (STN), usually strokes, have long been known to cause hemiballism [1]. There are also reports of patients with Parkinson’s disease (PD) who have improved after spontaneous haemorrhage into STN [2, 3]. After the success of pallidotomy and thalamotomy in the 1950s, surgeons attempted to improve those results with smaller lesions targeted at pallidofugal fibres. These pass through a small area within the H field of Forel that lies superior to STN. Targeting this area (campotomy) was a relatively common procedure; Mundinger [4] reported 500 cases. These lesions may well have involved STN to a greater or lesser extent [5]. Spiegel et al. [6] reported campotomy in 25 patients with benefit and without major side effects. Andy et al. [7] report the results of lesioning 58 patients. Their preferred target was the posterior subthalamus including the field of Forel and zona incerta. Although they provoked transient hemiballism in 5 patients, in no case was it prolonged. The lesions were reported to be otherwise safe. Thus, although confirmation of target accuracy in the pre-MRI era was questionable, it is a misapprehension that lesioning STN is new. It is intriguing that an effective surgical treatment for hemiballism is a lesion involving pallidofugal fibers and zona incerta [8], these fibers are immediately dorsal to STN. Since it is likely that lesions or deep brain stimulation of STN will involve zona incerta and pallidofugal fibers, it may be that damage to these areas is counteracting any prodyskinetic effect of the STN lesion itself. By the 1980’s the pivotal role of STN in basal ganglia function became evident with the greater theoretical understanding of the basal ganglia circuitry in the direct/indirect pathway model [9] and the availability of an animal model of PD in the MPTP-lesioned monkey. Evidence from

microelectrode recordings in MPTP-lesioned monkeys indicates that STN becomes continuously overactive with sustained increased firing rate [10]. Microelectrode recordings in patients undergoing surgery for PD also demonstrate STN overactivity [11]. Lesions of the STN in MPTP monkeys have been shown to alleviate many parkinsonian symptoms [12–15]. Bergman et al. [12] lesioned 2 monkeys, 1 of them had persisting hemichorea at sacrifice; subsequently Aziz et al. [13, 14] lesioned 6 monkeys in 3 of which there was hemichorea persisting for up to 8 weeks; Benazzouz et al. [15] report 2 lesioned monkeys with no hemichorea, and Guridi and Obeso [23] report 8 lesioned monkeys in which 3 had hemichorea and 1 hemiballism. Although STN appeared to be a rational target for functional surgery in PD, the possibility of hemiballism made surgeons reluctant in recent years to place a lesion in STN. Benabid et al. [16] observing that deep brain stimulation in the Vim thalamus had the same beneficial effect as a lesion, but if side effects occurred could be reversed, inserted deep brain stimulators bilaterally into STN [17]. They demonstrated 60% improvement in most aspects of ‘off’ state parkinsonism, including improvement in gait and axial symptoms that do not improve and may even be made worse with pallidotomy or pallidal stimulation [18]. Unlike pallidotomy, STN stimulation allows reduction of L-dopa intake by approximately 50% and consequently dyskinesia is significantly reduced [19]. Thalamic lesions or stimulation reduce tremor, but it has been demonstrated that even in tremor-predominant PD, STN stimulation is as effective [20] and is preferable since it will counter other PD symptoms not dealt with by thalamotomy. Therefore, STN may well be the optimal target for patients requiring surgery for PD. Stimulators are bulky and can be uncomfortable for the patient. Stimulators require regular adjustment especially in the early months after insertion. Stimulator units need to be replaced every 3–5 years. Lesions do not have these problems, but unlike stimulators, side effects may not be reversible. Complications of a lesion cannot be switched off nor, should their beneficial effect begin to wane, can lesions be adjusted. Nevertheless, placement and maintenance of bilateral stimulators is an expensive option both financially and in the time a neurologist will need to spend adjusting the parameters postoperatively; these problems make it inconceivable that the implantation of bilateral deep brain stimulators into STN could be a viable option for any but a few of the millions of patients worldwide who suffer from advanced PD. In recent years unilateral STN lesions have been reported in 11 patients by Alvarez et al. [21–23]. The results obtained by this group together with those from our group in Bristol, UK will be discussed.

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Patient Selection for Subthalamic Nucleotomy We believe that assessment of appropriateness and fitness for functional neurosurgery must be carried out by a team experienced in the task. The minimum infrastructure for preoperative assessment and postoperative care and assessment should be: a neurosurgeon, a neurologist, a neuropsychologist, a PD specialist nurse; ideally the team would also include a speech therapist, an occupational therapist and a physiotherapist. The generally agreed criterion for functional neurosurgery in PD is that it is reserved for those patients who have functionally disabling disease despite best medical therapy. This usually means that best medical therapy presents the patient with two unsatisfactory alternatives: either to be ‘on’ but dyskinetic for significant portions of the day or, with less L-dopa, to have less dyskinesia but to be ‘off’ for a significant portion of the day. Patients must be fully informed about the procedure and have a realistic idea of the outcome of surgery. There are generally agreed contraindications to functional neurosurgery in PD. An important role for the neurologist in the assessment team is to exclude patients who do not have idiopathic PD. Patients should be L-dopa responsive. Dementia is an important contraindication, a measure that could be used is a Folstein Mini-Mental score of less than 25. The patient should be able to function at a reasonable level of independence for at least some part of the average day; our impression is that patients who are bed bound with end-stage disease do less well from surgery. Age is not an absolute selection criterion, although analysis [24, 25] suggests that older patients do less well. As described above, the evidence from bilateral deep brain stimulation of STN from Benabid et al. [16] suggests that STN rather than internal pallidum is the preferred target for any patient with PD who requires functional neurosurgery, no matter the predominant symptoms. We can hope that as further evidence allowing comparison of outcomes in various patient groups emerges it will be clearer whether this view is correct. If it is decided for a given patient that STN is the appropriate target, then the issue of whether a lesion should be placed or stimulators implanted remains to be determined. Most patients with PD have bilateral symptoms and require bilateral procedures. Procedures that may be safe unilaterally may have significant morbidity when carried out bilaterally. The evidence is now clear that bilateral thalamotomy has significant risk of postoperative dysarthria and other problems [26–28], so that most centres would not now contemplate bilateral thalamotomy. The evidence that bilateral pallidotomy carries significant risk is not clear cut. Some authors report few significant postoperative

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complications after bilateral pallidotomy [29]; others regard bilateral pallidotomy as carrying too significant a risk to speech or cognitive function for it to be a surgical option for most patients [24, 30]. There has been no significant neuropsychological or speech deficit after bilateral implantation of deep brain stimulators into STN [17]; the complications after unilateral and bilateral STN lesions remains to be determined – we shall discuss available results subsequently.

Pre- and Postoperative Assessment Subthalamic lesioning is still at a developmental stage and therefore patients must be rigorously assessed preoperatively and at intervals postoperatively. The Bristol group assesses all patients with the following protocols preoperatively and at least annually postoperatively: Unified Parkinson’s Disease Rating Scale (UPDRS), Core Assessment Program for Intracerebral Transplantation (CAPIT) [31], Neuropsychometry, Quality of Life Questionnaires, Speech Assessment.

Surgical Technique There is no general agreement amongst neurosurgeons about the best and safest way to locate the target nucleus in functional PD surgery. Some centres use MRI and microelectrode recording and regard the microelectrode recording as a sine qua non for accurate placement [32]. Other centres feel that accurate placement is possible with good quality image guidance and without the potential danger of repeated microelectrode puncture, this is our own view [T. Aziz, chapter 9, this volume]. The following procedure is adopted in Bristol. The subthalamic nucleus is localized with high-resolution MRI T2 scan sequences (1.5 T TR 2,500, TE 150, TSE 11, NSA 12) and peroperative macrostimulation. Under general anaesthesia a modified Leksell stereotactic frame is fitted parallel to the orbitomeatal plane. The anterior-posterior commissural (ACPC) plane is identified on a mid-sagittal planning scan. Axial images, 2 mm thick, are obtained parallel to the AC-PC plane and coronal images orthogonal to these are then obtained. We have found that these sequences give optimum delineation of STN and related structures. Using magnified hard copies of the MRI scans and after comparison to the Schaltenbrand atlas [33], the boundaries of STN are identified. The boundary of STN is coregistered on the coronal and axial scans giving optimum three-dimensional target definition. Stereotactic coordinates of the target, the dorsolateral portion of STN, are recorded and a trajectory is planned. At surgery, patients are awake and in an ‘off’ state, anti-parkinsonian medications having been stopped 24 h previously. A 1.24-mm diameter electrode with a 2-mm exposed tip is guided to the dorsolateral STN. The target is stimulated at 100 Hz, 1 ms pulse width

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and between 0.75 and 2 V during which change in tremor, rigidity and bradykinesia are monitored. Probe position is adjusted to gain maximal clinical improvement in the observed parameters without the development of side effects. At the optimal position one or two radiofrequency lesions are made, typically at 80ºC for 60 s. The patient undergoes a postoperative high-resolution MRI scan to confirm lesion position (fig. 1). Anti-parkinsonian medication is reintroduced as required.

Clinical Results of Subthalamic Nucleotomy In recent years, only two centres have published results of STN ablative surgery: Havana, Cuba [21, 22, 34] and Bristol, UK [35, 36]. The Cuban group reports 11 patients who have undergone unilateral subthalamic lesions, where STN was localized with CT and semi-microelectrode recording. They report improvement in axial motor tasks, facial expression and all parkinsonian signs on the side contralateral to the lesion. The improvements were maintained for up to 24 months. Hemiballismus occurred in 1 patient 7 days after surgery associated with an infarction of the whole subthalamic region and part of the thalamus. No other patients had hemiballism after surgery. The Bristol group has performed 13 unilateral lesions, 10 bilateral lesions and 4 lesions on one side with a deep brain stimulator placed on the other side. Importantly we have seen no major complications of STN lesions. One patient has significant post-operative hemiballism on the contralateral side to an STN lesion, this persisted for approximately 3 weeks as it gradually settled without active treatment. Two other patients have had minor choreiform involuntary movement after STN lesions, these settled down quickly in the postoperative period. None of the 22 patients had intracerebral haemorrhage, none had blepharospasm, none had significant confusion. One patient had worsening of his pre-existing dysarthria. All our patients after STN lesions showed improvement in contralateral tremor, rigidity and bradykinesia. Patients still need to take L-dopa; overall their L-dopa intake is approximately halved and with this there is a reduction in dyskinesia by approximately 70%. Their activities of daily living scores in the subscale II of UPDRS improved in all cases. Total daily ‘on’ time, without significant dyskinesia, more than doubled.

Conclusions Preliminary results from the two groups have demonstrated that this procedure can be carried out relatively safely with good therapeutic effect.

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A

B Fig. 1. A Inverted T2 MRI planning image. B T2 MRI image showing bilateral subthalamic lesions.

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Hemiballismus has not been a problem: combining the series in total 48 lesions have been placed with no case persisting hemiballism, there has been 1 infarct and 1 case of worsened dysarthria. Despite this lesioning STN should be regarded as an experimental procedure; it is not one that should yet be undertaken routinely by neurosurgical centres. As more data accumulate regarding the safety and efficacy of STN lesions, it may prove to be a viable alternative to the placement of bilateral deep brain stimulators in STN. References 1 2 3 4

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Shannon KM: Ballism; in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders, ed 3. Baltimore, Williams & Wilkins, 1998, pp 365–376. Sellal F, Hirsch E, Lisovoski F, Mutschler V, Collard M, Marescaux C: Contralateral disappearance of parkinsonian signs after subthalamic hematoma. Neurology 1992;42:255–256. Vidakovic A, Dragasevic N, Kostic VS: Hemiballism: Report of 25 cases (comments). J Neurol Neurosurg Psychiatry 1994;57:945–947. Mundinger F: Results of 500 subthalamotomies in the region of the zona incerta; in Gillingham FJ, Donaldson IML (eds): Third Symposium on Parkinson’s Disease. Edinburgh, Livingstone, 1968, pp 261–263. Fager CA: Evaluation of thalamic and subthalamic surgical lesions in the alleviation of Parkinson’s disease. J Neurosurg 1968;28:145–149. Spiegel EA, Wycis HT, Szekely EG, Adams J, Flanagan M, Baird HW: Campotomy in various extrapyramidal disorders. J Neurosurg 1963;20:871–881. Andy OJ, Jurko MF, Sias FR: Subthalamotomy in treatment of parkinsonian tremor. J Neurosurg 1963;20:860–870. Krauss JK, Mundinger F: Functional stereotactic surgery for hemiballism. J Neurosurg 1996;85: 278–286. Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders (comments). Trends Neurosci 1989;12:366–375. Bergman H, Wichmann T, Karmon B, DeLong MR: The primate subthalamic nucleus. II. Neuronal activity in the MPTP model parkinsonism. J Neurophysiol 1994;72:507–520. Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, Lozano AM: Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998; 44:622–628. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1438. Aziz TZ, Peggs D, Sambrook MA, Crossman AR: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 1991;6:288–292. Aziz TZ, Peggs D, Agarwal E, Sambrook MA, Crossman AR: Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT)-exposed primate. Br J Neurosurg 1992;6:575–582. Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B: Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 1993;5:382–389. Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin P, Gay E, Payen I, Benazzouz A: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders (comments). J Neurosurg 1996;84:203–214. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–1111.

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Bejjani B, Damier P, Arnulf I, Bonnet AM, Vidailhet M, Dormont D, Pidoux B, Cornu P, Marsault C, Agid Y: Pallidal stimulation for Parkinson’s disease. Two targets? (comments). Neurology 1997; 49:1564–1569. Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Bennazzouz A, Benabid AL: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998;121:451–457. Krack P, Benazzouz A, Pollak P, Limousin P, Piallat B, Hoffmann D, Xie J, Benabid AL: Treatment of tremor in Parkinson’s disease by subthalamic nucleus stimulation. Mov Disord 1998;13:907–914. Alvarez A, Macias J, Guridi J, Lopez G, Maragato C, Teijeiro A, Torres E, Pavon N, Ochoa L, Jouncos J, DeLong M, Obeso JA: Unilateral dorsal subthalamotomy for Parkinson’s disease. Mov Disord 1998;13(suppl 2):266. Obeso JA, Alvarez LM, Macias RJ, Guridi J, Rodriguez MC, Ramos E, Linazaro GJ, Gorospe A, DeLong MR: Lesion of the subthalamic nucleus in Parkinson’s disease. Neurology 1997;48:A138. Guridi J, Obeso JA: The role of the subthalamic nucleus in the origin of hemiballism and parkinsonism: New surgical perspectives. Adv Neurol 1997;74:235–247. Lozano AM, Lang AE: Pallidotomy for Parkinson’s disease. Neurosurg Clin North Am 1998;9: 325–336. Baron MS, Virek JL, Bakay RAE, Green J, Kaneote Y, Hashimoto T, Turner RS, Woodward JL, Cole SA, McDonald WM, DeLong MR: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355–366. Blumetti AE, Modesti LM: Long-term cognitive effects of stereotactic thalamotomy on non-parkinsonian dyskinetic patients. Appl Neurophysiol 1980;43:259–262. Kocher U, Siegfried J, Perret E: Verbal and nonverbal learning ability of Parkinson patients before and after unilateral ventrolateral thalamotomy. Appl Neurophysiol 1982;45:311–316. Krayenbuhl H, Wyss OAM, Yasargil MG: Bilateral thalamotomy and pallidotomy as treatment for bilateral parkinsonism. J Neurosurg 1961;18:429. Iacono RP, Shima F, Lonser RR, Kuniyoshi S, Maeda G, Yamada S: The results, indications, and physiology of posteroventral pallidotomy for patients with Parkinson’s disease (comments). Neurosurgery 1995;36:1118–1125; discussion 1125–1127. Scott R, Gregory R, Hines N, Carroll C, Hyman N, Papanasstasiou V, Leather C, Rowe J, Silburn P, Aziz T: Neuropsychological, neurological and functional outcome following pallidotomy for Parkinson’s disease. A consecutive series of eight simultaneous bilateral and twelve unilateral procedures. Brain 1998;121:659–675. Langston JW, Widner H, Goetz CG, Brookes D, Fahn S, Freeman T, Watts R: Core assessment program for intracerebral transplantation (CAPIT). Mov Disord 1992;7:2–13. Vitek JL, Bakay RA, DeLong MR: Microelectrode-guided pallidotomy for medically intractable Parkinson’s disease. Adv Neurol 1997;74:183–198. Schaltenbrand G, Baily P: Einfu¨hrung in die stereotaktischen Operationen mit einem Atlas des menschlichen Gehirns. Stuttgart, Thieme, 1959. Obeso JA, Guridi J, Alvarez L, Macias R, Linazasoro G: Ablative surgery of Parkinson’s disease; in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders, ed 3. Baltimore, Williams & Wilkins, 1998, pp 1049–1064. Gill SS, Heywood P: Subthalamotomy can be performed safely. Mov Disord 1998;13(suppl 2):201. Gill SS, Heywood P: Bilateral dorsolateral subthalamotomy for advanced Parkinson’s disease. Lancet 1997;350:1224.

Dr. Peter Heywood, Consultant Neurologist, Frenchay Hospital, Bristol BS16 1LE (UK) Tel. +44 117 9753951, Fax +44 117 9753824, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 196–226

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Subthalamic Nucleus Deep Brain Stimulation Alim Louis Benabid, Adnan Koudsie, Abdelhamid Benazzouz, Brigitte Piallat, Nade`ge Van Blerkom, Vale´rie Fraix, Pierre Pollak Department of Clinical and Biological Neurosciences, INSERM Preclinical Neurobiology U-318, Joseph Fourier University of Grenoble, Hoˆpital A. Michallon, Grenoble, France

Coming from surgical practice and from basic experimental research, the role in motor control of various nuclei of the basal ganglia has been known for long, including the thalamus, the pallidum and the subthalamic nucleus (STN) as well as other structures like the centrum medianumparafascicularis complex (CM-Pf ) and the substantia nigra pars reticulata (SNr). Currently we may consider essentially three surgical targets for Parkinson’s disease (PD), which can be represented on the Guiot’s scheme based on the posterior and anterior commissures, the top of the thalamus and the laterality from the midline in millimeters: (1) the thalamic target in the ventralis intermedius nucleus (Vim), and additionally the CM-Pf [1]; (2) the internal pallidum or globus pallidus internus (GPi) is the second target, which was reintroduced in the early 1990s by Laitinen et al. [1] after it was initiated by Leksell [2], and (3) the STN, which is now our current target since 7 years. These three targets have been surgically inhibited so far by lesioning as well as by high-frequency stimulation (HFS). We will not discuss in this paper the reasons why at the moment HFS is becoming the preferred method and will address the advantages and drawbacks of STN HFS in the discussion chapter. It suffices to say that during stereotactic lesions of the thalamus for PD rest tremor and essential tremor, it has been observed that stimulation at the site of the lesion could either induce an increase of the tremor or a diminution of the amplitude of the tremor. We clearly established in 1987 [3–5] that this duality of responses was related to frequency, low frequency

increasing the tremor and high frequency 1100 Hz being able to alleviate totally the tremor during acute test in surgery. One may briefly consider why in turn STN has become the principal target for PD. Although highly efficient on tremor, the thalamic Vim stimulation quickly appeared to be uniquely efficient on this symptom without any significant improvement of the other parkinsonian symptoms, essentially rigidity and akinesia, as already known about thalamotomy [6–22]. Therefore, the evolution of the disease in these patients initially tremoric and becoming akineto-rigid made Vim stimulation subsequently useless as well as in the initially akineto-rigid patients [23]. There was no solution for these highly disabling symptoms in advanced stages, except pallidotomy or more exceptionally deep brain grafting, which was not and still is not practically efficient at the therapeutic level [24]. The data obtained by physiologists in rodents and monkeys showed that the STN was playing a key role in the organization of basal ganglia [25–31], therefore allowing us to extend to it the concept of electrical neuroinhibition and to use it as a human therapeutic target [32–35]. STN stimulation was then proposed in 1993 by the Grenoble group [1] in the treatment of advanced PD and has proven since to be one of the most effective neurosurgical procedure to improve patients severely disabled by chronic levodopa-induced motor complications.

Indications of STN Stimulation So far, the published results of STN stimulation concerned patients with PD. However, given the benefit of STN stimulation on parkinsonian tremor [36], dyskinesias [37] and dystonia [38], other movement disorders may benefit from STN stimulation. As in animal models of epilepsy, changes in STN activity can block the expression of some types of epilepsies [39], STN stimulation is worthwhile in epileptic humans. In parkinsonian patients, the main criteria for the indication of STN stimulation rest on the type of disease the patient suffers from, the general health state of the patient, his or her cognitive and effective state, the results of brain MRI and on other more subjective factors.

Type of Parkinson’s Disease Candidates for STN stimulation must suffer from idiopathic PD complicated by motor fluctuations and dyskinesias. Out of 10 patients with diagnosis other than PD operated undergoing STN stimulation, 2 suffered from par-

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kinsonism and dementia, 2 from multiple system atrophy and 1 from postanoxic parkinsonism. The benefit they drew from surgery was moderate or nil. Surgery did not prevent from the subsequent worsening of nonmotor impairment and did not eventually justify the risk of surgery. Actually, only off-motor symptoms responded to STN stimulation, proportionally to their presurgical response to levodopa. This result is expected as the overactivity of the STN was shown in animal models with pure dopaminergic lesions sensitive to levodopa replacement therapy. Cognitive, dysautonomic, or bulbar symptoms are thought to stem from nondopaminergic lesions [40]. The degree of severity of off-motor symptoms does not influence the outcome after surgery, provided these symptoms respond well to dopaminergic drugs. The only exception to this rule is tremor, which may resist to levodopa and not to STN stimulation. However, most parkinsonian tremors are improved at the peak dose of an acute very high dose of levodopa or apomorphine. If before surgery the patient feels like normal even for a few minutes per day, often after the first levodopa intake in the morning, STN stimulation will be dramatically beneficial, reproducing this favorable state permanently. This emphasizes the importance for the neurologist to capture the patient at his best before surgery, by using a suprathreshold dose of levodopa during a levodopa challenge. For example, the disappearance of tremor, freezing of gait or the normalization of the pull test at this patient’s best motor state are all features predicting an excellent postsurgical outcome. The age of onset of PD mainly affects the response to levodopa therapy, because it may increase the prevalence of nondopaminergic lesions of the brain [41]. Therefore, a young age of onset of PD with a relative young age at the time of levodopa-induced motor complications and parallel young age at the time of surgery should positively influence a good outcome from STN stimulation.

Degree of Disability As any implantation of a probe in the brain bears the risk of severe permanent morbidity in about 2–5% of patients, STN stimulation as other neurosurgical therapies should be proposed in severely disabled patients, namely those unable to cope with activities of daily living or requiring some assistance, after failure of all drug strategies. This attitude should be modulated by the fact that operating on very disabled patients who have been dependent on caregivers for many years raises enormous psychological problems in relation with the relearning of a new independent life. Severely akinetic patients are more at risk for general health complications in the perioperative period. Moreover, there are some theoretical reasons favoring a possible neuroprotec-

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tive role of STN surgery. However, surgery in patients without levodopainduced motor complications seems unwise to maintain a positive benefit/risk ratio. We suggest that candidates for surgery should have a motor examination score of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the worstoff medication condition of at least 30/108 (generally 40–80/108), expect for tremor-dominant PD patients who may have a lower global score. A suprathreshold dose of levodopa in the morning should decrease this score by at least 50%. Patients who tend to fall spontaneously at the time of the best on-motor periods (pull test q3/4 must be contraindicated from surgery. Therefore, patients should not be operated on too late nor too early. Personal, social and professional consideration will help the patient along with the way he or she copes with the activities of daily living to decide the more suitable time for surgery.

Good General Health As age exponentially increases the rate of complications, a biological age 070 is recommended for bilateral STN stimulation. The exclusion criteria are the presence of unstable angina pectoris, severe cerebral macroangiopathy, uncontrolled hypertension, an evolving cancer or other life-threatening conditions, severe heart, pulmonary, renal or hepatic failure, anticoagulant or antiplatelet therapy (aspirin, nonsteroid anti-inflammatory drugs, lisuride) and immunodepression. Any previous surgery for PD can be accepted, provided no pseudobulbar adverse effects occurred. We must pay attention to the normality of the cognitive and affective functions. But what does this mean in patients with PD? Based on our experience, we propose to exclude patients with dementia defined as Mini-Mental State Examination 024/30 and Mattis Dementia Scale 0130/144. Patients with a score between 120 and 130 must be considered on an individual basis after the completion of a neuropsychological test battery evaluating the frontal lobe dysfunction. At the time of surgery, we exclude patients with hallucinations or psychosis, even minimal, and patients with severe depression in on-drug condition assessed by the Beck’s scale or the MADRS.

A Brain MRI within Normal Range We exclude patients with a brain MRI showing features greatly increasing the risk of intracranial bleeding such as severe atrophy or multiple hyperintense signals on T2-weighted sequence.

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Other Subjective Variables To avoid the patient or caregiver disappointment after surgery, we address the following issues: What are the patient’s expectations? Does the realistic prediction of benefit, derived from the presurgical levodopa response, correspond to the expectations of the patient? What are the families’ and caregivers’ expectations? What are the doctors’ expectations? What is the social, familial and professional situation? Is the patient psychologically prepared? Did he or she anticipate the outcome, in terms of both benefit and complications? Improving patients’ cooperation and psychological attitude during all the perioperative period necessitates to explain the individual benefit/risk ratio to the patient, to inform them about medical and surgical alternatives, to provide written information on the surgical procedure, to check the adequacy between everyone’s expectations. No immediate decision is taken and we leave enough time to the patient to take his or her decision with his family and to ask for a second opinion if required. We provide the patient with a psychologist’s support and socioprofessional counseling if needed. Finally, the geographical distance between the patient’s home place and the hospital is considered because of the multiple electrical settings of stimulation during the postoperative period. This consideration is less important from the availability of the Kinetra dual-channel stimulator with the Access therapy device, which allows the patient to set the electrical variables within a range of values predetermined by the physician. However, this possibility of electrical setting self-adjustment can only be envisaged in the patients and/or familial and personal circle cooperative and able to understand the way and reasons to change the variables.

Unilateral or Bilateral STN Stimulation In our experience [33] and that of others [42], bilateral STN deep brain stimulation (DBS) improves parkinsonism considerably more than unilateral STN DBS. Bilateral simultaneous electrode implantation may be the most appropriate surgical option for most patients with bilateral as well as asymmetrical symptoms. Since STN stimulation allows a major decrease in levodopa dose [34, 43], parkinsonism may become unmasked on the nonoperated side. Unilateral STN DBS results in major improvement in contralateral tremor [42, 44] and can be advocated in some patients with highly asymmetric tremordominant PD.

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Indications Patients and Methods One hundred and ten patients have been currently operated in STN, most of them bilaterally. For the evaluation of long-term benefit we will concentrate on the first 57 consecutive PD patients (29 men and 28 women) with a mean of 55×8 years at the time of surgery who were operated on between January 1993 and April 1998. The mean duration of illness was 15×5 years. Their mean Hoehn and Yahr stage was 4.4×0.7 in off-motor condition and 2.4×0.5 in on-motor condition. All patients were treated with levodopa combined with a peripheral dopa decarboxylase inhibitor (mean daily levodopa dose 1,110×560 mg), 41 were treated with an oral dopamine agonist, and 15 used subcutaneous apomorphine. Clinical evaluations were based on the Core Assessment for Intracerebral Transplantation (CAPIT) [45]. Videotaped evaluations were completed twice preoperatively and postoperatively at 3 and 12 months and then yearly. The motor examination of the UPDRS part III [46] was assessed in off- and on-drug conditions preoperatively and in four different conditions postoperatively: offdrug/off-stimulation, off-drug/on-stimulation, on-drug/off-stimulation, and ondrug/on-stimulation. The off-drug state was assessed in the morning following an overnight fast and drug withdrawal. Preoperatively the on-drug state was assessed following the administration of a suprathreshold dose of liquid levodopa and benserazide (MadoparÔ dispersible) calculated as following: the usual levodopa morning dose plus 20%, plus the levodopa dose equivalent to dopamine agonist drugs taken usually by the patient. Postoperatively the patient received the same dose of levodopa as before surgery. If at that time the dose of levodopa was either nil or 0300 mg/day, we gave domperidone 60 mg/day for at least 2 days before the levodopa challenge. The patients were blinded to the stimulation condition. For the off-stimulation conditions, the stimulator was arrested at least 20 min except in 1 patient who could not tolerate the stimulator arrested 15 min because of the severity of parkinsonism. A detailed cognitive analysis was completed for each patient preoperatively and each year postoperatively. The battery of tests included the Mattis Dementia Rating Scale (maximal score, 144) [47] for global cognitive assessment and a frontal score adapted from Pillon et al. [48] (maximal score, 50). The frontal score includes the following tests: verbal fluency, two series of motor sequences, two series of graphic writing sequences, and the Wisconsin Card Sorting Test [49]. Electrical Setting The setting of electrical parameters was performed after surgery and at each follow-up visit. The effect of different electrical parameters was first

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studied off-drug, each contact being successively selected as cathode with the pulse generator case as anode (monopolar stimulation). A constant pulse width of 60ls and a frequency of 130 Hz were initially used and the voltage was progressively increased. Beneficial effects on rigidity, akinesia and tremor, and adverse effects were evaluated. The contact which gave improvement in parkinsonian symptoms with the lowest voltage without adverse effects, was selected for chronic stimulation. The amplitude of the chronic stimulation was progressively increased over the first few postsurgical days. In on-drug condition the effect of the stimulation of dyskinesias was checked. Bipolar stimulation, at least one contact selected as cathode and one selected as anode, was used when the effect was better than with monopolar stimulation. This occurred especially in case of disabling dyskinesias during the postoperative period. In the first 10 patients we tried not to decrease drug dosages before the 3-month follow-up. For subsequent patients, we decreased dosages immediately after surgery while stimulation voltage was progressively increased. Data Analysis We used the UPDRS III total score (maximal score 108) and subscores evaluating limb akinesia (items 23–26, maximal score 32), rigidity (item 22, maximal score 20), tremor (items 20 and 21, maximal score 28), speech (item 18, maximal score 4), postural stability (item 29, maximal score 4), gait (item 30, maximal score 4) and an axial subscore (UPDRS III items 29 and 30 + UPDRS II items 13–15, maximal score 20) [50]. The activities of daily living were assessed by the UPDRS II total score (maximal score 52) and the Schwab & England score (maximal score 100%). The motor complications were assessed by the UPDRS IV total score (maximal score 23) and subscores evaluating the duration of dyskinesias (item 32, maximal score 4), dyskinesia disability (item 33, maximal score 4), the presence of morning dystonia (item 35, maximal score 1), and the duration of off-periods (item 39, maximal score 4). Analysis was performed using either analysis of variance for repeated measures (using Surgery (before/after surgery), Time (time of the follow-up), Stimulation (on-stimulation/off-stimulation) and Drug (on-drug/off-drug) as within subject factors) or paired Student’s test or paired Wilcoxon signed rank test when appropriate. Considering the number of analyses and to avoid a type I error, a p value of 0.005 was considered as statistically significant. Material and Methods Stereotactic Technique The technique is obviously stereotactic. In brief, we still base our methods on ventriculography, which is in our opinion the gold standard we need during what is still an evaluation

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period, and one can build on it the diagram which allows to have a pretargeting of most of the targets (fig. 1), including STN, on the lateral and on the AP view. MRI is also used, but we do think that, at the moment, computerized image guidance is not sufficient and atlases can be misleading when targeting one nucleus: for instance, it can be satisfactory on the sagittal view, and on the axial view but frequently it does not match with the coronal view where the target representation happens often to be in the peduncle. Therefore, we still need electrophysiology during surgery to make sure that we are in the right place [51–54]. We aim at these targets with a set of 5 microelectrodes, and all along the track microstimulation and microrecording are performed. To avoid a too long procedure for the patient, we had divided the surgery for thalamic implantation of electrodes into 5 steps (3 surgical sessions and 2 MRI sessions on different days). During Step I, under general anesthesia, bone screws (StevisÔ, Sofamor) are implanted into the skull, and remain in place in order to allow further painless repositioning and positive contrast ventriculography. Ventriculography is done by direct puncture of the frontal horn of the lateral ventricle (90 mm from nasion, 25 mm from midline) with 65-mm long Cushing cannula. Its placement is confirmed by control X-ray after injection of a 5-ml air bubble. Using these landmarks and the air bubble test, we have never observed any of the reported complications [55, 56] which, in our opinion, are not potential risks of ventriculography but only the expected results of technical errors. Injection of 6.5 ml of Iopamiron 200 (Schering) under telaradiological conditions (3.5 min between X-ray tube and film, with an average magnification coefficient of 1.05) in the supine and prone positions, provides a very precise delineation of the midline of the third ventricle and of the anterior (AC) and posterior (PC) commissures, which are used to calculate statistical estimation of the coordinates of STN initially derived from the stereotactic atlases of Schaltenbrand and Bailey and Talairach [57, 58] (fig. 1). The coordinates of the STN target are: anteroposterior: 5.15 (×0.71)/12 of AC-PC length; height: Ö1.45 (×0.68)/8 of the height of the thalamus, below the AC-PC plane, and laterality: 11.78 (×2.47) mm from midline of the third ventricle. Step II is preoperative MRI in stereotactic conditions and pretargeting stereotactic MRI (1.5 Tesla Philips Gyroscan), using T1-weighted sagittal images (IR-TSE) and T2-weighted coronal sections, provides the coordinates of the small almond-shaped STN, 1–2 mm anterior to the red nucleus, 2–3 mm superior and slightly lateral to the subtantia nigra, externally limited by the internal capsule, and posterior to the mamillary bodies. The theoretical target STN can be defined by the conjunction of data based on (i) geometrical landmarks obtained from ventriculography (which provides a preliminary statistical estimation of the target position), using the modified proportional geometric scheme of Guiot based on the AC-PC line [10, 58, 59] (fig. 2) and (ii) on MRI data (which visualizes clearly GPi and STN and may help in adjusting the coordinates for each patient, particularly for laterality (fig. 2, combined ventriculographic, schematic (Guiot) and MRI-derived theoretical STN target). On this basis, the stereotactic parameters (x,y,z coordinates of the target point and of the entry point) are calculated, manually or using an image-guided neuronavigation software (Stereoplan Radionics). Precise calibration of MRI gradients ensure minimal distortion of the images in the central part of the brain, including the basal ganglia. The patient is placed in the MRIcompatible CRW Radionics stereotactic frame capable of reproducible repositioning. The titanium screws make repositioning fast, easy and painless (local anesthesia is not required). T1-weighted images (IR-TSE) are made in the sagittal and coronal (perpendicular to the AC-PC line) planes, and allow visualization of the thalamus and the pallidum. T2-weighted coronal sections are taken in planes perpendicular to the AC-PC line to show the STN

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Fig. 1. Schematic drawings for determination of the Vim, STN and GPi DBS targets based on the third ventricle anatomical landmarks. The Vim target is drawn as follows according to Guiot et al. [59]: On the lateral view (below): a rectangle is constructed with the AC-PC line, as its base the ends of which rise perpendicular to the AC-PC line, one at the inner border of AC and the other of PC. The top is a line parallel to the AC-PC line, tangential to the top of the thalamus. A third line, parallel to AC-PC, is drawn at the mid-height of the thalamus. The ACPC line is divided into 12 parts. The height of the thalamus is divided into 8 parts. The schematic representation of Vim extends from 2/12 to 3/12 on the AC-PC line and from 4/12 to 5/12 on the mid-height line. The Vim area is represented by the resulting parallelogram. On the AP view (above): that laterality is set at 11.5 mm from the lateral wall of the third ventricle. The STN target is situated below the middle third of AC-PC. On the AP view, the average laterality is 12 mm. The GPi target is situated in the anterior third of AC-PC, from 2/8 of HT above to 2/8 below the AC-PC plane. Laterality extends from 15 to 22 mm from the midline.

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Fig. 2. Ventriculography-based determination of the DBS targets. The significant landmarks, which can be clearly seen, if necessary by taking the X-ray pictures in the recumbent position, are, on the lateral view (above): AC, PC and the top of the thalamus, and on the AP view (below), the midline of the third ventricle and its lateral walls. The target points of the Vim nucleus are therefore drawn according to figure 1. nucleus. These images are later enlarged to the same degree of magnification as the X-ray images obtained by ventriculography, thereby allowing accurate matching of the two sets of morphological data by simple superimposition. Stereotactic MRI slices taken in the plane of the trajectory show the position of the pyramidal tract and could help in positioning the electrode in an oblique trajectory parallel to the internal capsule. It shows also the cortical sulci, namely the F1–F2 sulcus which should be avoided because of the bleeding risk.

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Step III is stereotactic implantation of the electrodes under local anesthesia after a 12hour drug withdrawal. Microelectrode Insertion For STN implantation, we have designed a new system to allow simultaneous introduction of a set of 5 parallel recording-stimulating electrodes (4 electrodes concentrically disposed around a central one, at 2 mm distance) (tungsten microelectrodes FHC, Brunswick ref. 17.300.2, 1-lm tip, 10 MX, protruding from the guide tube by 15 mm to avoid lesion of the target by the guide tubes), aimed directly at the theoretical location of the desired target. During progression of this exploring set, electrophysiological procedures are performed. The track which provides the best functional results is chosen for final implantation of the DBS electrode which is inserted in this track, in place of the test electrode. Obviously, the risk of hitting a blood vessel is theoretically 5 times higher with this method than with the previous one but was not observed in our series. However, a larger area is probed at the same time, increasing the probability of finding the best electrode location. Finally, the chronic electrode is precisely guided and inserted exactly in the track where the best results are observed. The theoretical STN target is approached in double obliquity, and parallel to the anterior border of Vim. Due to individual variations, the final target could be significantly different from the theoretical target (based on atlases, ventriculography and MRI) when the intraoperatively acquired electrophysiological features are taken into account (which provide information on the specific spontaneous and evoked neuronal firing patterns of these structures, and on effects of stimulation). Microrecording Spontaneous as well as evoked multi- and single-unit neuronal activities are recorded at various sites along the trajectory down to the AC-PC line, using conventional preamplifiers (WPI DAM-5A), AC-DC amplifiers (Neurolog NL106), filters (Neurolog NL125), and spike triggers (Neurolog NL201) and processed through a MacLab 4 WPI system a Macintosh II CX computer with an 80-MB hard disk. More recently we have used the AlphaOmega integrated system which allows simultaneous recording of five electrodes, data processing and storage and stimulation as well. The recorded pattern depends on the nucleus to be investigated and on the type of electrode used. With a semi-macroelectrode, only multi-unit activity can be recorded: the amplitude of the spikes, described as ‘neuronal noise’ [60, 61], varies along the track and can provide information about the boundaries of the different nuclei. White matter bundles are usually silent and recognizable by their low neural noise. This neural noise is high in Vim and diminishes markedly when the electrode enters the internal capsule. Similar patterns are being observed in STN and in GPi [62]. With a microelectrode (FHC Brunswick, ref. 17.300.2), single units are recorded. STN cells produce large, asymmetrical spikes with a high-frequency (35.2×8.8 Hz) firing rate, and biphasic spikes at a lower rate (11.1×2.3 Hz) responsive to passive movements and to tremor. Multi-and single-unit recordings showed an increase in neuronal firing rate in STN as compared to the surrounding area. This effect was observed regularly at the site where STN is located by MRI and where the best effects on rigidity and akinesia were obtained. Below STN level, larger spikes unresponsive to all kinds of stimuli can be recorded in the SNr.

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Microstimulation Stimulation may identify surrounding structures but essentially provides the functional criteria of effectiveness by showing directly, during surgery, to what extent tremor or other symptoms are suppressed by stimulation and where this can be achieved. A constant current stimulator (WPI Accupulser A310) with an isolation unit (WPI A365R) was used to stimulate structures during the electrode placement procedure, at various sites along the trajectory. Test stimulation was done with a 60-ms pulse width, frequency at 130 Hz, the current intensity varied from 0.1 to 10 mA. The electrode is always used as a cathode. The effect of stimulation on tremor was quantified using an accelerometer attached to the patient’s finger. The expected effect of 130-Hz stimulation (in STN and in GPi suppression of rigidity and decrease in bradykinesia with the lowest (0.2–2 mA) current strength) is the major criterion in choosing the final placement. For each track, comparison between motor and sensory threshold helps to determine the optimal electrode placement. During STN HFS, continuous monitoring of passive rigidity of the patient’s wrist revealed changes related to efficient stimulation. The best effects on rigidity and akinesia were obtained at the site where STN is located by MRI and where recordings showed an increase in neuronal firing rate as compared to the surrounding area. The exact position of each stimulating and/or recording site was checked by X-rays and mapped onto the final operating diagram. This provides a set of data with which the exact location of the chosen nucleus can be mapped, providing a corrected target into which the chronic DBS electrode will be implanted. Even though the MRI visualization of the visible STN evidently helps to position more precisely the point the track will be aimed at, shifts of several millimeters between the theoretical (MRI and/or ventriculographybased) and the corrected (electrophysiology-based) targets may be observed, confirming the necessity of the electrophysiological studies for target localization. However, these shifts are rather small, the first localization of the target by the ventriculographic approach being nearly always correct. These data support the interest of ventriculography to define the target, even if a careful electrophysiological study is performed. Spontaneous as well as stimulation-induced changes can be precisely evaluated and correlated with stimulation parameters. STN stimulation induced a recovery of limb akinesia when the patient was in a frozen situation. Motor performance rates were significantly increased, although this type of assessment’s reproducibility was limited, owing to patient fatigue. A very significant decrease in wrist rigidity was actually the most reliable intraoperative test. Continuous monitoring by the neurologist of passive rigidity during manipulation of the patient’s wrist revealed easily detected changes related to efficient stimulation.

Chronic Electrode Insertion At the end of the exploration, the multidisciplinary team tries to put together all the information required during surgery including microrecordings and recognition of typical patterns, beneficial effects of microstimulation on the clinical symptoms assessed by the neurologists, as well as side effects, both being a good pre-evaluation of what will be the therapeutic result in the long term. Finally, based on this brainstorming session, the best electrode (chosen as one of the five electrodes yielding the best positive effects and the least side effects) is withdrawn and replaced by the chronic electrode which is secured to the skull. Electrode 1 which is the one aimed at the target, is finally chosen only in 37% of the cases,

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the other cases being almost equally distributed along the four other tracks which are just 2 mm apart. The positioning of the contralateral electrode is symmetrical only in 62% of the cases emphasizing also how it is important to assess the functional location of the target during surgery even if the anatomical positioning looks correct. A total of 215 electrodes have been implanted up to this writing in 110 patients, unilaterally only in 5 patients. They are tetrapolar (Medtronic 3387 or 3389) with four contacts, 1.5 mm in diameter and 1.5 mm long, separated each by 1.5 or 0.5 mm, respectively. When control X-rays confirm the correct final placement, the electrode is fixed to the skull by a suture anchored in the skull through a short drilled hole intersecting the track hole in a Y-shaped pattern. The knot in the suture is then embedded using dental cement (methyl methacrylate CMW1 Cat. No. 3012040). The DBS electrode is connected to its percutaneous extension which exits the skin in the parietal region. The extra length of wire is folded under the pericranium which is carefully closed as is the skin. All incisions were closed by nonresorbant sutures. When the symptoms (tremor or bradykinesia) are bilateral, the contralateral side is implanted during the same session, following the same procedure (fig. 3). Step IV: Postoperative and Control MRI. A control stereotactic MRI is performed using titanium screws a few days after electrode implant. The Medtronic tetrapolar electrodes 3387 and 3389 are MRI-compatible and provide images in which the four contacts can be located precisely by their small magnetic artifact surrounding an area devoid of signal. Control MRIs were not performed after generator implant, although it has been reported that this could be harmless [63]. Step V: Implantation of Programmable Stimulators. Internalization of stimulators is done within a week of implantation with the external extensions after Step II tests are completed under general anesthesia. The programmable stimulus generator (Medtronic Itrel II in the 88 first patients and dual-channel Kinetra in the 22 last patients) is placed in a subcutaneous pocket in the subclavicular area and connected to the distal tip of the electrode via an extension passed subcutaneously up the neck to the cephalic area. Local instillation of antibiotics (rifamycin) is done at the level of every surgical wound. After implantation of the stimulators, patients were kept at the hospital for a week for evaluation of the effects of stimulation and other symptoms. The parameters of the implanted Itrel were set at 60-ms pulse width, 130 Hz and 0.5–8 V, depending on the target and on the clinical effects. They were progressively adjusted according to the needs of each patient, during the follow-up period. If needed the frequency range of the Itrel II could be extended to 185 Hz.

Results We will analyze the mortality and morbidity of over 110 operated patients since 1993 with a follow-up of 29.8×18.9 months (min. 1, max. 83.6), and the long-term follow-up benefits in a series of 57 first operated patients. Mortality There was no operative mortality. One patient died suddenly on the 11th postoperative day from pulmonary embolism due to previously existing cardio-

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Fig. 3. Postoperative control X-ray showing the position of the bilateral STN electrodes.

vascular insufficiency, although he had recovered from stereotaxy and was able to walk into the neurosurgery department. Seven others died from various nonneurological diseases at 3, 6, 7, 10, 11, 23 and 116 months. Due to long distance referral of most of these patients, postmortem pathological examination was not available.

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Morbidity and Side Effects Complications and side effects are so far not so frequent. We had unfortunately 2 hematomas out of 100 patients, 1 in the supraventricular area, from a pericallosal branch injured by the exploratory electrode and died 3 years later, 1 in the thalamus, fortunately not at the moment in the subthalamic nucleus itself. We had 3 nonsymptomatic brain concussions along the tracks of the electrode, 5 postoperative or late infections, 3 patients showed on the postoperative systematic MRI asymptomatic presence of blood in the ventricular system, due to the transventricular approach. One patient had secondary scalp ulceration in front of the electrode-to-extension connection. Permanent hemiballism was never observed during clinical follow-up. However, acute and transient hemiballism, which resolved within 24 h, was observed in 1 case at the moment of insertion of the permanent 3389 electrode. In several cases, advancement of recording electrodes and in 5 cases final insertion of chronic electrodes induced various degrees of peripheral limb dyskinesias and involuntary movements, which we considered as symptoms of STN penetration. In 3 cases, a lesioning DC current leak from a defective test generator was responsible for a hemiballism, transient in all patients, but 1 of them, at 6 months after surgery, still experiences a major resolution of the PD symptoms with no deficit, making stimulation useless so far. Seven patients were confused and disoriented for a few days to 3 months, and this was related to the age of the patient. The temporary mental confusion depends on the clinical state of the patient and the younger they are the better it is. This confusion may persist 1 day to 3 weeks and has never left any permanent sequel. We have observed the appearance of eyelid apraxia in about 20% of the cases; 11 patients exhibited transient eyelid opening apraxia, which in 4 cases needed botulinum toxin injection in the eyelids. Eyelid opening apraxia is known to happen in parkinsonian patients and the pathophysiology of which is unknown. It could be related to the proximity of the SNr which projects onto the colliculus superior which is related to the vertical eye movements, including extrinsic movements of the eyelids, hypophonia which is discussed later is quite often observed in about 20% of the patients, the worsening of motor performance is extremely rare and it is possible to abnormally induce dyskinesias exactly similar to the levodopa-induced involuntary movements which actually are part of the physiology of the STN. Most of the patients had weight gain related to recovery of normal behavior, loss of dyskinesias and not related to hypothalamic-like hormonal disturbances, as it is observed also after pallidotomy [64]. Some side effects are not related to the target and happen as a consequence of the procedure, and of the general condition of the patients. Observation of complications in patients treated in Vim or GPi in our center may help in defining the specific morbidity of STN implantation versus

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the nonspecific complications of DBS. Then, in over 197 patients operated on 316 sides, we observed 1 large supraventricular hematoma (0.5% of patients, 0.3% of operated sides), 3 microhematomas with transient or slight permanent symptoms (1.7% of patients, 0.95% of operated sides), 3 asymptomatic microhematomas (1.7% of patients, 0.95% of operated sides), 2 subdural bleedings (1.01% of patients, 0.6% of operated sides) (1 was surgically explored), 3 MRI hyper-signals along the electrodes’ tracks (1.7% of patients, 0.95% of operated sides), 3 asymptomatic presence of blood in the ventricles related to the transventricular approach of the target (1.7% of patients, 0.95% of operated sides), 7 local late infections, erosion or granuloma of the external leads (3.5% of patients, 2.2% of operated sides), 1 local hematoma in the stimulator subcutaneous pocket (0.5% of patients, 0.3% of operated sides), 4 ruptures of the external extension needing replacement (2% of patients, 1.3% of operated sides), 3 repositionings of the stimulators because of patient’s discomfort (1.7% of patients, 0.95% of operated sides), 3 thrombophlebitis with 2 pulmonary embolisms with good resolution (1.7% of patients, 0.95% of operated sides), 17 postoperative confusion often related to the previous general status of the patients (8.6% of patients, 5.4% of operated sides). Apraxia of the eyelid opening (5.6% of patients, 3.5% of operated sides) was also observed in 11 out of 51 STN patients (who needed botulin toxin injection in 6 patients and lasted more than 6 months in 3 of them) (21.6% of patients, 11.6% of operated sides) and in 1 GPi patient. Four patients who had previous demented states were not improved and had their mental status impaired permanently. These complications can be also analyzed for each target. Clinical Benefits and Indications Of the 57 operated patients, 51 have been followed for 1 year, 30 for 2 years, 16 for 3 years, 9 for 4 years and 4 for 5 years. UPDRS III Total and Subscores Off-Drug/On-Stimulation Condition. In off-drug condition, stimulation greatly improved the UPDRS III total score in all groups of patients and at all follow-up periods in comparison with the preoperative evaluation. For groups 1–3 the improvement was superior to 60% after 1 to 3 years’ followup (p00.0001). In groups 4 and 5 the improvement was superior to 50% and was maintained in the long term (p00.0005 in group 4 and p00.005 after 3 and 4 years in group 5). Whereas speech was not significantly modified, the scores for akinesia, rigidity and tremor were greatly improved in the offmedication/on-stimulation condition in comparison with the preoperative offdrug condition and this improvement was sustained in the long term. The degree for tremor improvement was the greatest with a percentage ranging

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between 63 and 100%. The rigidity score decreased from 50 to 76%. Akinesia was improved between 43 and 69%. These percentages of improvement tended to mildly decrease at each follow-up. The postural stability score significantly improved for all groups during the first years of follow-up. However this improvement was no longer significant after 3 and 4 years in group 4 and after 3 and 5 years in group 5. Gait significantly improved for groups 1–4 (between 52 and 70%). For the 4 patients followed during 5 years, an initial improvement was observed during the first 4 years of follow-up (between 56 and 75%). However, after 5 years, the improvement decreased to 29%. In fact, gait remained clearly improved in 2 patients but became impossible in the two others. On-Drug/On-Stimulation Condition. In on-drug condition, stimulation did not statistically change the UPDRS III total score in comparison with the preoperative evaluation. However, the patients followed 5 years presented a clear deterioration essentially due in 2 of the 4 patients. Speech was not significantly modified but tended to worsen at 4 and 5 years’ follow-up. The postural stability score improved for groups 1–3 (p00.005 only in group 2). In groups 4 and 5 it was initially improved during the first 2 years of follow-up and then deteriorated after 3, 4 and 5 years (p00.005 after 5 years in group 5). Off-Drug/Off-Stimulation Condition. In off-drug/off-stimulation, the UPDRS III total score decreased from 7 to 22% in all groups and at all periods of follow-up in comparison with the preoperative off-drug condition. However, these differences were not significant. Speech tended to worsen in the long term. Akinesia did not significantly change. The tremor score tended to decrease but this was not significant. The postural stability and gait scores were significantly improved in groups 1 and 2. In group 5 there was a progressive deterioration of postural stability after an initial improvement. UPDRS II Total Score and Schwab and England Score for Global Activities of Daily Living In off condition, the UPDRS II decreased in all groups and at all followup periods. After 1 year the score decreased by 58–64% in all groups (p00.0001 for groups 1–4). This improvement was maintained at the longest follow-up (decreased by 51–61%). The score of Schwab and England improved by more than 100% for all groups and at all follow-up periods. In one condition, the UPDRS II and Schwab and England scores did not change. However, a slight tendency of deterioration was observed in the groups followed 3–5 years. Axial Score In off-drug condition, the axial score greatly improved under stimulation. For groups 1–4 this improvement ranged from 55 to 70% and was statistically

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significant. For group 5 the improvement was 77% after 1 year, 55% after 2–4 years and then decreased to 37% at 5 years. In on-drug condition, we can observe a progressive deterioration of the axial score in the patients followed 4 and 5 years. UPDRS IV and Subscores The UPDRS IV total score was improved by more than 65% for all groups and at all follow-up periods. The dyskinesia duration and disability scores as well as the morning dystonia score decreased by 50–100% for all groups and at all follow-up periods. Off-periods duration was significantly decreased by more than 65% for groups 1–3 and by more than 50% for groups 4 and 5. Treatment The daily doses of levodopa decreased in all groups. For groups 1 and 2, the decrease was superior to 60%. For groups 3 and 4 the percentage of decrease was superior to 40 and was maintained during the long-term followup. For group 5 the initial decrease was 30% but was superior to 40% after 4 and 5 years. The number of patients treated by dopaminergic agonist drugs also decreased progressively for all groups. Apomorphine was discontinued after surgery in all cases. On the whole, about 10% the patients remained without levodopa and about 6% without any antiparkinsonian treatment. At 5 years’ follow-up, 1 patient remained without any antiparkinsonian drug. Electrical Parameters The mean voltage stimulation was 2.8×0.6 V at 1 and 2 years’ followup and increased to 3.0×0.6 V afterwards. The pulse width was generally 60 ls and rarely 90ls. The rate was 130 Hz for most patients and could reach 185 Hz. One contact was used as monopolar stimulation in the majority of cases. A few patients were stimulated using two adjacent contacts with the same polarity. Bipolar stimulation was applied in only 5% of patients.

Discussion Target Target Choice: Why Is STN the Target in Akinesia? Rigidity and akinesia are the most dopamine-dependent symptoms and patients with severe akinetic-hypertonic forms of PD are therefore most

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dependent on levodopa treatment. Long-term dopa therapy induces motor fluctuations and different patterns of dyskinesias, resulting in highly disabling ‘on-off ’ fluctuations which constitute an important therapeutic challenge requiring alternative therapeutic strategies, such as surgical procedures. The Vim target has not proven to be able to reduce significantly these symptoms, either by lesions or by stimulation. The observed effects of Vim stimulation on levodopa-induced dyskinesias (LIDs) [65–67] may be related to involvement of adjacent structures such as CM-Pf or paralemniscal radiations [68]. The reintroduction of GPi as a surgical target has been very successful but long-term follow-up of either pallidotomies [1, 50. 69] or pallidal stimulation [70, 71] have shown that the effects are spectacular on LIDs but rather disappointing on the triad symptoms, at least not allowing the decrease of drugs or even requiring their increase [72–74]. Destructive stereotactic surgery, such as pallidotomy [1, 50, 75], is currently the most effective procedure for suppressing rigidity and akinesia in PD patients. Neural grafts could represent an elegant solution, but present results are only moderately satisfactory. Destruction of STN in human patients cannot be considered, due to the high risks of inducing hemiballismus. We assumed that HFS could inhibit STN in the same manner as it inhibits the Vim nucleus for tremor [3, 4, 76, 77]. STN HFS has been proposed on the basis of previous extensive experimental investigation on the basal ganglia and the resulting concept of their functional connectivity [25, 26]. In MPTP monkeys, dopaminergic deafferentation induces hyperactivity in STN [27–29] and destruction [29, 30] or HFS [31] of STN suppresses rigidity and akinesia. Past clinical history has obviously demonstrated that STN lesion induced long-term hypotonia associated with ballism, while STN is hyperactive in disorders with rigidity such as in PD. This encouraged us to perform STN HFS in human patients, in whom we also observed the alleviation of akinesia and rigidity in the operating room [32–38, 44] (as well as some temporary dystonic movements at the time of electrode insertion). In our opinion, destruction of STN in human patients could not be considered, due to the high risks of inducing hemiballismus, although there are recent reports of STN ablative procedures with mild or no complications [78] and although a spontaneous hematoma in STN is known to sometimes suppress parkinsonian signs [79]. Target Approach Immediate postoperative morbidity has been observed to be higher in STN patients than in Vim patients. This might be due to the fact that patient’s populations are different, although the STN implanted are not significantly older (56.6×7.6 years, n>60) but are in a more severe stage of their disease than the Vim bilaterally implanted patients who are of a similar age (59.3×11.4

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years, n>118) but are most often only disabled by their tremor and in a better general clinical status. This could also be due to the target itself and to the localization of the stereotactic approach. The target itself does not seem to be responsible for the observed side effects as these were not always present. The track however is closer to the midline, and might involve at the upper level the white matter of the supplementary motor area or the thalamocortical frontal projections. In the last 6 patients, we have slightly modified the track, using a 25-mm laterality entry point, which creates a double obliquity. The immediate outcome seems to have been better, without any periods of confusion but the series is relatively short as compared to the rest of the patients and cannot be considered at the moment as significantly different.

Technical Aspects and Costs Ventriculography This is still the gold standard of the ventricular landmarks used for the definition of the target, and reports of the final position of the electrodes are clearly visible and not subject to distortion as long as teleradiological conditions are observed. MRI So far, magnetic distorsion cannot be totally ruled out and corrected. Moreover, it depends on the sequence and is irreversibly produced by artifact sources such as ferromagnetic implants patients may have in their body, principally tooth implants. Comparison in the same patients of ventricular and MRI dimensions of the third ventricle features shows that a significant degree of mismatch is still encountered. In addition, the recognition of STN from SNr in axial cuts, which are the most often used in image-guided software, is far from easy and only the T2 coronal sections permit this accurate distinction. Electrophysiology Electrophysiology, as already stressed by Guiot [20, 51–53, 80–85], is the ultimate method for optimizing the position of the electrode as it has been for thalamotomy. Stimulation may identify VPL as well as the pyramidal tract but essentially provides the functional criteria of effectiveness by showing directly, during surgery, to what extent the tremor is suppressed by stimulation and where this can be achieved. Neuronal activity recording may give additional information which is interesting scientifically in that it may help to understand the involved mechanism. As has already been shown, neurons firing in bursts synchronous with the tremor are recorded in Vim and

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thalamotomy at this site provides a very good result [52, 61, 84] as well as, in our experience, stimulation at high frequency. Below this area, neuronal silence is characteristic of the internal capsule and provides the inferior limit for electrode positioning. Similar comments apply to STN and GPi electrode placement. Costs This method is obviously more expensive than thalamotomy. In addition to the stereotaxic procedure, which is almost the same in both methods, stimulation requires electrodes, extension leads, and stimulators. However, since May 1989, we have implanted 208 Itrel II, all targets included. Due to the high frequency at which they are used (130–185 Hz), battery life should be relatively short, replacement of the Itrel I stimulators in Vim has been already performed in 18 out of 20 patients after 38.7×23.5 months (range 17–109). The lifetime of the 90 Itrel II which has not yet been changed in this STN series averages 87 months. However, the significant decrease in drug dosage which is currently observed in our STN patients induces a reduction in the cost of the procedure which must be evaluated further and could be competitive with the medical treatment.

Comparison with Other Surgical Methods Pallidotomy and GPi HFS The present data are already significant enough to demonstrate that STN HFS relieves parkinsonian tremor, rigidity, akinesia and LIDs, has no mandatory complications, such as hemiballismus, and even no specific side effects. Ventroposterolateral pallidotomy [64, 86–90] however, has been recently reintroduced and is under investigation in several centers. The results reported are in the same range as those of STN HFS and it has been claimed that pallidotomy relieves all the motor symptoms of PD, especially LIDs, but bilateral procedures have been reported to produce cognitive dysfunction. Moreover, the growing experience acquired recently by several teams with pallidal HFS [50, 69–71, 73, 91] tends to suggest that the indications of pallidal inhibitions could be done by HFS rather than by destruction, at least because bilateral procedures will again have less morbidity using HFS methods. However, our experience with GPi HFS have allowed us to compare the merits of the two methods in two matched series of young-onset parkinsonian patients and our conclusions favor definitely STN HFS which has become our first intention method for akinetic-rigid as well as tremoric PD [70, 71, 73]. We

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have shown [70, 71] that STN improves all the UPDRS items by more than 60% while they are improved by less than 60% in GPi-stimulated patients, in the medication-off situation. When they are in the medication-on situation, another specificity of GPi stimulation appears, as a loss of sensitivity to levodopa treatment which has to be increased [72, 73]. Neural Grafts In our opinion, indications of STN HFS are the same as those for neural grafts. Considering the ethical and technical problems raised by neural grafts and still not yet resolved and the only moderate improvement reported so far, STN HFS can be offered as a reasonable alternative which leaves the future open, as long as neural grafting has not yielded significantly better results [24].

STN Stimulation and Symptoms Dyskinesias The improvement of the LIDs following STN stimulation is due to the strong improvement of akinesia and rigidity [37, 38], allowing to decrease by about 55% the amount of drugs in those patients, which as a consequence eliminate the dyskinesias. About 10% of our patients are drug-free now. Actually, by overstimulating the patient higher than needed to control the parkinsonian symptoms, one can induce dyskinesias, which could be described as ballismus or choreoballic dyskinesias. It is interesting to note that because of this decrease of levodopa doses and of the continuous stimulation, there is a tendency with time for those patients not to react so strongly to levodopa challenges which previously had induced LIDs. Similarly, the tendency to develop abnormal movements under STN stimulation vanishes with time, which raises the question of postsynaptic desensitization as observed also during apomorhine long-term administration. The improvement is visible also on midline symptoms: gait, arising, stability are improved, speech also is improved although not as well as the others. One of the most spectacular symptoms like off-dystonia is strongly improved in 16 of our 20 patients who had it in this survey. When the stimulator is turned on, dystonia disappears within seconds, and, when the stimulator is turned off again, reappears as quickly, as well as of course the akinesia and the rigidity. Hypophonia It must not be considered as a complication of surgery as it may respond to increased doses of levodopa or even to stimulation. However, in these

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patients, the reduction in voice volume may be disabling as the patient is by period barely understandable. The current hypothesis to try to explain this phenomenon could be due to a somatotopic organization of the STN: the current functional method of targeting is actually based on the rigidity assessed by the passive mobilization of the wrist, which by the way is a good indicator for the limbs but probably not for the orofacial activity. It might be then that if the midline functions, such as the voice, are located in a different part of the STN, we might consistently miss it according to the method employed. Therefore, the patient during chronic stimulation, being strongly improved as far as rigidity and akinesia of the limbs are concerned, is deprived of levodopa which is no longer useful and also participates in the induction of dyskinesias. As a consequence it might be that the patient, as far as the hypophonia is concerned, is not medically treated because of the significant reduction of drug doses and is not surgically treated because of the nonplacement of the electrode into the STN area corresponding to voice control. This must be confirmed but it pushes us to develop intraoperative methods of voice exploration which would allow us to target better this symptom. Cognitive Functions Modified by STN HFS? Over stimulation may also be responsible for spreading of the current to immediately adjacent structures and for induction of side effects related to these abnormally involved structures: this could be strong depressive stages [74] or on the contrary irrepressible laughter, as we have observed in 1 patient [92]. Neuropsychological testing has not shown any change after long-term stimulation in STN. Participation to the Understanding of the Role of Basal Ganglia in Motor Control The observations made during surgery may provide original insight on the functional model of motor control by the basal ganglia. For instance, the SNr which lays into the same functional box as GPi actually does not behave as GPi: when electrodes enter the SNr area at the bottom of the STN, they do not record any evoked activity and proprioceptive activity in SNr, which is the contrary of what is observed in STN and GPi. The activity of the SNr cells, the neuronal firing patterns of which are clearly distinguishable from the STN neurons, is strictly not responding to the classical maneuvers we use to check the patients and the stimulation also has none of the beneficial effects which are usually observed in STN and even in GPi (fig. 2). The role of the SNr seems therefore to be different from what is suggested by the currently accepted model.

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Long-Term Stability As reported before [32, 34, 43, 93], we confirmed in a series of more than 50 patients followed at least 1 year that bilateral STN stimulation dramatically improved the severity and reduced the duration of off-period symptoms in patients with PD. Moreover, we observed that this improvement persisted for at least 5 years of follow-up. Akinesia, rigidity and tremor decreased and remained improved for the long term. Tremor almost disappeared, justifying that STN stimulation may be a more appropriate choice than Vim stimulation or thalamotomy for parkinsonian tremor [36]. Gait, postural stability and a combined axial score were also greatly improved. Speech was less improved than other motor symptoms. Given the complexity of the articulatory organs, other evaluation methods are probably necessary to evaluate speech with more precision [94]. In the small group of patients followed for 5 years, we can observe a nonsignificant tendency to worsening. This was principally due to a deterioration of axial symptoms in 2 out of the 4 patients. We can postulate that nondopaminergic symptoms continue to worsen with the evolution of the disease in the same way as in patients under levodopa treatment [40]. The activities of daily living were also clearly improved in off condition and the patients became independent for most activities. Moreover, this improvement remained stable in the long-term follow-up. Motor fluctuations were attenuated in the long term and patients with sudden on-off fluctuations before surgery experienced mild wearing-off or no fluctuations thereafter. Off-period dystonia was almost totally suppressed. Drugs were decreased after surgery to at least half of the initial dosage and this reduction was maintained up to 5 years’ follow-up. In the long term, LIDs were greatly decreased. The reduction in dopaminergic drug dosage is likely to be an important factor of this improvement. However, a direct action of chronic STN stimulation and the replacement of pulsatile dopaminergic stimulation by continuous functional inhibition of the STN may also play a role [38]. In off-drug and off-stimulation condition, representing the basal parkinsonian motor state, we observed a slight but nonsignificant decrease in UPDRS motor scores. This decrease remained after 5 years’ follow-up. These results have to be compared to the spontaneous evolution of the disease. It has been estimated that the off-period UPDRS motor score worsens by 8–9% per year [95, 96]. This could be related either to a microsubthalamotomy effect, to a too short stimulation arrest before assessment with a long-lasting effect of the stimulation, to relearning of some motor functions thanks to the absence of off-motor period after surgery or to a neuroprotective mechanism [97, 98]. Speech was the only item with a trend to progressive deterioration [40, 96].

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Our long-term follow-up of patients treated by bilateral STN stimulation confirms the relative low morbidity of the technique. Cognitive functions were on average unchanged after surgery [99]. The most severe complication was an intracerebral hematoma, an inherent risk in stereotactic neurosurgery estimated to occur in 2–8% of patients [100]. Eyelid-opening apraxia, a symptom observed in idiopathic PD and other degenerative disease involving basal ganglia, worsened or appeared in some patients after STN stimulation. The exact mechanism of this symptom is unknown. The transient confusion observed in some patients may have been related to nonspecific factors such as the long duration of brain surgery and the acute intraoperative withdrawal of dopaminergic drugs.

Conclusion In conclusion, bilateral STN stimulation seems one of the most effective surgical treatments of PD patients suffering from levodopa-induced motor complications. The relative low percentage of permanent adverse effects makes the benefit/risk ratio of this procedure highly positive. Although randomized comparative studies between STN stimulation and other surgical procedures have not been carried out so far, long-term results of pallidotomy or pallidal stimulation do not look so favorable [1, 50, 87–91, 101–111]. Reports of STN lesioning are rare [78, 112, 113]. The interest of this type of treatment is reversibility (particularly of side effects in case of misplacement of the electrode which can even be changed or replaced), adaptability of the parameters to fit the patient’s clinical status and even follow the evolution of its disease), the possibility of performing bilateral implantation in one session without significant permanent neuropsychological side effect (which is most often needed and was not possible to achieve by lesioning methods, such as thalamotomy or pallidotomy), levodopa doses can be reduced which as a consequence decreases dyskinesias and finally the potential neuroprotection effect. STN HFS is in our experience a remarkable therapeutic agent against all symptoms of PD and appears currently to be the method of choice which can be proposed systematically as a first alternative when evolution of the disease and failure of the medical treatment to provide the parkinsonian patient with an acceptable quality of life call for a surgical approach. Moreover, this procedure would not exclude the patient from a consideration for another type of treatment, such as fetal transplant in the future. Finally, STN HFS provides a privileged experimental opportunity, due to its reversibility and adaptability, to study and understand the mechanisms of PD as well as of normal motor control in humans.

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Acknowledgments This work was supported by grants from INSERM, MRT, CNAMTS, the Rhoˆne-Alpes Region, France Parkinson Association, Fondation pour la Recherche Me´dicale, Fondation de l’Avenir, ARSEP, CNEP and the Joseph Fourier University of Grenoble.

References 1 2

3

4

5

6 7 8 9

10 11

12 13 14 15 16 17 18 19

Laitinen L, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Svennilson E, Torvik A, Lowe R, Leksell L: Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Neurol Scand 1960;35: 358–377. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J: Combined (thalamotomy and stimulation) stereotactic surgery of the Vim thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987;50:344–346. Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, Perret J, de Rougemont J: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406. Benabid AL, Pollak P, Gao DM, Hoffmann D, Limousin P, Gay E, Payen I, Benazzouz A: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–214. Deroˆme PJ, Jedynak CP, Visot A, Delalande O: Traitement des mouvements anormaux par le´sions thalamiques. Rev Neurol (Paris) 1986;142:391–397. Fox MW, Ahlskog JE, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991;75:723–730. Goldman MS, Ahlskog JE, Kelly PJ: The symptomatic and functional outcome of stereotactic thalamotomy for medically intractable essential tremor. J Neurosurg 1992;76:924–928. Hirai T, Miyazaki M, Nakajima H, Shibazaki T, Ohye C: The correlation between tremor characteristics and the predicted volume of effective lesions in stereotaxic nucleus ventralis intermedius thalamotomy. Brain 1983;106:1001–1018. Kelly P, Derome P, Guiot G: Thalamic spatial variability and the surgical results of lesions placed with neurophysiological control. Surg Neurol 1978;9:307–315. Matsumoto K, Asano T, Baba T, Miyamoto T, Ohmoto T: Long-term follow-up review of cases of Parkinson’s disease after unilateral or bilateral thalamotomy. Appl Neurophysiol 1976–77;39: 257–260. Matsumoto K, Shichijo F, Fukami T: Long-term follow-up review of cases of Parkinson’s disease after unilateral or bilateral thalamotomy. J Neurosurg 1984;60:1033–1044. Nagaseki Y, Shibazaki T, Hirai T, Kawashima Y, Hirato M, Wada H, Miyazaki M, Ohye C: Longterm follow-up of selective Vim-thalamotomy. J Neurosurg 1986;65:296–302. Narabayashi H: Stereotaxic Vim thalamotomy for treatment of tremor. Eur Neurol 1989;29:29–32. Ohye C, Maeda T, Narabayashi H: Physiologically defined Vim nucleus. Its special reference to control of tremor. Appl Neurophysiol 1997;39:285–295. Ohye C, Hirai T, Miyazaki M, Shibazaki T, Nakajima H: VIM thalamotomy for the treatment of various kinds of tremor. Appl Neurophysiol 1982;45:275–280. Ohye C: Roˆle des noyaux thalamiques dans l’hypertonie et le tremblement de la maladie de Parkinson. Rev Neurol (Paris) 1986;142:362–367. Stellar S, Cooper IS: Mortality and morbidity in cryothalamectomy for Parkinson’s disease. A statistical study of 2,868 consecutive operations. J Neurosurg 1968;28:459–467. Talairach J, Hecaen H, David M, Monnier M, de Ajuriaguerra J: Recherches sur la coagulation the´rapeutique des structures sous-corticales chez l’homme. Rev Neurol (Paris) 1949:81:4–24.

Subthalamic Nucleus Deep Brain Stimulation

221

20

21 22 23

24

25 26 27 28

29 30

31

32

33 33

35

36

37 38

39

40

Taren J, Guiot G, Derome P, Trigo JC: Hazards of stereotaxic thalamotomy. Added safety factors in corroborating X-ray target localization with neurophysiological methods. J Neurosurg 1968;29: 173–182. Tasker RR, Organ LW, Hawrylyshyn PA: Investigation of the surgical target for alleviation of involuntary movement disorders. Appl Neurophysiol 1982;45:261–274. Tasker RR, Siquiera J, Hawrylyshyn P, Organ LW: What happened to Vim thalamotomy for Parkinson’s disease? Appl Neurophysiol 1983;46:68–83. Benabid AL, Benazzouz A, Gao DM, Hoffmann D, Limousin P, Koudsie´ A, Krack P, Pollak P: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus and of other nuclei as a treatment for Parkinson’s disease. Tech Neurosurg 1999;5:5–30. Kordower JH, Freeman TB, Chen EY, Mufson EJ, Sanberg PR, Hauser RA, Snow B, Olanow CW: Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease. Mov Disord 1998;13:383–393. Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders. Trends Neurosci 1989;12:365–375. Alexander GE, Crutcher MD: Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends Neurosci 1990;13:266–271. DeLong M: Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990; 13:281–285. Feger J, Robledo P: The effects of activation or inhibition of the subthalamic nucleus on the metabolic and electrophysiological activities within the pallidal complex and substantia nigra in the rat. Eur J Neurosci 1991;3:947–952. Bergman H, Wichmann T, DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1346–1348. Aziz TZ, Peggs D, Sambrook MA, Crossman AR: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 1991;6:288–292. Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B: Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 1993;5:382–389. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995;345:91–95. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Broussolle E, Perret JE, Benabid AL: Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–674. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–1111. Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret J: Effets de la stimulation du noyau sous-thalamique dans la maladie de Parkinson. Rev Neurol (Paris) 1993;149:175–176. Krack P, Benazzouz A, Pollak P, Limousin P, Piallat B, Hoffmann D, Xie J, Benabid AL: Treatment of tremor in Parkinson’s disease by subthalamic nucleus stimulation. Mov Disord 1998;13: 907–914. Krack P, Limousin P, Benabid AL, Pollak P: Chronic stimulation of subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson’s disease. Lancet 1997;350:1676. Krack P, Pollak P, Limousin P, Benazzouz A, Deuschl G, Benabid AL: From off-period dystonia to peak-dose chorea: The clinical spectrum of varying subthalamic nucleus activity. Brain 1999; 122:1133–1146. Vercueil L, Benazzouz A, Deransart C, Bressand K, Marescaux C, Depaulis A, Benabid AL: Highfrequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: Comparison with neurotoxic lesions. Epilepsy Res 1998;31:39–46. Bonnet AM, Loria Y, Saint-Hilaire MH, Lhermitte F, Agid Y: Does long-term aggravation of Parkinson’s disease result from nondopaminergic lesions? Neurology 1987;37:1539–1542.

Benabid/Koudsie/Benazzouz/Piallat/Van Blerkom/Fraix/Pollak

222

41 42 43 44 45 46

47 48 49 50 51

52 53

54 55 56 57 58 59 60 61 62

63 64 65

Blin J, Dubois B, Bonnet AM, Vidailhet M, Brandabur M, Agid Y: Does ageing aggravate parkinsonian disability? J Neurol Neurosurg Psychiatry 1991;54:780–782. Kumar R, Lozano AM, Sime E, Halket E, Lang AE: Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation. Neurology 1999;53:561–566. Moro E, Scerrati M, Romito LM, Roselli R, Tonali P, Albanese A: Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson’s disease. Neurology 1999;53:85–90. Krack P, Pollak P, Limousin P, Benazzouz A, Benabid AL: Stimulation of subthalamic nucleus alleviates tremor in Parkinson’s disease (letter). Lancet 1997;350:1675. Langston JW, Widner H, Goetz CG, et al: Core Assessment Program for Intracerebral Transplantations (CAPIT). Mov Disord 1992;7:2–13. Fahn S, Elton R: Unified Parkinson’s Disease Rating Scale; in Fahn S, Marsden CD, Calne D, Goldstein M (eds): Recent Developments in Parkinson’s Disease. Florham Park NJ, MacMillan Healthcare Information, 1987, vol II, pp 153–163. Mattis S: Mental status examination of organic mental syndrome in the elderly patient; in Bellak L, Karatsu TE (eds): Geriatric Psychiatry. New York, Grune & Stratton, 1976, pp 77–121. Pillon B, Dubois B, Lhermitte F, Agid Y: Heterogeneity of cognitive impairment in progressive supranuclear palsy, Parkinson’s disease and Alzheimer disease. Neurology 1986;36:1179–1185. Nelson HE: A modified card sorting test sensitive to frontal lobe defect. Cortex 1976;12:313–324. Lozano A, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovski JO: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Albe-Fessard D, Arfel G, Guiot G, Hardy J, Vourc’h G, Hertzog E, Aleonard P: Identification et de´limitation pre´cise de certaines structures sous-corticales de l’homme par l’e´lectrophysiologie. Son intereˆt dans la chirurgie ste´reotaxique des dyskinesies. CR Acad Sci Paris 1961:253:2412– 2414. Guiot G, Derome P, Arfel G, Walter S: Electrophysiological recordings in stereotaxic thalamotomy for parkinsonism. Prog Neurol Surg 1973;5:189–221. Albe-Fessard D, Arfel G, Guiot G, Hardy J, Vourc’h G, Hertzog E, Aleonard P, Derome P: De´rivations d’activite´s spontane´es et e´voque´es dans les structures ce´re´brales profondes de l’homme. Rev Neurol (Paris) 1962;106:89–105. Albe-Fessard D, Arfel G, Guiot G: Activite´s e´lectriques caracte´ristiques de quelques structures ce´re´brales chez l’homme. Ann Chir 1963;17:1185–1214. Cheshire WP, Ehle AL: Hemi-parkinsonism as a complication of an Ommaya reservoir. J Neurosurg 1990;73:774–776. Marks PV, Wild AM, Gleave JRW: Long-term abolition of parkinsonian tremor following attempted ventriculography. Br J Neurosurg 1991;5:505–508. Schaltenbrand G, Wahren W: Atlas of Stereotaxy of the Human Brain, ed 2. Thieme, 1977. Talairach J, David M, Tournoux P, Corredor H, Kvasina T: Atlas d’anatomie ste´reotaxique des noyaux gris centraux. Paris, Masson, 1957, pp 1–294. Guiot G, Arfel G, Deroˆme P: La chirurgie ste´reotaxique des tremblements de repos et d’attitude. Gaz Me´d France 1968;75:4029–4056. Ohye C, Narabayashi H: Physiological study of presumed ventralis intermedius neurons in the human thalamus. J Neruosurg 1979;50:290–297. Ohye C, Shibazaki T, Hirai T, Wada H, Hirato M, Kawashima Y: Further physiological observations on the ventralis intermedius neurons in the human thalamus. J Neurophysiol 1989;61:488–500. Hutchinson WD, Lozano AM, Davis KD, Saint-Cyr JA, Lang AE, Dostrovsky JO: Differential neuronal activity in segments of globus pallidus in Parkinson’s disease patients. Neuroreport 1994; 5:1533–1537. Tronnier VM, Staubert A, Ha¨hnel S, Sarem-Aslani A: Magnetic resonance imaging with implanted neurostimulators: An in vitro and in vivo study. Neurosurgery 1999;44:118–126. Lang AE, Lozano A, Tasker R, Duff J, Saint-Cyr J, Trepanier L: Neuropsychological and behavioral changes and weight gain after medial pallidotomy. Ann Neurol 1997;41:834–836. Caparros-Lefebvre D, Blond S, Pecheux N, Pasquier F, Petit H: Evaluation neuropsychologique avant et apre`s stimulation thalamique chez 9 malades parkinsoniens. Rev Neurol (Paris) 1992;148: 117–122.

Subthalamic Nucleus Deep Brain Stimulation

223

66

67

68

69

70 71 72 73 74

75

76

77

78 79 80 81 82 83 84 85 86 87

Caparros-Lefebvre D, Blond S, Vermersch P, Pecheux N, Guieu JD, Petit H: Chronic thalamic stimulation improves tremor and levodopa-induced dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1993;56:268–273. Blond S, Caparros-Lefebvre D, Parker F, Assaker R, Petit H, Guieu JD, Christiaens JL: Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg 1992;77:62–68. Caparros-Lefebvre D, Blond S, Feltin MP, Pollak P, Benabid AL: Improvement of levodopa-induced dyskinesias by thalamic deep brain stimulation is related to slight variation in electrode placement: Possible involvement of the centre median and parafascicularis complex. J Neurol Neurosurg Psychiatry 1999;67:306–314. Volkmann J, Sturm V, Weiss P, Kappler J, Voges J, Koulousakis A, Lehrke R, Hefter H, Freund HJ: Bilateral high-frequency stimulation of the internal globus pallidus in advanced Parkinson’s disease. Ann Neurol 1998;44:953–961. Krack P, Pollak P, Limousin P, Hoffmann D, Benazzouz A, LeBas JF, Koudsie A, Benabid AL: Opposite effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43:180–192. Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Benazzouz A, Benabid AL: Subthalamic nucleus of internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998;121:451–457. Verhagen L, Mouradian M, Chase T: Altered levodopa dose-response profile after pallidotomy (abstract). Neurology 1996;46:A416–A417. Krack P, Pollak P, Limousin P, Hoffmann D, Benazzouz A, Benabid AL: Inhibition of levodopa effects by internal pallidal stimulation. Mov Disord 1998;13:648–652. Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, Cornu P, Pidoux B, Samson Y, Agid Y: Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 1999;340:1476–1480. Iacono R, Shima F, Lonser RR, Kuniyoshi S, Maeda G, Yamada S: The result, indications and physiology of posteroventral pallidotomy for patients with Parkinson’s disease. Neurosurgery 1995; 36:1118–1127. Benabid AL, Pollak P, Louveau A, Hommel M, Perret J, de Rougemont J: Chronic Vim-thalamic stimulation in movement disorders; in Crossman AR, Sambrook MA (eds): Current Problems in Neurology. 9. Neural Mechanisms in Disorders of Movement. London, Libbey, 1998, pp 413– 415. Benabid AL, Pollak P, Hommel M, Gaio JM, de Rougemont J, Perret J: Traitement du tremblement parkinsonien par stimulation chronique du noyau ventral interme´diaire du thalamus. Rev Neurol (Paris) 1989;145:320–323. Gill SS, Heywood P: Bilateral dorsolateral subthalamotomy for advanced Parkinson’s disease. Lancet 1997;350:1224. Sellal F, Hirsch E, Lisovoski F, Mutschler V, Collard M, Marescaux C: Contralateral disappearance of parkinsonian signs after subthalamic hematoma. Neurology 1992;42:225–256. Adams JE, Hosobuchi Y, Fields HL: Stimulation of internal capsule for relief of chronic pain. J Neurosurg 1974;41:740–744. Akimoto H, Yamaguchi N, Pkabe K, et al: On-sleep induced through electrical stimulation on dog thalamus. Folia Psychiatr Neurol Jpn 1956;10:117–146. Hassler R, Riechert T, Mundinger F, Umbach W, Gangleberger JA: Physiological observations on stereotaxic operations in extrapyramidal motor disturbances. Brain 1960;83:337–350. Jasper HH, Bertrand G: Recording from microelectrode in stereotaxic surgery for Parkinson’s disease. J Neurosurg 1996;24:219–221. Ohye C, Nakamura R, Fukamachi A, Narabayashi H: Recording and stimulation of the ventralis intermedius nucleus for the human thalamus. Confin Neurol 1975;37:258. Sem-Jacobsen CW: Depth-electrographic observations related to Parkinson’s disease. J Neurosurg 1966;24(suppl 10):388–402. Eskandar EN, Cosgrove GR, Shinobu LA, Penney JB: The importance of accurate lesion placement in posteroventral pallidotomy. J Neurosurg 1998;89:630–634. Lang AE, Lozano AM, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:1036–1042.

Benabid/Koudsie/Benazzouz/Piallat/Van Blerkom/Fraix/Pollak

224

88 89

90 91

92 93

94

95 96 97 98 99

100 101 102

103 104 105 106

107

108 109 110

Dogali M, Fazzini E, Kolodny E, Eidelberg D, Sterio D, Devinsky O, Beric A: Stereotactic ventral pallidotomy for Parkinson’s disease. Neurology 1995;45:753–761. Baron MS, Vitek JL, Bakay RA, Green J, Kaneoke Y, Hashimoto T, Turner RS, Woodard JL, Cole SA, McDonald WM, DeLong MR: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355–366. Tronnier VM, Fogel W, Kronenbuerger M, Steinvorth S: Pallidal stimulation: An alternative to pallidotomy? J Neurosurg 1997;87:700–705. Siegfried J, Lippitz B: Bilateral chronic electrostimulation of ventroposterolateral pallidum: A new therapeutic approach for alleviating all parkinsonian symptoms. J Neurosurg 1994;35:1126– 1130. Kumar R, Pollak P, Krack P: Transient acute depression induced by high frequency deep brain stimulation. N Eng J Med 1999;341:1003–1004. Kumar R, Lozano AM, Kim J, Hutchinson WD, Sime E, Halket E, Lang AE: Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998;51:850–855. Gentil M, Garcia Ruiz P, Pollak P, Benabid AL: Effect of stimulation of the subthalamic nucleus on oral control of patients with parkinsonism. J Neurol Neurosurg Psychiatry 1999;67: 329–333. Poewe W, Wenning GK: The natural history of Parkinson’s disease. Neurology 1996;46(suppl 3): 146–152. Klawans HL: Individual manifestations of Parkinson’s disease after ten or more years of levodopa. Mov Disord 1986;3:187–192. Piallat B, Benazzouz A, Benabid AL: Neuroprotective effect of chronic inactivation of the subthalamic nucleus in a rat model of Parkinson’s disease. J Neural Transm 1999;55(suppl):71–77. Rodriguez MC, Obeso JA, Olanow CW: Subthalamic nucleus-mediated excitotoxicity in Parkinson’s disease: A target for neuroprotection. Ann Neurol 1998;44:S175–S188. Ardouin C, Pillon B, Peiffer E, Bejjani P, Limousin P, Damier P, Arnulf I, Benabid AL, Agid Y, Pollak P: Bilateral subthalamic or pallidal stimulation for Parkinson’s disease affects neither memory nor executive functions. A consecutive series of 62 patients. Ann Neurol 1999;46:217–223. Lepore FE, Duvoisin RC: ‘Apraxia’ of eyelid opening: An involuntary levator inhibition. Neurology 1985;35:423–427. Golbe LI: Pallidotomy for Parkinson’s disease: Hitting the target? Lancet 1998;351:998–999. Galvez-Jimenez N, Lozano AM, Duff J, et al: Bilateral pallidotomy pronounced amelioration of incapacitating levodopa-induced dyskinesias but accompanying cognitive decline. Mov Disord 1996; 11:242. Samii A, Turnbull IM, Kishore A, Schulzer M, Mak E, Yardley S, Calne DB: Reassessment of unilateral pallidotomy in Parkinson’s disease. A 2-year follow-up study. Brain 1999;122:417–425. Fazzini E, Dogali M, Sterio D, Eidelberg D, Beric A: Stereotactic pallidotomy for Parkinson’s disease: A long-term follow-up of unilateral pallidotomy. Neurology 1997;48:1273–1277. Kondziolka D, Bonaroti E, Baser S, Brandt F, Kim YS, Lunsford LD: Outcomes after stereotactically guided pallidotomy for advanced Parkinson’s disease. J Neurosurg 1999;90:197–202. Samuel M, Caputo E, Brooks DJ, Schrag A, Scaravilli T, Branston NM, Rothwell JC, Marsden CD, Thomas DGT, Lees AJ, Quinn NP: A study of medial pallidotomy for Parkinson’s disease: Clinical outcome, MRI location and complications. Brain 1998;121:59–75. Schrag A, Samuel M, Caputo E, Scaravilli T, Troyer M, Marsden CD, Thomas DGT, Lees AJ, Brooks DJ, Quinn NP: Unilateral pallidotomy for Parkinson’s disease: Results after more than 1 year. J Neurol Neurosurg Psychiatry 1999;67:511–517. Pahwa R, Wilkinson S, Smith D, Lyons K, Miyawaki E, Koller WC: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997;49:249–253. Gross C, Rougier A, Guehl D, et al: High-frequency stimulation of the globus pallidus internalis in Parkinson’s disease: A study of seven cases. J Neurosurg 1997;87:471–498. Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R: Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997;42:283–291.

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Ghika J, Villemure JG, Fankhauser H, Favre J, Assal G, Ghika-Scmid F: Efficiency and safety of bilateral contemporaneous pallidal stimulation (deep brain stimulation) in levodopa-responsive patients with Parkinson’s disease with severe motor fluctuations: A two-year follow-up review. J Neurosurg 1998;89:713–718. Guridi J, Obeso JA: The role of the subthalamic nucleus in the origin of hemiballism and parkinsonism: New surgical perspectives; in Obeso JA, DeLong MR, Ohye C, Marsden CD (eds): The Basal Ganglia and New Surgical Approaches for Parkinson’s Disease. Advances in Neurology. Philadelphia, Lippincott-Raven, 1997, vol 74, pp 235–247. Gill SS, Heywood P: Bilateral subthalamic nucleotomy can be accomplished safely (abstract). Mov Disord 1998;13(suppl 2):201

A.L. Benabid, MD PhD, Department of Clinical and Biological Neurosciences, INSERM Preclinical Neurobiology U-318, Joseph Fourier University of Grenoble, Hoˆpital A. Michallon, BP 217X, F–38043 Grenoble (France)

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Controversies, Adverse Events, Emerging Insights and Indications Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 227–235

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Movement Disorder Surgery: Lesions or Stimulation? Richard E. Clatterbuck, Jung-Il Lee, Frederick A. Lenz Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Md., USA

Surgery for movement disorders began with a cortical resection by Victor Horsely [1] for chorea in 1906. In the late 1930s, Meyers [2] pioneered a series of transventricular procedures in the basal ganglia for Parkinson’s disease. The next advance in surgery for movement disorders came with the application of stereotactic techniques to lesioning of structures in the basal ganglia [3]. Lesion targets were refined in the 1950s and 1960s leading to the practice of pallidotomy for the treatment of rigidity and akinesia [4] and thalamotomy for tremor [5]. However, surgery for the treatment of movement disorders was dramatically curtailed with the development of levodopa as pharmacologic therapy for Parkinson’s disease. With the long-term treatment of patients with levodopa, the complications of levodopa became evident [6] leading to renewed interest in the surgical options for treatment of movement disorders. Leksell’s posteroventral pallidotomy was reestablished as an effective treatment option for rigidity and akinesia in patients with Parkinson’s disease [7]. Stimulation of lesioning targets had long been known to be capable of alleviating symptoms in the operating room. In the early part of this decade, the development of improved technologies for implantable stimulating electrodes made deep brain stimulation (DBS) a viable option to surgical lesioning. We review here important studies from this decade, which present strong evidence for the efficacy of neurosurgical approaches to movement disorders. The discussion will be limited to posteroventral pallidotomy and ventral intermediate (Vim) thalamotomy as the most common lesioning operations. These procedures will be compared with the three most common DBS procedures: high-frequency stimulation (hfs) of the globus pallidus internus (GPi), Vim,

and subthalamic nucleus (STN). The potential complications and benefits of lesioning and stimulation will be discussed.

Posteroventral Pallidotomy and GPi Stimulation Posteroventral pallidotomy for Parkinson’s disease was reintroduced by Laitinen et al. [7]. In their study, 38 patients with Parkinson’s disease and a primary complaint of akinesia underwent stereotactic posteroventral pallidotomy and mean follow-up of 28 months. Motor function was assessed using writing, drawing, and gait tests. Near complete relief of rigidity and akinesia were reported in 92% of patients. Eighty-one percent of patients with tremor experienced dramatic improvement. Levodopa-induced dyskinesias were also improved. Six of these patients, however, suffered a permanent central homonymous visual field defect. A series of well-designed studies of posteroventral pallidotomy [8–12] have followed the lead of Laitinen et al. Several incorporated evaluation schemes in which observers reviewed patients’ exams by videotape and were blinded to the treatment patients had received [8, 9, 11]. These studies all employed Hoehn and Yahr (H&Y) patient staging [13] and assessment according to the Core Assessment Program for Intracerebral Transplantation (CAPIT) [14] which incorporates the Unified Parkinson’s Disease Rating Scale (UPDRS) [15]. No patient in these studies was better than a H&Y stage III in the ‘on’ state. Follow-up intervals from 3 months to 1 year demonstrated a range of improvement in the ‘off’ state in the UPDRS motor subscale score from 14 to 70%. These studies demonstrated marked contralateral improvements in rigidity, akinesia, tremor, gait, balance, levodopa-related dyskinesias, and ‘on-off’ fluctuations. These studies documented some ipsilateral improvements as well. The first of these studies reported an ‘off’ state improvement in the UPDRS motor score of 71% at 1 year postoperatively [8]. In the study of Lozano et al. [9] UPDRS total motor score in the ‘off’ state improved by 30% at 6 months, while the total akinesia score improved by 33%. This study also noted a 15% improvement in the gait score in the ‘off’ state and a 92% reduction in contralateral dyskinesias. In a study by Baron et al. [10], a 25% improvement in the UPDRS motor score in the ‘off’ state at 3 months was seen. Shannon et al. [12] noted a 15% improvement in the ‘off’ state mean motor UPDRS score at 6 months, and a contralateral ‘off’ state combined tremor, rigidity, and bradykinesia score improved by 26%. In this study the dyskinesia severity score was improved by 73% at 6 months. In the study of Ondo et al. [11], total ‘off’ state UPDRS motor scores improved 14%. Improvement in UPDRS

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total tremor subscore improved by 59%, gait scores by 22%, and body bradykinesia by 17%. Lang et al. [16] have published a 2-year follow-up on 11 patients after posteroventral pallidotomy. The initial results in their group of 40 patients were similar to the above studies at 6 months with overall improvement in motor function of 28%. The effect of pallidotomy on contralateral bradykinesia, dyskinesia, and rigidity were maintained at 2 years, while ipsilateral effects were generally lost. Siegfried and others began work with chronic implantable central nervous system stimulation in the early 1980s. Much of the early clinical work with stimulation was done for intractable pain and for tremor. Siegfried and Lippitz [17], inspired by Laitinen’s work in the posteroventral pallidum, first reported bilateral GPi-hfs in 3 patients in 1994. All 3 patients with advanced Parkinson’s disease (H&Y stage IV or worse) experienced dramatic improvements in Webster scores with dramatic decreases in ‘on-off’ phenomena and levodopainduced dyskinesias. Effects were reversed, though not immediately, when stimulation was discontinued. Several other groups have demonstrated marked improvement in patients treated with unilateral and bilateral GPi-hfs. Pahwa et al. [18] reported the treatment of 5 patients with Parkinson’s disease with GPi-hfs, 3 with bilateral implants. All patients had disabling symptoms with H&Y stage III disease or worse. At 3-month follow-up the amount of time in the ‘on’ state increased from 21 to 65%. UPDRS motor scores in the ‘off’ state without stimulation improved 24% at 3 months postoperatively compared to the preoperative ‘off’ state. UPDRS motor scores at 3 months postoperatively in the ‘on’ state with stimulation were improved 60% over the preoperative ‘on’ state. In the ‘off’ state at 3 months’ follow-up, turning on stimulation improved UPDRS scores 21%. In a similar series, Gross et al. [19] reported 7 patients with H&Y stage III–IV disease who underwent placement of unilateral GPi-hfs electrodes. Mean improvement over ‘off’ state UPDRS motor scores (postprocedure) were 33% with levodopa, 35% with stimulation, and 63% with both. ‘Off’ state scores pre- and postprocedure were similar. In addition, 4 of 5 patients with tremor experienced considerable improvement. No patients experienced ipsilateral effects. These therapeutic benefits were purchased at a cost. Among the 15 patients undergoing pallidotomy reported by Baron et al. [10], 2 (13%) suffered subclinical frontal hemorrhages, 1 (7%) suffered transient dysarthria, 1 (7%) suffered persistent worsening of a baseline dysarthria, and 1 (7%) had a persistent superior quadrantanopsia. Several patients in this study also experienced transient confusion and several experienced transient facial weakness. Ondo et al. [11] reported that among 34 patients undergoing pallidotomy, 5 (15%) ex-

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perienced transient side effects which included aphasia (3%) and altered mental status (12%). Shannon et al. [12] reported 26 patients who underwent pallidotomy. One patient (4%) had a fatal hemorrhage and 3 (12%) had nonfatal hemorrhages. In addition, 2 patients (8%) had cognitive changes, 1 patient (4%) developed aphasia, 3 patients (12%) experienced persistent frontal lobe dysfunction, 1 patient (4%) developed a mild but persistent hemiparesis, and 1 patient (4%) experienced persistent increase in dysarthria. This study also reported some transient side effects including altered mental status, facial weakness, and dysarthria. Dogali et al. [8] reported no significant complications related to pallidotomy in 18 patients. In the 5 patients included in the GPi-hfs studies of Pahwa et al. [18], the only complications reported included a single asymptomatic intracranial hemorrhage, a transient speech difficulty and hemiparesis related to stimulation which resolved in the operating room, and a facial dystonia and paresthesia which required electrode repositioning. Adverse side effects of stimulation included 1 patient with a visual disturbance (transient) and 1 patient with stimulation-related chorea of a foot. Gross et al. [19] reported 7 patients undergoing pallidal stimulation procedures without any complications.

Ventral Thalamotomy and Vim Stimulation One of the first large post-levodopa series of stereotactic thalamotomies for Parkinson’s disease with medically intractable tremor was completed at the Mayo Clinic [20]. In this study, 36 patients (mean H&Y stage 2.4) were treated with 37 thalamotomies and 31 (86%) experienced complete relief of their tremor. Another 3 (5%) were significantly improved. During the followup period, which ranged from 14 to 68 months, only 2 patients suffered from recurrent tremor (both within 3 months). Diederich et al. [21] blindly compared tremor on the operated and unoperated side in 17 patients with Parkinson’s disease at a mean of 10.9 years following stereotactic thalamotomy/subthalamotomy using videotaped examinations. At follow-up the mean H&Y stage was 1.8 and UPDRS motor subscore was 17.8. Severity scores for upper extremity tremor were significantly better on the side contralateral to surgery than on the ipsilateral side. In all these patients, the surgical side was initially chosen to treat the side with the more severe tremor. The largest recent series [22] retrospectively reviewed the outcomes in 60 patients with parkinsonian tremor (42 patients), essential tremor (6), cerebellar tremor (6), and posttraumatic tremor (6). These patients all underwent unilateral stereotactic Vim thalamotomy with the exception of 2 Parkinson’s patients who underwent bilateral procedures, and 1 patient who underwent lesioning

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more anteriorly. With a mean follow-up of 53.4 months, Parkinson’s patients experienced moderate to marked improvement in 86% of the cases. Patients with essential tremor showed similar improvement in 83% of cases. Results were not as dramatic for those patients with cerebellar tremor (67%) or posttraumatic tremor (50%). Our own experience with stereotactic Vim thalamotomy for essential tremor provides confirmation of these reports with a blinded measure of pre- and postoperative status [23]. Patients were evaluated preoperatively and at 3 and 12 months postoperatively with a functional disability score and a blinded handwriting/drawing score. Significant improvements in both scores were found postoperatively. Within patients, analysis demonstrated statistically significant improvement in 72% of patients. With the advent of chronic DBS in the central nervous system for movement disorders, stimulation of the Vim nucleus has been examined as a treatment for tremor. The largest study [24] included 117 patients (177 operated sides) with movement disorders, including 80 with Parkinson’s disease and 20 with essential tremor. Bilateral implantation was undertaken in 59 patients and 14 patients underwent implantation contralateral to a previous thalamotomy. The follow-up period was as long as 7 years for the earliest procedures. At last follow-up 88% of Parkinson’s patients had complete or near complete relief of tremor, and another 10% had slight to moderate improvement. Global scores including all four limbs were slightly lower. Rigidity and akinesia were not significantly affected. In this series the effect on essential tremor was less dramatic with only 61% of patients experiencing complete or near complete relief of tremor at last follow-up. The effect of Vim DBS was inconsistent for patients with other dyskinesias or tremors. Other studies have reported similar results. Koller et al. [25] studied unilateral Vim DBS in 24 patients with Parkinson’s disease and 29 patients with essential tremor in a multicenter trial using a blinded 3-month postoperative evaluation and an open label 1-year follow-up. Complete resolution of tremor was seen in 31% of essential tremor patients and 58.3% of Parkinson’s patients. Only 3.4% of essential tremor patients and only 4.2% of Parkinson’s disease patients had no change in their tremor. No ipsilateral effects were detected. One direct comparison of thalamotomy and thalamic DBS for tremor found essentially equal efficacy in abolishing tremor (63.7 vs. 62.5%), however, 27% of thalamotomies had to be repeated for tremor recurrence while none of the DBS procedures needed revision [26]. Transient complications of thalamotomy were seen in 58–70% of patients and included contralateral weakness, dysarthria, dysphasia, confusion, dystonia, and sensory disturbances [20, 22]. One patient in these two series died at 7 days postoperatively from a pulmonary embolism. The number of patients with long-term or permanent complications was much smaller, in the range

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of 14–23%. Among these complications, weakness/dyspraxia and dysarthria figured most prominently. Only 1 patient in these series experienced permanent cognitive difficulties after a unilateral procedure. In one series of Vim DBS [25], 6 of 53 procedures were aborted secondary to intraoperative complications including failure of stimulation to suppress tremor (2 patients), intracranial hemorrhage (1), and subdural hemorrhage (1). One patient in this series experienced a postoperative seizure. Transient side effects of stimulation included paresthesias, experienced by most patients, and gait disorders, that were much less common. The long-term complications seen in this series in the first year included 2 superficial wound infections, 1 extension wire erosion, and 1 failure of the implantable pulse generator. In the large series of Benabid et al. [24], 5.1% of patients experienced small hematomas as a result of electrode passage (half of these were transiently symptomatic), and 31.6% of patients experienced minor side effects that were reversible with discontinuation of stimulation. These included paresthesias (9%), foot dystonia (9%), dysequilibrium (9%), and contralateral dystonia (5%). Dysarthria was seen in 23 patients (19.6%). Interestingly, 14 of these patients were receiving bilateral stimulation and 4 had a contralateral thalamotomy. Three secondary scalp infections (3%) leading to hardware removal were observed.

Bilateral Subthalamic Nucleus Stimulation Two recent prospective studies have been published which demonstrate an alternative target for the treatment of Parkinson’s disease symptoms, the STN [27, 28]. The evolution of DBS has made STN procedures feasible. Kumar et al. [27] carried out a double-blind evaluation of 7 patients with end-stage Parkinson’s disease that underwent bilateral STN-hfs. Patients experienced an improvement in mean UPDRS motor scores postoperatively of 58% in the ‘off’ state with stimulation. In the ‘on’ state with stimulation, patients’ mean UPDRS motor score improved by 41% compared to the preoperative ‘on’ state. Time in the ‘off’ state and dyskinesias were both decreased postoperatively. Two patients experienced transient hemichorea as a result of the procedure, and 4 patients experienced some degree of postoperative cognitive difficulty (1 experienced a venous infarction and another a thalamic lesion). Limousin et al. [28] reported 24 patients with Parkinson’s disease (H&Y stage IV–V in the ‘off’ state) that underwent bilateral STN-hfs. At 1-year follow-up, mean UPDRS motor scores improved 60% with stimulation in the ‘off’ state and 10% in the ‘on’ state. As in the Kumar et al. [27] series, patients were significantly improved in the ‘off’ state with the stimulator off. Rigidity, akinesia, tremor, gait, and dyskinesias were all improved. Complications in-

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cluded a large intracerebral hematoma (4%) leading to paralysis and aphasia and a subcutaneous infection (4%) requiring hardware removal. Eight patients experienced transient cognitive difficulties, and 1 patient had permanent worsening of preoperative cognitive deficits. Five patients experienced an eyelid apraxia requiring treatment. In two larger series of DBS for chronic pain [29, 30], among a total of 263 patients, 10 intracerebral hemorrhages (4%) (including 3 deaths), 23 infections (9%), 10 hardware erosions (4%), and 7 foreign body reactions (3%) were seen. With technical improvements in DBS systems the rate of these complications may be lower than reported in earlier series.

Conclusions In the last decade many new options have become available for the surgical treatment of movement disorders. The principal procedures currently in use include posteroventral pallidotomy, ventrolateral thalamotomy, and DBS in Vim, GPi and STN. With the development of technology allowing routine use of indwelling stimulating devices in the central nervous system, DBS has become a more viable option. Although the collective experience with DBS is considerably smaller than that with lesioning procedures, present data suggests that stimulation is as effective as lesioning procedures. Posteroventral pallidotomy series demonstrate 14–70% improvement in ‘off’ state UPDRS motor scores following surgery. In patients treated with pallidal stimulation, turning on the stimulator in the ‘off’ state improved UPDRS motor scores by 21–35%. Similarly, most series place significant improvement in tremor following ventrolateral thalamotomy and Vim stimulation at over 80%. One series that directly compared the two modalities found both effective at around 63% [26]. These studies all suggest that lesioning and stimulation are equally efficacious in the treatment of movement disorders. DBS carries the obvious advantage of being reversible and adjustable. These advantages make bilateral procedures more practical and safe. It remains to be seen if these theoretical advantages will be borne out in larger series or randomized trials. It would appear from the data presented here that clinically significant hemorrhage risks are similar for permanent lesioning paradigms and stimulator lead placements, about 4%. The obvious disadvantages of permanent indwelling hardware, increased infection risk (3–9%) and mechanical failure, are born out to some degree with the present series. Other neurologic complications seen with stimulation such as paresthesias and dystonias generally resolved when stimulation was decreased. In comparison, complica-

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tions such as aphasia, cognitive worsening, mild hemiparesis, and visual field deficits seen with lesioning were in some cases permanent. Such complications were seen in as high as 14–23% of patients. Another aspect to be considered is the increased costs associated with implanting and maintaining DBS. It will take a multicenter, prospective, randomized trial with outcome measures including a cost-benefit analysis to address all these issues.

Acknowledgments Some of the studies reported here were supported by grants from the Eli Lilly Corporation and from the National Institutes of Health (NS28598, K08-NS1384, P01 NS32386Proj. 1, RDI NS38493) to F.A.L.

References 1 2 3 4 5 6 7 8 9

10

11 12 13 14 15

Horsley V: The function of the so-called motor cortex. Br Med J 1909;ii:125–132. Meyers R: Surgical procedure for postencephalitic tremor, with notes on the physiology of the premotor fibers. Arch Neurol Psychiatry 1940;44:455–459. Spiegel EA, Wycis HT, Marks M, Lee AJ: Stereotaxic apparatus for operations on the human brain. Science 1947;106:349–350. Svennilson E, Torvik A, Lowe R, Leksell L: Treatment of parkinsonism by sterotactic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Scand 1960;35:358–377. Hassler R, Riechert T: Indikationen und Lokalisationsmethode der gezielten Hirnoperationen. Nervenarzt 1954;25:441–447. Marsden CD, Parkes JD: Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet 1977;i:345–349. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Dogali M, Fazzini E, Kolodny E, Eidelbert D, Sterio D, Devinsky O, Beric A: Stereotactic ventral pallidotomy for Parkinson’s disease. Neurology 1995;45:753–761. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchison WD, Dostrovsky JO: GPi pallidotomy improves motor function in patients with Parkinson’s disease. Lancet 1995;346: 1383–1386. Baron MS, Vitek JL, Bakay RAE, Green J, Kaneoke Y, Hashimoto R, Turner RS, Woodward JL, Cole SA, McDonald WM, DeLong MR: Treatment of advanced Parkinson’s disease with microelectrode-guided pallidotomy: One-year pilot study results. Ann Neurol 1996;40:355–366. Ondo WG, Jankovic J, Lai EC, Sankhla C, Khan M, Ben-Arie L, Schwartz K, Grossman RG, Krauss JK: Assessment of motor function after stereotactic pallidotomy. Neurology 1998;50:266–270. Shannon KM, Penn MD, Kroin JS, Janko KA, York M, Cox SJ: Stereotactic pallidotomy for the treatment of Parkinson’s disease. Neurology 1998;50:434–438. Hoehn MM, Yahr MD: Parkinsonism: Onset, progression, and mortality. Neurology 1967;17: 427–442. Langston JW, Winder H, Goetz CG, Brooks D, Fahn S, Freeman T, Watts R: Core Assessment Program for Intracerebral Transplantations (CAPIT). Mov Disord 1992;7:2–13. Fahn S, Elton RL, members of the UPDRS Development Committee: Unified Parkinson’s Disease Rating Scale; in Fahn S, Marsden CD, Calne DB, Goldstein M (eds): Recent Developments in Parkinson’s Disease. Florham Park, MacMillan Health Care Information, 1987, vol 2, pp 153–164.

Clatterbuck/Lee/Lenz

234

16 17

18 19

20 21

22 23

24

25

26 27

28

29 30

Lang AE, Lozano AM, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1998;337:262–263. Siegfried J, Lippitz B: Bilateral chronic electrostimulation of the ventroposterolateral pallidum: A new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994;35: 1126–1130. Pahwa R, Wilkinson S, Smith D, Lyons K, Miyawaki E, Koller WC: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997;49:249–253. Gross C, Rougier A, Guehl D, Boraud T, Julien J, Bioulac B: High-frequency stimulation of the globus pallidus internalis in Parkinson’s disease: A study of seven cases. J Neurosurg 1997;87: 491–498. Fox MW, Ahlskog EJ, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refactory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991;75:723–730. Diederich N, Goetz CG, Stebbins GT, Klawans HL, Nitter K, Koulosakis A, Sanker P, Sturm V: Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy or subthalamotomy on tremor in Parkinson’s disease. Neurology 1992;42:1311–1314. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for parkinsonian, essential and other types of tremor. Neurosurgery 1995;37:680–687. Zirh AT, Reich SG, Dougherty PM, Lenz FA: Stereotactic thalamotomy in the treatment of essential tremor of the upper extremity: Re-assessment including a blinded measure of outcome. J Neurol Neurosurg Psychiatry 1999;66:772–775. Benabid AL, Pollak P, Gao D, Hoffman D, Limousin P, Gay E, Payen I, Benazzouz A: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as treatment of movement disorders. J Neurosurg 1996;84:203–214. Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang AE, Tuite P, Sime E, Lozano A, Hauser R, Malapira T, Smith D, Tarsy D, Myawaki E, Norregaard T, Kormos T, Olanow CW: High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997;42:292–299. Tasker RR, Munz M, Junn FSCK, Kiss ZHT, Davis K, Dostovsky JO, Lozano AM: Deep brain stimulation and thalamotomy for tremor compared. Acta Neurochir 1997;68(suppl):49–53. Kumar R, Lozano AM, Kim YJ, Hutchinson WD, Sime E, Halket E, Lang AE: Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998;51:850–855. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–1111. Hosobuchi Y: Subcortical electrical stimulation for control of intractable pain in humans. J Neurosurg 1986;64:543–553. Levy RM, Lamb S, Adams JE: Treatment of chronic pain by deep brain stimulation: Long-term follow-up and review of the literature. Neurosurgery 1987;21:885–893.

F.A. Lenz, Department of Neurosurgery, Meyer 7-113, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287 (USA) Tel. +1 410 955 2257, Fax +1 410 614 9877, E-Mail [email protected]

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What Does Stimulation in the Brain Actually Do? Peter Ashby Playfair Neuroscience Unit, University of Toronto, Toronto Western Hospital, Toronto, Ont., Canada

It is curious that high-frequency stimulation has the same effect as lesion. Logically one must conclude that stimulation ‘blocks’ neurons. But what does stimulation deep in the brain actually do? The best way to answer this question would be to record neural activity from multiple sites in a human patient or an animal model. There are few such studies to date. For now, we can consider certain general principles that should apply to stimulation in the human brain and review the limited evidence about the neurophysiological effects of deep brain stimulation (DBS) that is available from observations made on human patients.

General Principles It is useful to think about the effects of single stimuli and chronic highfrequency stimulation separately. After all, single (cathodal) stimuli can only excite neurons. The effects of single stimuli will indicate which neural elements are ‘within reach’ of the electrode. We can then consider what happens when these same elements are activated repeatedly. Single Stimuli: Which Neural Elements Are Most Likely to Be Stimulated? This topic has been considered by Ranck et al. [1], Yeo`mans [2] and Tehovnik [3]. The main points are: (1) Current flow between two electrodes in the brain will be distorted by the anisotropic nature of blood, CSF, gray and white matter which all have different resistances. (2) For a given current density at any particular point in the brain, some neural elements will be more readily excited that others. In general, a stimulus will excite axons before cell

bodies, large axons before small, those lying parallel to the direction of current flow before those lying transversely to it and axons near the cathode before those near the anode. There are many extra complexities [1, 4]. Stimulation with brief pulses at low intensities will preferentially excite large myelinated axons. Small fibers or neurons will be excited only close to the cathode. The distance at which a given neural element will be excited by stimuli through a Medtronic electrode can be estimated from figure 1. With very strong stimulation, anodal hyperpolarization may prevent impulse propagation [4]. High-Frequency Stimulation: Does It Block Neurons? Large myelinated axons have short refractory periods (~1 ms) and can transmit impulses at high frequencies. Thus, the very elements most likely to be recruited by DBS are the least likely to be blocked. Effects of DBS occurring within seconds may be due to the activation rather than blocking of neurons. Trains of 200 Hz stimuli lasting 1–10 min alter the excitability of axons in complex ways that persist for hours after the stimulation has ended. Axon excitability may be increased, so that spontaneous discharges occur, or decreased, so that the axon is less responsive to electrical stimulation [5–7]. Long trains of stimuli depress transmission at nerve terminals or synapses [8]. The changes described in the last three sentences require several minutes of stimulation and cannot be responsible for ‘immediate’ effects of DBS. Finally, given the known plasticity of the primate cortex, some plastic rearrangement of the nervous system would seem to be inevitable after days of high-frequency stimulation.

Neurophysiological Observations on Human Patients Ventrolateral Thalamic Stimulation for the Control of Tremor Thalamic stimulation alleviates parkinsonian and essential tremor [9–13]. The target area is a zone just anterior to Vc where recorded cells respond to limb movement, where cells discharge in synchrony with tremor or where high frequency stimulation stops tremor. This target is thought to be VIM(>VPLo), the proprioceptive or cerebellar thalamic relay (fig. 2). One autopsy showed that the electrode was at the top of brachium conjuntivum [14]. Effects of Single Thalamic Stimuli. Single stimuli delivered through contacts in the thalamus inhibit voluntary EMG of contralateral muscles with a latency of about 50 ms and a duration of over 100 ms [15, 16]. This inhibition must arise from the activation of large, myelinated axons as the chronaxie and refractory period are short. The effect is about the same at each of the 4 contacts implying that the responsible fiber system runs parallel to the axis of the electrode [16].

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Fig. 1. How to estimate the distances at which neurons will be activated by monopolar stimulation through a DBS electrode. Total current: The Medtronic DBS lead 3387 has a row of 4 cylindrical contacts with a center-to-center separation of 3 mm. Each has a diameter of 1.27 mm, a height of 1.52 mm and an area of 6 mm2. Stimuli can be given between a pair of these contacts (bipolar stimulation) or between one of them and the metal case of the stimulator (monopolar stimulation). The implanted stimulator is ‘constant voltage’. This means that the lower the tissue resistance, the greater the current flow. Typically, the impedance between the contacts is from 0.5 to 2 jX. If the impedance was 1 jX a 1 V stimulus would generate a total current of D1 mA. The curved lines show how current densities and charge densities fall off at various distances from a monopolar stimulating contact with total currents of (bottom up) 1, 2, 3, 5 and 10 mA. Current density>total current/area: With a 1-mA total current (lower curve with filled circles) the current density at the electrode contact (distance>0) is 1/6>0.16 mA/mm2. At a distance of 2 mm from the contact, the current density is 1/(4pr2>0.02 mA/mm2 ). Current density falls off with the square of the distance. Charge density>current density · time: The lower curve also represents the charge densities with a 1-mA total current and a pulse width of 100 ls. The charge density 2 mm from the contact is 0.02 lC/mm2. If the total current was increased to 2 mA or the pulse width to 0.2 ms, the charge density 2 mm from the contact would be 0.4 lC/mm2 (curve with open circles). Current-distance constants: It takes more current to activate a neuron at a greater distance. The product, K>total current/(distance)2, if roughly constant for a given neural element and pulse width. Tested with a 200-ls pulse, a myelinated axon might have a K of D250 lA/mm2 and a cell body a KD1,260 lA/mm2. These values correspond to charge densities of 0.04 and 0.2 lC/mm2.

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Fig. 2. Diagram of the subdivisions of the ventrolateral thalamus, their equivalent names and their postulated afferent and efferent projections from. After Percheron et al. [42]. The target for tremor control is VIM.

The inhibition could come from GPi, from local thalamic interneurons or from the reticular nucleus of the thalamus. The thalamic relay and reticular neurons are part of a larger system recently re-explored by Ando et al. [17] and shown diagramatically in figure 3. Strafella et al. [16] postulated that the inhibition produced by stimulating the ventrolateral thalamus resulted from the activation of this neural system via cerebellothalamic afferents, or relay cell efferents and their 11 collaterals to the reticular nucleus. Cerebellothalamic axons also have collaterals to the red nucleus, the medulla and the spinal cord [18] and antidromic activation of these axons could bring in a number of other mechanisms. Effects of High-Frequency Stimulation of the Thalamus. Continuous stimulation does not produces continuous inhibition. The mechanism evidently habituates. Strafella et al. [16] postulated that a train of stimuli delivered to the thalamus first caused and then extinguished the inhibition. High-frequency How far from the contact will various neural elements be activated? The intersections of the curve with open circles and the horizontal lines representing K of 250 and 1,260 (scale on left) indicate that a 200-ls, 1-mA pulse would be expected to excite myelinated axons up to 2 mm and cell bodies up to 0.7 mm from the cathode. Owing to the shape of the strengthduration curve, a 100-ls pulse of 1.7 (not 2) mA/mm2 is equivalent to a 200-ls pulse of 1 mA (curve with open circles). Current spread is much less with bipolar stimulation. The details of current flow (governed by the relative resistance of the surrounding tissue) and the orientation of the neural elements with respect to it will determine which elements are actually activated.

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Fig. 3. Diagram of some thalamic circuitry relevant to the effects of thalamic stimulation. Facilitatory neurons are white, inhibitory neurons are black. Based on Ando et al. [17]. Thalamic reticular neurons can produce prolonged hyperpolarization of thalamic relay cells.

stimulation would block oscillations involving this network and might explain the effect on tremor. Stimulation of GPi for the Control of Parkinsonism According to current models of basal ganglia function, parkinsonism results from uninhibited STN driving of the GPi and SNpr. Blocking GPi or STN would alleviate parkinsonism. This model does not take into account all of the known pathways in the region and may be superseded by others of greater sophistication [19, 20]. Several reports show that chronic, high-frequency stimulation of the GPi alleviates parkinsonian symptoms [21–25]. The model predicts that ‘blocking’ GPi would remove inhibition of the thalamo-prefrontal cortical system involved in the preparation of voluntary movements. One PET study reported increased blood flow in the SMA and dorsolateral prefrontal cortex during GPi stimulation [26] but another showed no change in these regions [27]. Brown et al. [28] found that GPi stimulation in parkinsonian patients improved strength and movement time but the improvements that might have been expected in the initiation of movements and in premovement cortical potentials

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Fig. 4. Diagram of some of the pathways relevant to a discussion of the effects of GPi and STN stimulation. Facilitatory neurons are white, inhibitory neurons are black. The projections to and from the SNpr (not shown) are considered to replicate those of GPi. Reducing the inhibition of thalamic neurons would be expected to alleviate the symptoms of parkinsonism. Based on Parent [43].

could not be demonstrated. Acute high-frequency stimulation of the GPi produces two conflicting effects depending on whether the upper or lower contacts are used. Stimulation through the upper contacts improves akinesia and produces dyskinesia while stimulation through the lower contacts produces akinesia and blocks the beneficial effects of L-dopa as well as L-dopa-induced dyskinesias [29, 30]. There may be two functionally distinct divisions of the GPi with opposing actions: an upper, inner portion projecting through the lenticular fasiculus and a lower, outer portion projection through the ansa (fig. 4). Alternatively, different neural elements might have been recruited at each site. The dyskinesias arising from the upper contacts (which are close to or even in GPe) could be explained by activation of inhibitory projections from GPe or by blocking of the facilitatory projections from STN to GPi. The antidopaminergic effects produced by stimulation through the lower contacts could be explained by activation of the ansa or afferents from the STN or by blocking of fibers from GPe or even the dopaminergic axons from SNpc.

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Neurophysiological Effects of Single and High-Frequency Stimulation of the GPi. Attempts to identify the neural elements activated by single stimuli delivered to the human GPi have been disappointing. If GPi neurons or the various white matter bundles that transverse the GPi are activated by single stimuli, they do not seem to give rise to any detectable short latency effects. Perhaps this is not surprising given the postulated indirect actions of GPi on motor function. Inhibition of voluntary EMG is never seen [31]. Findings in MPTP monkeys imply that GPi stimulation excites rather than blocks neurons [32]. High-frequency stimulation of GPi alleviated parkinsonism in MPTP monkeys. The firing rates of extracellularly recorded GPi neurons, normally about ~80 Hz, were greater in the MPTP monkeys, a mean of D106 Hz. With GPi stimulation, the firing rates of GPi neurons within a 3-mm radius of the stimulating electrode fell to a mean of ~86 Hz. The GPi neurons were not ‘blocked’, just slowed. The authors postulated that GABA release from the activation of axons from the striatum or GPe slowed GPi firing. Single stimuli delivered to the human GPi depress the firing of neighboring neurons [Lozano et al., pers. commun.]. STN Stimulation for the Control of Parkinsonism Bilateral STN stimulation can alleviate all the cardinal features of human parkinsonism: bradykinesia, rigidity and tremor [33–36]. Stimulation may induce dyskinesias resembling those induced by L-dopa [37], but the clinical improvement allows for a reduction in dopaminergic medications. This ‘titration’ and the report that a test dose of L-dopa predicts the outcome [38] implies that L-dopa and STN stimulation share a common mechanism. Clinical improvement can result from stimulation with narrow pulse widths (60 ls, 2.8 V, 130 Hz) [36], which would be expected to excite large fibers, and with rates as slow as 30 Hz [35] which would be unlikely, to block them. In normal subjects, voluntary movements are accompanied by an increase in blood flow in the dorsolateral prefrontal cortex, the supplementary cortex and the cingulate gyrus. These PET changes are lost in Parkinson’s disease but restored by high-frequency stimulation of the STN [27]. Neurophysiological Effects of Single Stimuli to the STN. Single stimuli delivered to the STN in human patients might not be expected to have any obvious short latency motor effects and, in general, they do not [39]. With weak stimulation (100 ls, =5 mA) half of the 77 contacts tested in 14 patients had no effect on ongoing voluntary EMG of contralateral muscles, one third showed inhibition, preceded or followed by facilitation, and the remainder showed short latency (=25 ms) facilitation. The short latency facilitation probably represents spread of current to the corticospinal tract. The inhibition, which resembles that seen with thalamic stimulation, occurred with

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more medial electrode placements. It could be obtained with narrow pulse widths (60 ls) and was about the same magnitude at each contact implying that it arose from a large fiber system running parallel to the long axis of the electrode. Neurophysiological Effects of High-Frequency Stimulation of STN. In some patients, high-frequency STN stimulation stopped tremor of the contralateral limbs abruptly for the duration of the stimulation. Strength-duration plots showed that this abolition of tremor arose from low threshold neural elements (with chronaxies similar to those responsible for the inhibition). Tremor control, like the inhibition, could be obtained at each of the contacts at about the same threshold [39]. This raised the possibility that tremor control from STN and thalamic stimulation have the same explanation. In normal rats stimulation of STN can increase or decrease the firing rate of neurons in the endopenduncular nucleus (the rat equivalent of GPi) and in SNpr [40]. Single stimuli (60 ls, 0.5 mA) facilitated SNpr neurons, so did trains of stimuli lasting 5 s if the rate of stimulation was =50 Hz. But with 5-s trains of more rapid stimulation (130 Hz, 60 ls, ?0.3 mA) the firing rates of neurons in GPe were increased (for subsequent 50–160 s) and the firing rates of SNPr and EP neurons were depressed for the subsequent 50–120 s. The authors postulated that the stimuli either activated GPe axons retrogradely or caused depolarization block of STN axons. Gao et al. [41] showed that STN stimulation in the rat, even with narrow pulses and slow stimulus rates (20–50 Hz), increased the firing rate of ventrolateral thalamic neurons. Stimulation at these rates is unlikely to block neural elements. Thus, the actions of DBS may be due to the activation rather than blocking of neurons.

Conclusion Single (cathodal) stimuli delivered to the neuropil can only activate neurons. Brief, low-intensity stimuli preferentially excite large myelinated axons which can transmit at high frequency without ‘blocking’. Prolonged high-frequency stimulation has complex effects on axon excitability and failure of transmission can occur at fine nerve terminals or at synapses in neural networks. Single stimuli delivered to the ventrolateral thalamus inhibit voluntary EMG probably by inhibition of thalamocortical neurons. The effect habituates at high frequency. Rapid stimulation could block oscillations, therefore, involving this network and might explain the effect on tremor. Stimulation of the GPi can produce conflicting actions depending on the site of stimulation; some of the described effects could be explained by activation rather than blocking of neurons. STN stimulation seems to reduce tremor by activating a large fiber system.

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References 1 2 3 4 5 6 7 8

9

10

11 12

13

14 15 16 17

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19 20 21 22 23

Ranck JB, Patterson MM, Kesner RP (eds): Electrical stimulation techniques, vol 1: Extracellular stimulation. New York, Academic Press, 1981, pp 2–36. Yeomans JS: Principles of Brain Stimulation. New York, Oxford University Press, 1990. Tehovnik EJ: Electrical stimulation of neural tissue to evoke behavioral responses. J Neurosci Methods 1996;65:1–17. Ranck JB: Which elements are excited in electrical stimulation of the mammalian central nervous system: A review. Brain 1975;98:417–404. Applegate C, Burke D: Changes in excitability of human cutaneous afferents following prolonged high-frequency stimulation. Brain 1989;112:147–164. Bostock H, Bergmans J: Post-tetanic excitability changes and ectopic discharges in human axon. Brain 1994;117:913–928. Burke D, Applegate C: Paraesthesiae and hypaesthesia following prolonged high-frequency stimulation of cutaneous afferents. Brain Res 1989;112:913–929. Macefield G, Burke D: Long-lasting depression of central synaptic transmission following prolonged high-frequency stimulation of cutaneous afferents: A mechanism for post-vibratory hypaesthesia. Electroencephalogr Clin Neurophysiol 1991;78:150–158. Benabid AL, Pollak P, Gervason C, Dongming G, Hommel M, Perret JE, DeRougemont J: Longterm suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406. Blond S, Caparros-Lefebvre D, Parker F, Assaker R, Petit H, Guieu MD, Christiaens JL: Control of tremor and involuntary movement disorders by chronic streotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg 1992;77:62–68. Hubble J, Busenbark K, Wilkinson S, Penn RD, Lyons K, Koller W: Deep brain stimulation for essential tremor. Neurology 1996;46:1150–1153. Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang AE, Sime E, Lozano AM, Hauser R, Malapira T, Smith D, Tarsy D, Miyawaki E, Norregaard T, Kormos T, Olanow CW: Highfrequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997;42:292–299. Benabid AL, Pollak P, Dongming G, Hoffmann D, Limousin P, Gay E, Payen I, Benazzouz A: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–214. Caparros-Lefebvre D, Ruchoux MM, Blond S, Petit H, Percheron G: Long-term thalamic stimulation in Parkinson’s disease. Neurology 1994;44:1856–1860. Ashby P, Lang AE, Lozano AM, Dostrovsky JO: Motor effects of stimulating the human cerebellar thalamus. J Physiol 1995;489:287–298. Strafella A, Ashby P, Munz M, Dostrovsky JO, Lozano AM, Lang AE: Inhibition of voluntary activity by thalamic stimulation in humans: Relevance for the control of tremor. Mov Disord 1997;12:727–737. Ando N, Izawa Y, Shinoda Y: Relative contributions of thalamic reticular nucleus neurons and intrinsic interneurons to inhibition of thalamic neurons projection to the motor cortex. J Neurophysiol 1995;73:2485. Bentivoglio M, Kuypers HGJM: Divergent axon collaterals from rat cerebellar nuclei to diencephalon, mesencephalon, medulla oblongata and cervical cord. A fluorescent double retrograde labeling study. Exp Brain Res 1982;46:356. Parent A, Cicchetti F: Current model of basal ganglia organization under scrutiny. Mov Disord 1998;13:199–202. Brown P, Marsden CD: What do the basal ganglia do? Lancet 1998;351:1801–1804. Siegfreid J, Lippitz B: Bilateral chronic electrostimulation of ventroposterolateral pallidum: A new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994;35:1126–1130. Pahwa R, Wilkinson S, Smith D, Lyons K, Miyawaki E, Koller WC: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997;49:249–253. Gross C, Rougier A, Guehl D, Feger J: High-frequency stimulation of the globus pallidus internalis in Parkinson’s disease: A study of 7 cases. J Neurosurg 1997;87:491–498.

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24 25

26

27

28

29 30 31 32

33

34 35

36

37

38 39 40

41 42 43

Tronnier VM, Fogel W, Kronenbuerger M, Steinvorth S: Pallidal stimulation: An alternative to pallidotomy? J Neurosurg 1997;87:700–705. Volkmann J, Sturm V, Weiss P, Kappler J, Voges J, Koulousakis A, Lehrke R, Hefter H, Freund HJ: Bilateral high-frequency stimulation of the internal globus pallidus in advanced Parkinson’s disease. Ann Neurol 1998;44:961. Davis KD, Taub E, Houle S, Lang AE, Dostrovsky JO, Tasker RR, Lozano AM: Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms. Nat Med 1997;3:674. Limousin P, Greene J, Pollak P, Rothwell J, Benabid AL, Frackowiak R: Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997;42:283–291. Brown RG, Limousin-Dowsey P, Brown P, Jahanshahi MP, Benabid AL, Rodrigues-Oroz MC, Obeso JA, Rothwell J: Impact of deep brain stimulation on upper limb akinesia in Parkinson’s disease. Ann Neurol 1999;45:473–488. Krack P, Pollak P, Limousin P, Hoffman D, Benazzouz A, Le Bas JF, Koudsie A, Benabid AL: Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43:180–192. Bejjani B, Damier P, Arnulf I, Bonnet AM, Vidailhet M, Dormont D, Pidoux B, Cornu P, Marsault C, Agid Y: Pallidal stimulation for Parkinson’s disease: Two targets? Neurology 1998;49:1564–1569. Ashby P, Strafella A, Dostrovsky JO, Lang AE: Immediate motor effects of stimulation through electrodes implanted in the human globus pallidus. Stereotact Funct Neurosurg 1998;70:1–18. Boraud T, Bezard E, Bioulac B, Gross C: High-frequency stimulation of the internal globus pallidus (GPi) simultaneously improves parkinsonian symptoms and reduces the firing frequency of GPi neurons in the MPTP-treated monkey. Neurosci Lett 1996;215:17–20. Benabid AL, Pollak P, Gross C, Hoffman D, Benazzouz A, Gao DM, Laurent A, Gentil M, Perret J: Acute and long-term effects of subthalamic nucleus stimulation in Parkinson’s disease. Stereotac Funct Neurosurg 1994;62:76–84. Limousin P, Pollak P, Benazzouz A, Hoffman D, Broussolle E, Perret J, Benabid AL: Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–674. Limousin P, Pollak P, Benazzouz A, Hoffman D, Le Bas JF, Broussolle E, Perret J, Benabid AL: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995;345:91–95. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffman D, Benabid AL: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–1111. Limousin P, Pollak P, Hoffman D, Benazzouz A, Perret J, Benabid AL: Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients. Mov Disord 1996; 11:231–235. Krack P, Pollak P, Limousin P, Hoffman J, Xie J, Benazzouz A, Benabid AL: Subthalamic nucleus or internal pallidal stimulation in young-onset Parkinson’s disease. Brain 1998;121:451–457. Ashby P, Kim YJ, Kumar R, Lang AE, Lozano AM: Neurophysiological effects of stimulation through electrodes in the human subthalamic nucleus. Brain 1999;122:1919–1931. Benazzouz A, Piallat B, Pollak P, Benabid AL: Responses of substantia nigra pars reticulata and globus pallidus complex to high-frequency stimulation of the subthalamic nucleus in rats: Electrophysiological data. Neurosci Lett 1995;189:77–80. Gao D, Benazzouz A, Bressand K, Piallat B, Benabid AL: Role of GABA, glutamate, acetylcholine and STN stimulation on thalamic VM in rats. Neuroreport 1997;8:2601–2605. Percheron G, Francois C, Talbi B, Meder JF, Fenelon G, Yelnik J: The primate motor thalamus analysed with reference to subcortical afferent territories. Stereotact Funct Neurosurg 1993;60:32–41. Parent A: Carpenter’s Human Neuroanatomy, ed 9. Baltimore, Williams & Wilkins, 1996, pp 1–795.

Peter Ashby, MD, FRCP(C), Playfair Neuroscience Unit, University of Toronto, Toronto Western Hospital, Toronto, Ont. M5T 2S8 (Canada) Tel. +1 416 603 5017, Fax +1 416 603 5768, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 246–265

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Complications of Movement Disorder Surgery and How to Avoid Them Marwan I. Hariz University Hospital, Umea˚, Sweden ‘Twenty-five years ago I agonized over the question of which risk is greater, the disease or the operation? … I used to wonder … when the anxiety, tension and pain of the decision … would disappear. I now know the answer to that question. When? Never – that’s when.’

Irving S. Cooper, 1981 The Vital Probe; My Life as a Brain Surgeon

The main aim of ablative or stimulative stereotactic procedures in surgery for movement disorders (MD) is to control the symptoms of the disease, not to cure the disease itself. This surgery, unlike most other neurosurgical operations, is not a ‘life-saving’ procedure because MD is not a life-threatening condition, and the patient still has the choice to not undergo surgery. Since the final goal of MD surgery is to alleviate the symptoms and hopefully the disability of the patient, the surgical procedure should therefore not provoke any new symptom or neurological deficit to the already disabled patient. In that sense, surgery for MD is a very sensitive and delicate procedure. Furthermore, it is a ‘blind’ operation performed deep in the brain and in local anaesthesia on an awake patient. This requires accurate preoperative imaging of the anatomical target aimed at, reliable intraoperative physiological investigation of the target area, and not the least, detailed information to the patient (and the relative!) about the various available surgical procedures, their chances and risks, their expectations and side effects, and also on what is required from the patient before, during and after surgery. Nashold [1] pointed out in 1970 that the success of stereotactic surgery depends among other factors on the cooperation of the patient. Ever since the beginning of human functional stereotactic surgery in the late 1940s, efforts have been made to not only improve its accuracy and efficacy,

but to minimize its complications. These complications were related partly to the disease and physical or mental state of the operated patients, and partly to radiological localization procedures, surgical techniques and lesioning instruments. While the old nonstereotactic functional surgery of Russel Meyers resulted in 15% mortality, the original stereotactic procedures of Spiegel and Wycis had a mortality of 2% [2]. The surgical mortality decreased further and reached 0–1% in the 1960s [3–5]. With the advent of CT, MRI, computers and refined microelectrode techniques, one would have expected a more precise and safer functional stereotactic surgery, with a radical decrease in morbidity and a virtual eradication of mortality. This has unfortunately not been the case. While Leksell’s pallidotomy for instance, performed by him in the 1950s, and published by the neurologist Svennilson [6] in 1960, resulted in no mortality, and very low morbidity, among the 81 operated patients, modern pallidotomy experience on much fewer patients, published from some centres in 1998, resulted in up to 7% mortality, not to mention the high rate of severe morbidity [7, 8]. It is therefore a paradox to realize that, with the worldwide renaissance and spread of modern surgery for MD, complications may be worse than 40 years ago despite all ‘state-of-the-art’ modernities in imaging, frames and surgical techniques. The only way to guarantee zero percent surgical complications is to abstain from surgery. The aim of this text, however, is to provide some guidelines to perform surgery for MD with maximal safety for the patient. In each step of a stereotactic surgical procedure for MD, the possible and potential risks and complications will be described and some measures to minimize their occurrence will be outlined. Then, potential complications that are specific for the respective brain targets aimed at in surgery for MD will be discussed.

General Complications and Their Avoidance General, nontarget-specific, complications include potential complications related to patient selection, stereotactic frame, imaging procedure, trephination, macro/microelectrode exploration, lesioning procedure and deep brain stimulation (DBS). Patient Selection The first step in complication avoidance consists in careful patient selection and in setting the proper indications for the specific surgery to be performed on the patient. The various indications for the different surgical procedures for MD, especially Parkinson’s diseases (PD), are now rather well known, and

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will not be detailed here: Needless to say that a PD patient whose main symptom is freezing of the gait may have a further deterioration of gait following thalamotomy or thalamic stimulation, and the balance of a patient with balance disturbances will definitely become worse following a thalamotomy. The age of the patient is not crucial as long as his/her mental abilities are adequate. A mini-mental test [9] or a psychometric test according to Kokmen et al. [10] are enough, in the clinical routine, to rule out dementia or a significant cognitive decline, which would constitute absolute contraindications for functional surgery regardless of procedure. Furthermore, it should be kept in mind that the older the patients are, the more likely they will have cortical or central atrophy, or the more probable they would have had a previous ischaemic stroke – no matter how asymptomatic, which will make surgery more risky (see below). Besides, high age as such is a factor influencing negatively a patient’s capacities for rehabilitation. Finally, high-age patients may have disabilities due to other chronic sicknesses, such as cardiac incompensation, hip or knee arthrosis, and the like, which will definitely add to their movement disorder-related disability. These conditions should be analysed carefully in order to have realistic expectation with respect to impact of a MD surgery on the total disability of the patient. An absolute requirement for complication avoidance is a normal coagulation and bleeding status. Anticoagulating treatment or medications containing acetylsalicylic acid or nonsteroid anti-inflammatory drugs should be stopped 10–14 days before surgery and for a minimum of 2 weeks following surgery. Other chronic conditions such as hypertension, angina pectoris, heart failure, diabetes, etc., should be well controlled prior to surgery. Stereotactic Frame Complications due to head-mounting of the stereotactic frame are very rare. There have been anecdotical reports of epidural haematoma due to perforation of the calvarium by the pin, and also rarely, reports on skin infection at pin sites. More important is the pain during application of the frame and the vaso-vagal reaction provoked sometimes by the pain, and the feeling of tightness on the head, which, combined with the anxiety of the patient who may have not received enough local anaesthesia and definitely no sedatives, may lead to hyperventilation and syncope, and in few cases epileptic seizures. Leksell used to never attach the frame to the table, allowing for free movement of head and frame, should an epileptic seizure occur during surgery. While sedatives using benzodiazepine should not be given during the hours preceding surgery, a premedication of atropine and a mild nonsedative analgeticum can be administered prior to the careful mounting of the frame on the head.

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Stereotactic Imaging Air and/or contrast ventriculography have been the gold standard in functional sterotaxis to define the ventricular landmarks. Ventriculography is still used in many centres but does harbour risks for potentially severe complications. Air insufflation may provoke brain shift [11, 12] and may provoke confusions and headache, especially in elderly patients with ventricular dilatation [13, 14]. Positive contrast agents may provoke epileptic seizures to the extent that some authors recommended a few years ago that patients undergoing thalamotomy should be pre- and postoperatively medicated with antiepileptics [15]! Besides, haemorrhage has been described following insertion of cannulae into the ventricle during stereotaxis. Once a ventriculography is done, the surgeon should be well trained at, and confident in, identifying properly the anterior and posterior commissures of the third ventricle and should not only rely on ‘guidelines’ from companies that can be erroneous, as those depicted on page 7, figure 2, in the brochure ‘Activa Implant Technique Guide’ published by Medtronic in 1997 (Medtronic Neurological, Minneapolis, USA, 1997). Modern stereotactic imaging using CT and/or MRI harbours no complications in itself, except for its consequences on accuracy in hitting the target during surgery. Misalignments of frame in relation to the head and/or in relation to the gantry, incompatibility between frame and radiological method used, and possible geometrical distortions, especially when MRI is used, may have a harmful impact on precision in reaching a functional target at surgery. The same applies for inability of the surgeon to identify the classical ventricular landmarks on a CT or MRI study, and identify the stereotactic target and calculate its coordinates. Whatever the imaging method used, a stereotactic radiological study constitutes an integral part of the functional stereotactic surgery. It is sometimes the most difficult part of the surgery and should be the responsibility of the neurosurgeon. The following statement of Leksell [16] in 1988 should be kept in mind: ‘In clinical practice brain imaging can now be divided in two parts: the diagnostic neuroradiology and the preoperative stereotactic localization procedure. The latter is part of the therapeutic procedure. It is the surgeon’s responsibility and should be closely integrated with the operation’. Trephination Many surgeons use a twist drill, which may contribute to decreasing CSF leak through the burr hole during surgery, and thus, decreasing brain shift due to air entering the head. However, a ‘blind’ insertion of the electrode may damage a cortical vessel and provoke a subdural or subcortical haematoma. The present author uses a standard drill hole, 8 mm in diameter, on an elevated

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head. The dura should be opened just enough to allow visualization of the cortex to avoid cortical vessels when inserting the electrode, and to avoid contact between electrode and the edge of the opened dura during insertion. Eventual CSF leak is minimized by elevating the head and by applying some bone wax to the burr hole, once the electrode is at the target, or by using dedicated burr hole-plugging devices. Intraoperative Physiological Exploration Intraoperative physiological corroboration of the radiologically-defined anatomical target constitutes perhaps the most important step to prevent neurological complications in functional stereotaxis. Whatever the means of physiological exploration of the target, be it impedance monitoring, macrostimulation, microrecording, microstimulation, evoked potentials or microinjection of anaesthetic agent, one important prerequisite is that the involved surgeon is confident with the physiological technique used, and is able to interpret its results prior to lesioning. No surgeon should be ‘forced’ to use one technique instead of the other, unless fully confident in that technique. If macroelectrode is used, a proper impedance monitoring is very helpful in determining whether the probe tip lies in white or grey matter or in CSF space. A reliable stimulation response can be obtained by using a relatively thin probe, with a maximum noninsulated tip length and diameter of 2 mm, to ensure a location specificity of the stimulation. Multiple trajectories should be avoided if possible, unless one is forced to change the coordinates of the electrode due to untoward stimulation responses. In the Vim, macrostimulation with high frequency that stops the tremor without provoking untoward effects may be enough to ascertain a good position of the probe in the target area. Sometimes the responses of such stimulation procedure may be difficult to interpret, especially when stimulating in the pallidal area, where one can obtain no response at all from the target. In that case it may not be enough to stimulate for a few seconds, but instead, the intraoperative stimulation should be applied for several minutes at each target level to try to elicit a response from the various levels of the pallidal target. Macrostimulation in trained hands is often enough to verify that the probe does not lie in an adjacent structure such as the VPL-VPM complex, or in the motor internal capsule or in the immediate vicinity of the optic tract. Microelectrode-guided exploration may provide better surgical results, by selectively assessing the physiological properties of the cells in the target area aimed at. In some expert hands, the reported rate of complications using this technique has been very low [17, 18]. However, there have been some recent reports of an alarmingly high rate of severe complications, including severe haemorrhage, from some otherwise experienced centres using microelectrode

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tecniques [7, 8, 19–21]. Few centres have reported a nonnegligible rate of mortality [7, 8]. Part of these morbidities and mortalities may have resulted from the multitrajectories used during physiological exploration of the brain target, and it has been stated in various surveys by this author and by others that complications may become more frequent when microelectrodes are used than when surgery is performed only with macroelectrode guidance [23, 24]. These surveys of literature may, however, be biased by the fact that microelectrode groups tend to publish more frequently than nonmicroelectrode groups do. An additional risk of using microelectrodes in functional stereotaxis is that this technique prolongs undoubtedly the operating time compared to macroelectrode, which may increase the risk for infection. The risk for brain shift, if no special measures are taken to avoid CSF leak, will also increase: Vitek et al. [25] reported a postoperative death due to acute subdural haematoma in 1 of their patients who had a severe brain shift following microelectrodeguided pallidotomy. Regardless of physiological exploration technique, the fact is that if the surgeon is experienced in the technique used, good results and low complications rate will result, no matter if macroelectrodes [6, 26, 27] or microelectrodes [17, 18, 28] are used. Moreover, from a scientific research point of view, microelectrode techniques in careful and expert hands have contributed greatly to the understanding and knowledge of basal ganglia physiology in various MD [29]. In the clinical routine, it must be borne in mind that no matter which technique is used, the physiological exploration should not be conducted in absurdum: it is better to interrupt the surgery in time if a comprehensive exploration does not yield satisfactory answers, rather than stubbornly seek for the physiological target through a multitude of intersecting tracks in the brain in order to place a very proper lesion, at the risk of provoking a haematoma, and ending up obtaining a very well-placed pallidotomy lesion in a dead or hemiplegic patient. In MD surgery, the aim of physiological exploration is not only to assess the target structure and the effects of intraoperative stimulation on the symptom to be relieved by surgery, but also the side effect of stimulation on a multitude of other – normal – functions, that ought to remain normal and not be harmed during surgery. The following should always be assessed during intraoperative stimulation, and during and after each lesioning step at the target area: alertness, orientation, short-term memory, speech articulation and voice, swallowing, occurrence of nausea or dizziness, facial expression, limb strength, limb movements, limb dexterity, limb coordination, sensation at fingertips, cheek, tongue and lips, eye movements, vision and visual fields. A

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conversation should be kept with the patient who is asked to report if he/she feels anything special, anywhere in the body, during stimulation and during lesioning. Surgery should be stopped if any of the listed functions shows sudden decline or negative change that is not expected during surgery. Radiofrequency (RF ) Lesion RF power is the safest means to make a sterotactic lesion in surgery for MD. The size of the lesion is mainly influenced by the heating temperature and the size of the probe, all other parameters are equal. The rise of temperature during lesioning should not be too fast because it will provoke popping of tissue which may provoke a haematoma. The lesioning probe should not be too big; it is better to heat several small adjacent points in the target area, along the electrode track, than to use a big electrode (?3 mm in length or ?2 mm in diameter of noninsulated tip) for one single heating. Some authors advocate incremental heating, starting by a temperature of about 45 ºC to obtain a reversible inactivation of tissue and assess for effects and side effects following that low-temperature heating. Then they may proceed to ‘standard’ heating at temperatures varying between 70 and 85 ºC for making the final lesion. This procedure may add safety, especially if the stimulation responses prior to heating have been difficult to interpret. Other obvious steps to avoid complications during RF lesioning are the necessity to have a large indifferent electrode, an undamaged insulation of the lesioning electrode, and other measures of general electrical safety in operating theatres. Also of prime importance is to observe and assess the patient during RF lesioning and not only during the stimulation procedure. One main argument against using a Gamma knife for surgery of MD, apart from the total inability to physiologically assess the target prior to lesioning, is that a Gamma knife lesion cannot be stopped, should advese effects appear during lesioning. Gamma knife surgery’s adverse effects, due to oedema, radionecrosis and/or malplaced lesion may not appear before several months following the procedure. Deep Brain Stimulation The main argument advanced by proponents of DBS in movement disorder surgery is that this technique reduces the risk of complications. While lesions are virtually definite and irreversible, DBS is characterized by its reversibility and adaptability: By altering the electrical parameters or by switching off the stimulation, the side effects would disappear [28, 30, 31]. This is, however, not always the case. The specific complications and side effects of DBS according to the stimulated brain target will be detailed below in the section ‘Target-Specific Complications’. Generally speaking and compared to

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lesions, DBS techniques may harbour higher risks than lesions in some aspects: The risk for infection during DBS procedures is not negligible [20, 21], but is extremely rare in ablative surgery [32]. Intraoperative and postoperative antibiotics for up to 1 week after surgery may be recommended, surgical time should not be too long and, whenever possible, trial stimulation with externalized electrode should be avoided. Electrode break may happen, especially if the connection part between electrode and cable is placed in the upper area of the neck, below the mastoid, that is, at the level of C2–C3; if placed on the side of the head above the ear, skin erosion may occur or the connection may provoke pain when the patient lies on that side of the head. This complication is best avoided by placing the connection part on the calvarium not for from the burr hole. Dislocation of the electrode from the target may occur if the electode is poorly attached to the burr hole. Formation of seroma in the subcutaneous pocket receiving the pulse generator may occur if that pocket is made too large. Finally there are issues that, although not being strictly complications, should be taken into account when considering the overall side effects of DBS procedures: These issues include the high costs of the procedure, the (repeated) implant cost, length of surgery, length of stay in hospital, and the need for the patient to have several visits to the doctor in order to adjust the stimulation parameters in the weeks, months and years, following surgery [33].

Target-Specific Complications and Their Avoidance In surgery for MD, there are currently three different brain targets, on which RF lesions or DBS electrodes may be applied. The choice of target depends largely on the diagnosis and on the symptomatology of the patient. While the ventral intermediate nucleus (VIM) of the thalamus is the target of choice in essential tremor and tremor of other diseases, including PD, the posteroventral pallidum (PVP) or subthalamic nucleus (STN) are almost exclusively reserved for treating multisymptomatic advanced PD. Dystonia has recently been treated with lesions in the PVP [29]. This section will discuss those potential side effects and complications that are more or less specific to the specific nucleus or pathways that have been lesioned or stimulated – or even missed – at surgery. Needless to say that many of the listed complications, regardless of brain target, may often, but not always, result from malplaced lesions or DBS electrodes. Many of the listed side effects are indeed transient and will disappear a few weeks after surgery when the oedema around the lesion resolves, or when the stimulation parameters of the DBS electrode are modified. Finally, the occurrence or not

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of a complication does not always parallel the success or not of surgery on the symptom for which the patient has been operated. Speech, for example, can deteriorate markedly after a left-sided thalamotomy that has been otherwise very successful for tremor. The issue at task is to recognize the possible complication, inform the patient pre- and intraoperatively of its potential occurrence and try by all means to avoid its occurrence or minimize its impact on the patient’s disability. A comprehensive review of literature listing all possible and imaginable complications that have been reported through decades of stereotactic surgery is not only useless, but may require a book for itself. In the following, more or less common complications, deemed pertinent in the clinical routine, will be discussed.

Complications of Surgery on the Thalamus Thalamotomy Many complications of VIM thalamotomy appear generally during surgery or immediately after. Most but far from all complications are fortunately transient, lasting from 1 week to a couple of months. Some may require that patients receive rehabilitation and training by physiotherapists and occupational therapists to decrease the complication’s impact on the patient’s disability and to teach the patient how to cope with what remains of these unfortunate complications. Muscular hypotonia of the leg is not uncommon after thalamotomy, especially if the lesion encroaches on the subthalamic area and zona incerta area. This may lead to balance disturbances and tilting of patient towards operated side upon walking. This muscular hypotonia may be misinterpreted as a decrease in rigidity, or at worse as a paresis, but in fact it is an iatrogenic disturbance of the proprioceptive feedback of the contralateral leg muscles [34, 35]. The gait is perhaps the only motor function that cannot be assessed intraoperatively for obvious reasons, and therefore, a VIM thalamotomy should not extend below the level of the AC-PC line. Additionally, a VIM thalamotomy may increase bradykinesia and the freezing of gait of PD patients. A too anterior and/or too medial VIM thalamotomy, or even a ‘wellplaced’ thalamotomy may provoke contralateral hemi-inattention and/or ideomotor dyspraxia, leading to the paradoxical and often observed fact that a tremor patient does not spontaneoulsy use his/her contralateral hand and arm postoperatively despite absence of tremor. VIM thalamotomy may provoke deficit in hand proprioception leading to impairment or decrease in ability for fine motor movements like writing.

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Short-term memory decrease, either verbal or visual, may result from VIM lesions in the respective hemisphere. Even a slight encroachment of the VIM lesion on internal capsule may provoke paresis, dysphonia, or dysphagia, and if in dominant hemisphere, dysarthria is not uncommon. Encroachment of lesion on sensory thalamus may provoke numbness and in worst cases a syndrome of severe deafferentation pain in contralateral fingers, hand and face. Confusion and disorientation, usually transient, are not uncommon following VIM thalamotomy in elderly patients and in patients with ventricular dilatation. DBS on the Thalamus DBS on the VIM may result in several – sometimes nonadjustable – complications: Development of tolerance, and appearance of tremor rebound when turning off stimulation, are two issues that are more common than previously thought [36] and may have not been enough addressed in the literature. Invariably all patients with VIM stimulation will need incremental increase of current parameters, sometimes over several months and beyond, to maintain the initial effect of this surgery on tremor [33]. In some patients who have had stimulation for several months, the tremor may become much worse upon shutting off stimulation than it was before surgery, a worsening definitely not due to any progression of the disease, but to the very chronical stimulation. This will lead to the patient maintaining stimulation on, day and night without interruption, which will contribute to more tolerance and eventually more increase of voltage, and thus, will provoke more rebound upon attempt to shut off stimulation. This vicious circle may be avoided by an as low as possible stimulation voltage and by asking the patient to turn off the stimulator at night and sustain the often temporary rebound of tremor that will decline within 30–60 min, eventually helped by a light sedative before sleep. VIM DBS if too posteriorly placed will provoke sensory paresthesias in fingers and lips; if too laterally or too deeply placed, it will provoke muscular cramp, dysarthria, gait and balance disturbances, and dizziness. These symptoms may of course decrease if stimulating current voltage or pulse width are decreased or if electrode polarity is changed, but sometimes at the costs of diminished effect on the tremor! Rarely VIM DBS will result after some time in the appearance of a new movement disorder in the form of a low-frequent proximal tremor, or ataxia of the arm that is more disabling for the patient than the original tremor itself. This complication is not adjustable and appears only when the stimulation is

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turned on. The author has no explanation for this phenomenon other than it may result from a too medial and/or too deep placement of the electrode in the ventrolateral thalamus. VIM DBS may also provoke contralateral impaired proprioception, dyspraxia, increased akinesia and decrease in fine motor movement abilities, during stimulation. Bilateral Thalamic Surgery Bilateral lesions on the thalamus should be avoided, even if staged. Up to 50% risk of dysarthria has been reported [30] not to mention the risks for impaired balance and memory. Bilateral DBS procedures can safely be done, even in one session. Also quite safe is bilateral surgery involving a thalamotomy on one side (preferably the nondominant side) and DBS on the other side. In both these instances, however, there might be risk for dysarthria, more pronounced if one side of the brain includes a lesion than if both sides are chronically stimulated [27, 28]. Finally, a ‘complication’ worth mentioning in thalamic surgery is the observed phenomenon that an ipsilateral tremor may become worse following unilateral thalamotomy or thalamic DBS. This phenomenon, almost not mentioned in the literature, is difficult to explain rationally and is neither due to progression of disease nor to the fact that the ipsilateral tremor that became worse after surgery did exist before albeit ‘hidden’ by the dominating tremor of the contralateral hand before surgery. The author has observed several times this phenomenon when a DBS patient is asked to turn off the stimulator: While the previously stimulated hand starts then to shake, the less obvious shaking of the ‘nonoperated’ hand ceases. When the patient is asked to turn the stimulator on, the contralateral hand tremor stops abruptly, and at the same time tremor of the previously nontremorous ipsilateral hand appears. This has led to many patients requiring surgery for the other hand soon after the first – successful – procedure.

Complications of Surgery on the Pallidum Pallidotomy Generally speaking, the risks of pallidotomy are less than those of thalamotomy. This surgery is better tolerated by elderly patients, despite their being in more advanced stages of PD than the typical ‘thalamotomy patient’, and despite the average pallidotomy lesion being larger than the average thalamotomy lesion [38, 39]. Besides, many of the side effects of pallidotomy are usually transient. However, unlike after thalamotomy where complications

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appear generally immediately during surgery, many of pallidotomy’s complications may become evident days or weeks after surgery. Cognitive impairment following pallidotomy has been debated. It seems that if the lesion is too medial, anterior and dorsal in the pallidum, the risk for cognitive and memory impairment is greater [40]. It must be remembered that the anterior dorsal medial pallidum is involved in cognitive striatolimbic fibres and should therefore not be damaged by a lesion that should remain in the sensory motor posteroventral pallidum. Nevertheless, the battery of tests usually applied in testing cognition of postpallidotomy patients is exhaustive and might detect many subclinical impairments. However, in the clinical routine, and in the daily life of the patient, these discrete impairments may not be noticeable, though. A safe rule is not to perform pallidotomy on any patient with clinically relevant cognitive or memory decline and to avoid including dorso-medio-anterior parts of the pallidum in the lesion. Weight gain, euphoria, and depression have been described following pallidotomy [18]. Weight gain is very common, and is most likely due to a radical decrease in the violent dyskinesias, rather than result from some behavioural disturbance. The author has observed patients who gained weight after a successful pallidotomy, then had a recurence of dyskinesias that provoked a new sustained weight loss, before they eventually came back to have a repeat surgery. Weight gain may therefore not even be a complication of pallidotomy since many PD patients with advanced dyskinesias either have difficulty feeding themselves or do lose such an amount of energy when dyskinetic that they lose weight and become sometimes cachectic before coming to surgery. Euphoria too is not uncommon following pallidotomy. This might be attributed to mood changes following this surgery and often is something positive for the patient. Depression on the other hand is a true complication requiring sometimes psychiatric expertise [39] and may not be related to the results of surgery on the motor symptoms of the patient. The optic tract is at risk during pallidotomy. In the initial experience of Laitinen et al. [27] there were 14% injury to the optic tract resulting in scotomas or homonymous inferior quadrant anopsia. This risk has decreased to less than 1% in the further experience of that author and his co-workers [41, 42]. The ideal target is typically very ventral at the base of the posterior pallidum while the optic tract runs just inferior and slightly medial from that targeted area. Careful macrostimulation performed millimetre by millimetre, evoked potentials and microrecording, are all means to judge the proximity of the lesioning electrode to the optic tract. When using macrostimulation, this author has, as learned from Laitinen [43], changed the approach to the pallidum in such way that stimulation and coagulation are performed incrementally from dorsal to ventral instead of vice versa as was the case in the initial experience.

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This modification permitted to avoid thus an approach that would take the electrode first to the vicinity of the optic tract and then dorsally, which would result in a CSF channel between the optic tract and the electrode, leading heat to the optic tract when coagulation is performed from ventral to dorsal. Finally, even though all measures may have been taken to ensure integrity of optic tract, including meticulous microelectrode work, injury to it may still occur [44]. Therefore, the author recommends as an additional measure, a modified Donder manoeuvre to be performed also during each coagulation procedure of the ventral pallidal area. For this, the patient should still be alert and not have become very tired and therefore unreliable, in the course of a too long and tenuous surgery. Delayed stroke is a typical, although rare, complication of pallidotomy [39, 45], that has not been described to happen following thalamotomy. It may occur several days or weeks following a successful pallidotomy and may lead to hemiparesis and dysarthria. It may be due to progressive obliteration of small branches of the anterior choroidal artery. Avoiding to make a too large and too medial lesion may decrease the risk of this particular complication. Dysarthria and dysphonia may result from pallidotomy on either hemisphere, especially if the lesion encroaches on the internal capsule. Paresis, however, is a rare complication, even if the posteroventral pallidal lesion encroaches on the internal capsule because the capsule at the level of the medial ventral and posterior pallidum is not as much ‘motor’ as at the level of the more dorsally and more posteriorly located ventrolateral thalamus. Confusion and gait or balance distrubances are rare and in any case much less common than following thalamotomy. DBS on the Pallidum Pallidal DBS is by far less commonly performed than pallidotomy as evident from the relatively low amount of publications and from the much lower number of reported patients, even by those who only perform DBS procedures for movement disorders [46]. ‘Complications’ specific to pallidal DBS are usually rare, mostly reversible, and highly dependent on which electrode contacts happen to be activated. Increase in akinesia has been reported by Bejjani et al. [47] and by Krack et al. [46] when stimulation is delivered by the most ventral contact of the quadripolar electrode. This observation led to various theories about the mode of action of DBS at the pallidal level, in which, unlike at the thalamic level, a chronic high-frequency stimulation does not necessarily mimic a lesion, as far as effects on the symptoms are concerned. Although not a complication properly speaking, this peculiar and unexpected side effect of chronic stimulation is definitely of no help for the cardinal symptom, i.e. akinesia, for which

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the surgery was intended. In this author’s opinion, this increase of akinesia when stimulating the most ventral and medial pallidum may very well be due to propagation of the electrical current to the internal capsule medial and posterior to the target. Since high-frequency stimulation of internal capsule fibres is known to provoke tetanic cramp, it is theoretically possible that stimulation through the most ventral contact, especially if this is located at the lower posterior and medial edge of the pallidum and often below it – as in some of the cases described by Krack et al. [46] – may lead to activation of some motor internal capsule fibres provoking a more difficult initiation and performance of movement, i.e. a state of increased akinesia. On the other hand, more dorsal contacts of the pallidal electrode have been described to improve akinesia, but at the cost of less effect on dyskinesias [46, 47]. Induction of visual, motor, gait, or speech disturbances during DBS on the pallidum are likely to happen if the stimulated contact lies close to optic tract or internal capsule, respectively. Bilateral Pallidal Surgery Bilateral pallidotomies, either in one surgical session [48] or in a staged fashion [41], have been described. In recent years there have been warnings from many workers against bilateral pallidotomies because of highly increased risks for dysarthria, dysphonia and dysphagia. The following complications are according to this author, more or less specific for bilateral procedures: Increased drooling of saliva is more frequent when bilateral, even staged, pallidotomy is done. This symptom does not seem to be related to any otherwise impaired swallowing and is also unpredictable. Anticholinergics may help if this complication occurs. Worsening of dysarthria and dysphonia is not uncommon. Therefore a bilateral second pallidotomy should be avoided if the first surgery resulted in a noticeable decrease of voice strength and speech articulation, or if the progression of disease itself has brought up such a worsening of these symptoms. A contralateral DBS on the pallidum may then be preferable. Dysphagia is more likely to happen if corticospinal fibres have been involved bilaterally in the pallidotomy lesions. This may be the case when the pallidotomy lesions are directed at the most medial pallidum risking to include parts of the adjacent internal capsule. That is why Burchiel et al. [49], among others, did recommend to place the second pallidotomy more laterally than the first (contralateral) one, if bilateral surgery is to be done. The present author considers bilateral staged pallidotomy, with a minimum of 6 months between the two procedures, to be relatively safe, provided preoperative speech performance is good and provided integrity of internal capsule is respected [38].

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Bilateral pallidal DBS, even performed in one session, does not seem to carry any specific risk for complications aside from that of a unilateral DBS procedure [46, 47].

Complications of Surgery on the STN STN Ablation Ablative surgery on the STN has been performed in the pre-dopa era of stereotactic surgery but was soon abandoned due to the many reported complications, especially the development of hemiballism after surgery. In recent years, following better understanding of basal ganglia pathophysiology in PD, the role of the STN as the major movement-inhibiting output structure in PD led first in animals, then in humans, to treatment of the parkinsonian symptoms by inactivation of parts of the STN. The Grenoble group in France [50] published the first reports of DBS in STN in 1993 with remarkable results on all cardinal PD symptoms, and Gill [51] in Bristol, UK, published the first modern report in 1995 about RF lesioning of the dorsolateral STN leading to similar spectacular results. Since then, very few reports on STN lesioning have been presented, while a great multitude of abstracts on STN stimulation have been reported, notably at the latest meeting of the Movement Disorders Society in New York in October 1998. This bears witness to the fact that the stereotactic community is still reluctant to ablate a target like the STN, even though Obeso is reported to consider STN lesion as a future innovative surgical technique in the treatment of PD [Moving Along, A Movement Disorders Society Update, vol. 1, issue 2, 1998, p. 7, edited by Bill Koller and Eduardo Tolosa]. STN Stimulation STN stimulation is almost always performed bilaterally and in one session. ‘The risk cannot be minimized but the benefit is substantial’ stated Obeso in a recent abstract presenting preliminary experience from the ongoing multicentre STN DBS study [20]. Specific documented side effects, and other not yet fully documented, potential complications in STN DBS are listed below: Increased dyskinesias: This was first described by Limousin et al. [52] in 1996. However, most successful STN stimulation procedures will lead to a radical decrease in L-dopa doses, which in turn will decrease dyskinesias [53, 54]. The problem will arise if STN stimulation on one side is successful but not the other side. Then it may be difficult to manage that patient medically to avoid dyskinesias and yet provide a good motor status for the body side contralateral to the failed stimulation.

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Blepharospasm or so-called ‘eyelid-opening apraxia’ [53]: This has been a common complication reaching 25% of the patients according to Limousin et al. [53], necessitating sometimes the use of botulinum toxin injections into the patient’s eyelids to help him/her keep eyes open while STN stimulation is on [36]. There is no satisfying explanation to this phenomenon. Confusion and cognitive and memory impairment: The medial part of the STN is involved in cognition [H.J. Groenewegen: Functional anatomy of the basal ganglia; Proc. Second Workshop on Treatment in Parkinson’s Disease, Utrecht, The Netherlands, Nov. 20, 1998]. Therefore, DBS in STN should avoid the medial part of this relatively narrow nucleus, which is not always easy. Regardless of which part of the STN has been targeted, postoperative confusion, sometimes lasting for several weeks, has not been uncommon [53, 55]. Even long-standing memory and cognitive impairement have been described [53]. Possible explanations for the frequent confusional states may be that the surgery is almost always simultaneously bilateral, the medial STN may sustain some damage during extensive exploration, and the intraoperative exploration of the target necessitates that the electrodes traverse the anterior medial thalamus on their way to the STN, which would damage these areas of thalamus partly involved in cognitive functions. A way to decrease such a complication would be to never operate on the STN if the patient presents any memory or cognitive decline preoperatively and, in noncognitively affected patients, to avoid the medial STN, to avoid multiple electrode passes en route to the target area, and to avoid extensive microelectrode mapping by using appropriate MRI procedures, as suggested just recently by workers very expert in microelectrode techniques such as Kelly [56] and Starr and co-workers [57] from the Emory group. Hypersalivation: As for bilateral pallidotomy, bilateral STN stimulation may carry a risk for increased salivation, that is not necessarily due to swallowing difficulties. Here also anticholinergics may help, but they may predispose the patient for increased risk of confusion. Dysphonia/aphonia and dysarthria/anarthria: This is a seldom reported complication although it is unofficially acknowledged that it is by no means a rare complication. Bilateral STN stimulation may affect negatively the ability to articulate speech properly and may decrease the voice strength, in a significant proportion of bilaterally STN-stimulated patients. Even though voice and speech articulation are already affected by the very disease in the first place, and may fluctuate according to the patient being in ‘on’ or ‘off’ state, care should be taken not to neglect this side effect when providing information to the patient preoperatively. Bilateral STN stimulation should not be offered if the patient presents significant impairment of voice and articulation preoperatively when in ‘on’ state.

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Unknown complications: Since DBS in STN is relatively new, since its proponents are extremely enthusiastic because of its striking positive impact on the motor aspects of PD patients, and since this surgery has so far not been scientifically reported from more than a handful of centres worldwide, although many in the stereotactic community seem to be performing it (see Worldwide Medtronic Survey for DBS implants in 1997, London, UK), it is expected that more complications specific to this procedure may eventually appear and its long-term safety will be better judged in due time.

Conclusions Reviewing the literature, it appears that complications and pitfalls of surgery for MD are not uncommon. Fortunately, many may be considered light complications and most of them are transient. Surgical treatment for MD may require several operations and or/reoperations, as well as a long follow-up: The disease, especially PD, is progressive; some symptoms may recur postoperatively or/and new symptoms may appear successively in the course of the disease; the symptoms are often bilateral and may respond unevently to the various surgical procedures. These facts have to be made clear for the patient and have consequences for the individual patient in terms of potential and sometimes additive complications following each surgery and for the neurosurgeon and the neurologist in terms of dedication, analysis of consequences and of risk-benefit of each surgery for each particular patient, and ‘workload’ spent on every patient. This includes awareness of each potential complication at each step of the surgical procedure from preoperative patient selection to long-term postoperative patient assessment; critical analysis of each failure or symptom recurrence, and comprehensive clinical and radiological assessment of each complication following each surgical procedure. ‘Primum nil nocere’ should be the permanent leitmotiv of each neurosurgeon embarking on surgery of MD.

References 1 2 3 4 5

Nashold BS Jr: Stereotactic neurosurgery: The present and the future. Am Surg 1970;36:85–93. Spiegel EA: History of human stereotaxy (stereoencephalotomy); in Schaltenbrand G, Walker AE (eds): Stereotaxy of the Human Brain. Stuttgart, Thieme, 1982, pp 3–10. Kelly PJ, Gillingham FJ: The long-term results of stereotaxic surgery and L-dopa therapy in patients with Parkinson’s disease. A 10-year follow-up study. J Neurosurg 1980;53:332–337. Nashold BS Jr: Operative complications due to stereotactic surgery. Confin Neurol 1968;30:325–336. Selby G: Stereotactic surgery for the relief of Parkinson’s disease. 2. An analysis of the results in a series of 303 patients (413 operations). J Neurol Sci 1967;5:343–375.

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Svennilson E, Torvik A, Lowe R, Leksell L: Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Neurol Scand 1960;35: 358–377. Samuel M, Caputo E, Brooks DJ, Schrag A, Scaravilli T, Branston NM, Rothwell JC, Marsden CD, Thomas DGT, Lees AJ, Quinn NP: A study of medial pallidotomy for Parkinson’s disease: Clinical outcome, MRI location and complications. Brain 1998;121:59–75. Shannon KM, Penn RD, Kroin JS, Adler CH, Janko KA, York M, Cox SJ: Stereotactic pallidotomy for the treatment of Parkinson’s disease. Efficacy and adverse effects at 6 months in 26 patients. Neurology 1998;50:434–438. Folstein MF, Folstein SE: ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. Kokmen E, Naessens JM, Offord KP: A short test of mental status: Description and preliminary results. Mayo Clin Proc 1987;62:281–288. Hariz MI, Bergenheim AT: A comparative study on ventriculographic and computed tomographyguided determinations of brain targets in functional stereotaxis. J Neurosurg 1990;73:565–571. Hariz MI, Bergenheim AT, Fodstad H: Air-ventriculography provokes an anterior displacement of the third ventricle during functional stereotactic surgery. Acta Neurochir 1993;123:147–152. Hariz MI, Bergenheim AT: Clinical evaluation of CT-guided versus ventriculography-guided thalamotomy for movement disorders. Acta Neurochir Suppl 1993;58:53–55. Siegfried J, Zumstein H: Thalamotomies ste´re´otaxiques pour troubles fonctionnels chez les personnes aˆge´es. Neurochirurgie 1976;22:536–539. Fox MW, Ahlskog JE, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991;75:723–730. Leksell L, Leksell D, Schwebel J: Stereotaxis and nuclear magnetic resonance. J Neurol Neurosurg Psychiatry 1985;48:14–18. Alterman RL, Sterio D, Beric A, Kelly PJ: Microelectrode recording during posteroventral pallidotomy: Impact on target selection and complications. Neurosurgery 1999;44:315–323. Lang AE, Lozano AM, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:1036–1042. Linasazoro G, Guridi J, Gorospe A, Ramos E, Mozo A, Obeso JA: Posteroventral pallidotomy in Parkinson’s disease: Clinical results in 27 patients (abstract). Mov Disord 1996;11(suppl 1):240. Obeso JA, for the Deep Brain Stimulation in Advanced Parkinson’s Disease Study Group: Deep brain stimulation of the subthalamic nucleus in advanced Parkinson’s disease (abstract). Mov Disord 1998;13(suppl 2):303. Lang AE: Long-term effect of pallidotomy and DBS of GPi in Parkinson’s disease (abstract). Mov Disord 1998;13(suppl 2):18–19. Rodriguez-Oroz MC, Gorospe A, Guridi J, Ramos E, Linazasoro G, Obeso JA: Chronic stimulation of the subthalamic nucleus and globus pallidum internum in the treatment of Parkinson’s disease (one-year follow-up) (abstract). Mov Disord 1998;13(suppl 2):304. Carrol CB, Scott R, Davies LE, Aziz T: The pallidotomy debate. Br J Neurosurg 1998;12:146–150. Hariz MI, Bergenheim AT, Fodstad H: Crusade for microelectrode guidance in pallidotomy (letter to the editor). J Neurosurg 1999;90:175–177. Vitek JL, Bakay RA, Hashimoto T, Kaneoke Y, Mewes K, Yu Zhang J, Rye D, Starr P, Baron M, Turner R, DeLong MR: Microelectrode-guided pallidotomy: Technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998;88:1027–1043. Kondziolka D, Bonaroti E, Baser S, Brandt F, Kim YS, Lunsford LD: Outcomes after stereotactically guided pallidotomy for advanced Parkinson’s disease. J Neurosurg 1999;90:197–202. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin P, Gay E, Payen I, Benazzouz A: Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 1996;84:203–214. Lozano AM, Kumar R, Gross RE, Giladi N, Hutchison WD, Dostrovsky JO, Lang AE: Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997;12:865–870.

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Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998;49:145–154. Tasker RR, Munz M, Junn FSCK, Kiss ZHT, Davis K, Dostrovsky JO, Lozano AM: Deep brain stimulation and thalamotomy compared. Acta Neurochir Suppl 1997;68:49–53. Hood TW, Yap JC: A survey of infections in stereotactic surgery. Appl Neurophysiol 1981;44: 314–319. Shamsgovara P, Hariz MI: Changes of electrical parameters over time in chronic thalamic stimulation for tremor (abstract). Mov Disord 1998;13(suppl 2):73. Struppler A: Stereoencephalotomy and control of skeletal muscle tone. Stereotact Funct Neurosurg 1990;54/55:136–139. Van Manen J: Postural instability after ventrolateral thalamic lesions; in Gillingham FJ, Donaldson IML (eds): Third Symposium on Parkinson’s Disease. London, Livingstone, 1969, pp 237–241. Fogel W, Kronenbuerger M, Tronnier VM, Eifert B, Meinck HM: Tremor rebound as a side-effect of thalamic stimulation for suppression of tremor (abstract). Mov Disord 1998;13(suppl 3):139–140. Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, Perret JE, De Rougemont J: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406. Hariz MI: Controversies in pallidal surgery. Acta Neurochir Suppl 1997;68:1–10. Hariz MI, DeSalles AAF: The side-effects and complications of posteroventral pallidotomy. Acta Neurochir Suppl 1997;68:42–48. Trepanier LL, Sait-Cyr JA, Lozano AM, Lang AI: Neuropsychological consequences of posteroventral pallidotomy for the treatmment of Parkinson’s disease. Neurology 1998;51:207–215. Laitinen LV: Pallidotomy for Parkinson’s disease. Neurosurg Clin North Am 1995;6:105–112. Laitinen LV, Hariz MI: Movement disorders; in Youmans JR (ed): Neurological Surgery, ed 4. Philadelphia, Saunders, 1996, pp 3575–3609. Laitinen LV: Ventroposterolateral pallidotomy for Parkinson’s disease: Technical aspects. Funct Neurosurg 1994;33:14–16. Biousse V, Newman NJ, Carroll C, Mewes K, Vitek JL, Bakay RAE, Baron MS, DeLong MR: Visual fields in patients with posterior Gpi pallidotomy. Neurology 1998;50:258–265. Lim JY, DeSalles AAF, Bronstein J, Masterman DL, Saver JL: Delayed internal capsule infarctions following radiofrequency pallidotomy. J Neurosurg 1997;87:955–960. Krack P, Pollak P, Limousin P, Hoffmann D, Benazzouz A, Le Bas JF, Koudsie A, Benabid AL: Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43:180–192. Bejjani B, Damier P, Arnulf I, Bonnet AM, Vidailhet M, Dormont D, Pidoux B, Cornu P, Marsault C, Agid Y: Pallidal stimulation for Parkinson’s disease. Two targets? Neurology 1997;49:1564–1569. Iacono RP, Shima F, Lonser RR, Kuniyoshi S, Maeda G, Yamada S: The results, indications and physiology of posteroventral pallidotomy for patients with Parkinson’s disease. Neurosurgery 1995; 36:1118–1127. Burchiel KJ, Favre J, Taha J: Pallidotomy for Parkinson’s disease: Surgical technique and results (abstract). J Neurosurg 1996;84:336A. Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret J: Effects de la stimulation du noyau sous-thalamique dans la maladie de Parkinson. Rev Neurol 1993;149:175–176. Gill SS, Heywood P: Bilateral dorsolateral subthalamotomy for advanced Parkinson’s disease. Lancet 1997;350:1224. Limousin P, Pollack P, Hoffman D, Benazzouz A, Perret JE, Benabid AL: Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients. Mov Disord 1996; 11:231–235. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–1111. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995;345:91–95.

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Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, Lang AE: Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998;51:850–855. Kelly PJ: Comments. Neurosurgery 1999;44:314. Starr PA, Vitek JL, DeLong M, Bakay RAE: Magnetic resonance imaging-based stereotactic localization of the globus pallidus and subthalamic nucleus. Neurosurgery 1999;44:303–313.

Marwan I. Hariz, MD, PhD, Department of Neurosurgery, University Hospital, S–901 85 Umea˚ (Sweden) Tel. +46 90 785 00 00, Fax +46 90 12 24 48, E-Mail [email protected]

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Neuropsychological Considerations in Movement Disorder Surgery1 Jean A. Saint-Cyr a–c, Lisa L. Tre´panier c, d Departments of a Surgery and b Psychology, University of Toronto; c Playfair Neuroscience Unit, The Toronto Western Hospital, and d Department of Psychology, York University, Toronto, Ont., Canada

The resurgence of neurosurgical interventions for the treatment of selected patients with movement disorders has brought dramatic symptomatic relief to many patients [1, 2]. The careful selection of suitable candidates remains the most important factor in ensuring a successful outcome. Neurological screening permits the elimination of those patients who are known not to benefit from these procedures (e.g. patients who do not respond to L-dopa). From a neuropsychological perspective, one would want to eliminate patients from consideration if there is a risk of dementia or psychiatric disturbance [3, 4]. If a patient were to become agitated or confused during the surgical procedure, there is a fair chance that the operation would be unsuccessful, or even cause iatrogenic harm (e.g. loss of visual field, paralysis due to inaccurate feedback to surgeon), if it could be completed at all. Postoperatively, the patient at risk because of cognitive weaknesses, could become significantly impaired and unable to fully benefit from the expected motor improvement. Psychiatric complications might ensue in other patients due to decompensation brought about by the stress of the procedure or because of interactions between lesion location and organic predisposition. Patients and families with unrealistic expectations concerning outcome, may also emerge disappointed. It is also useful to have a videotape showing the surgical procedure to patients in order for them to fully appreciate what awaits them. 1

Supported by The Parkinson Foundation of Canada.

Assessment A full history and clinical interview, often including caregivers is essential. Patients are questioned concerning preexisting conditions of both a cognitive and behavioral nature. For example, claustrophobic reactions, anxiety and panic reactions, stress tolerance (e.g. during long dental procedures), prior experience with MRI, or adverse reactions to medications or to their withdrawal, must be noted. Patients with a risk of panic attack (including hyperventilation syndrome or history of syncope) must be identified to prepare the OR staff for such events. For anxious patients, systematic relaxation exercises, education and supportive counselling 1–2 days prior to surgery has proved to be beneficial. A nurse known to the patient or the neuropsychologist may also elect to provide reassurance during the procedure. In addition, subtle early signs of dementia such as word-finding, confusional states, personality change, or recent decline in memory are explored. Specifically, the psychometric portion of the cognitive and personality assessment follows [see 3–6 for test specifics]. Premorbid intellectual capacity is estimated using convergent information from education and work history, as well as instruments such as the New Adult Reading Test – Revised (NART-R) or the Barona Index [6]. Compared against this estimation, current intellectual capacity is measured with a structured instrument such as the Wechsler Adult Intelligence Scale (WAIS-III) [6] – (verbal section to make allowances for motor impairment) or the Kaufman Brief Intelligence Test (K-BIT) [5, 6]. Test results should conform with the expected cognitive profile of PD [7, 8]. Modest decreases in tasks of problemsolving and working memory are normal in PD but any significant weaknesses in intellect, attention, memory, word-finding or frontal executive functions, including judgment, must be taken seriously as the surgery might further reduce those capacities that rely on the functional integrity of frontostriatal circuitry [3, 4, 9]. Attentional capacity should be relatively normal unless very demanding tasks are used. Digit spans are normal while the Trail Making Test should only be moderately slowed, largely as a function of bradykinesia. Bradyphrenia is not expected in PD but there may be an impression of slowed thinking or response speed in certain tasks (allowances must be made for bradylalia). Lapses of attention, distractibility and fluctuating state of alertness may be due to a host of factors including medications, poor sleep pattern, on-off periods, bouts of dyskinesia or freezing and task demands. In some cases, a fluctuating pattern may signal the presence of Lewy body disease [10]. Language functions, apart from hypophonia and some reduced flexibility for complex or effort-demanding processing, are expected to be normal. Only

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modest declines in letter and category fluency are expected [11]. Any significant difficulties may be indicative of a dementing process [12]. Confrontational naming (i.e. Boston Naming Test) should be normal. Memory in PD is characterized by poor implicit encoding of supraspan information [7, 8, 13] with free recall scores about 1 SD below predicted levels but normal recognition. Memory for nonverbal information is typically more problematic. This is partly due to the inherently less familiar and abstract nature of the material but also because testing often involves drawing and other visuomotor skills which may be impaired [8]. The unavoidable distraction caused by dyskinesias, freezing, and micrographia, for example, tax the patient’s capacity to focus fully. Visual-spatial working memory abilities are more at risk in PD [14]. In addition, working, prospective and procedural memory, as well as memory for sequences, source and temporal order are expected to be modestly impaired [7, 8, 13]. Executive functions, which are reliant on the functional integrity of frontal-striatal circuitry, are recognized as being particularly vulnerable in PD [7, 8, 13]. Specifically, deficits in novel problem-solving are expected and difficulties are often encountered when forming or switching mental sets. Behavior and mood state are affected in PD. Depression is quite common (40–60%), being attributable to a combination of organic (e.g. lability, monoamine loss) and reactive factors (e.g. a function of symptom severity and limitations in ADL) [15, 16]. Anhedonia, lack of initiative, and social withdrawal are also quite common. Severity may range from lability to a ‘psychic akinesia’. The Geriatric Depression Inventory [6] and the Frontal Lobe Personality Scale (FLOPS) [3, 4] have been quite useful in detecting changes in depression, apathy, disinhibition, or executive functions. Because of loss of insight, denial or the wish to appear more functional to guarantee acceptance for surgery, caregivers must also be questioned closely with regard to the patients’ behavioral capacity and changes. The State Trait Inventory [6] may also be helpful to examine the pervasiveness of anxiety. In general, executive and frontal behavioral impairment should correspond with the state and severity of disease. Unusually high levels of impairment would be considered too risky for surgery.

Outcome Lesions of the GPi (PVP) are typically made unilaterally and result in hemisphere-specific cognitive costs [3, 4]. Specifically, left hemisphere lesions cause long-lasting impairments in controlled verbal fluency and loss of verbal learning and memory capacity by about 1–2 SD in 60% of our sample. Younger

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patients with higher intellectual capacity are generally well protected from such an impact. Right hemisphere lesions result in diminished visual-spatial constructional and mnemonic processes but these changes are usually clinically irrelevant to the patient. If tests are carefully selected, a diminution of frontalexecutive capacity can be demonstrated [9] but this is not always apparent [3, 4]. Some tasks may not reveal changes due to floor effects. It is suspected that many of those functions dependent on the integrity of frontostriatal circuits, may already have been partly taken over by other brain regions prior to surgery [17]. Within the GPi, differential cognitive decline is location-specific with more anteromedial lesions resulting in greater cost [21]. Bilateral lesions, even if made in two stages, may result in significant cognitive and behavioral impairment, even in patients with a prognostically optimistic profile [4]. Patients with unilateral lesions present with behaviorally significant personality changes in 25–30% of cases [3]. These changes are usually amplifications of preexisting personality features but may also be quite out of character. Disruption of frontostriatal functions are thought responsible, as well as nonspecific stress on the organism due to the intervention (i.e. edema, electrode tracks). In severe cases, usually but not exclusively after bilateral lesions, environmental dependency and utilization behaviors have been noted [3, 4]. Impulsivity, poor judgment, disinhibition and loss of insight are relatively common [3, 4]. The latter makes the identification of these problems difficult if only the patient’s opinion is solicited. Typically, such patients are delighted with the clinical neurological outcome since their dyskinesias have been virtually eliminated. Due to their newly recovered motor control, they are eager to resume previously enjoyed activities. Unfortunately, they may no longer have the cognitive capacity or social judgment necessary and so difficulties arise, ranging from social embarrassment to physical and financial consequences. The advent of deep brain stimulation (DBS) and the target choice of the subthalamic nucleus (STN), rather than the GPi, have resulted in changed expectations with regard to outcome [18]. With the STN-DBS group, patients typically experience a period of confusion postoperatively lasting a few days to 2 weeks [19]. Once DBS parameters have been stabilized and optimized, neurological response is favorable [19]. Patients aged 65 years or younger are the norm for this surgery and they do well with few, if any complaints [20]. Patients aged 70 or older may fall prey to a PSP-like syndrome of reduced arousal and capacity [4]. Systematic studies comparing GPi vs STN placements have yet to be done but the first publications report comparable results in the two groups [4, 5]. One disturbing result has been the elicitation of severe depression with onset of STN-DBS, with at least one suicide and a few attempted cases [unpubl. observations].

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Conclusion Clearly, neurosurgical interventions in the treatment of movement disorders have resulted in a significant reduction of symptoms and improved independence and quality of life for most carefully selected patients. However, these procedures do carry some risk for iatrogenic sequelae (beyond the expected 2% rate of surgical complications such as hemorrhage) [2] despite our best efforts at screening and evaluation [3, 4]. The neuropsychological assessment must be considered essential to minimize such risks and to help manage patients postoperatively, to counsel families and to further our understanding of the underlying neurobiology and psychological impact of these treatments. As new therapies, such as GDNF or other neurotrophic substance infusions, transplantations or eventually molecular biological approaches are developed, neuropsychologists will play an increasingly important role in the evaluation of their outcomes. References 1 2 3 4

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Lang AE, Lozano AM: Parkinson’s disease: First of two parts. N Engl J Med 1998;339:1044–1053. Lang AE, Lozano AM: Parkinson’s disease: Second of two parts. N Engl J Med 1998;339:1130–1143. Tre´panier L, Saint-Cyr J, Lozano A, Lang A: Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson’s disease. Neurology 1998;51:207–215. Tre´panier LL, Kumar R, Lozano AM, Lang AE, Saint-Cyr JA: Neuropsychological outcome of neurosurgical therapies in Parkinson’s disease: A comparison of GPi pallidotomy and deep brain stimulation of GPi or STN. Brain Cogn (special issue) 2000, in press. Tro¨ster AI, Fields JA, Wilkinson SB, Pahwa R, Miyawaki E, Lyons KE, Koller WC: Unilateral pallidal stimulation for Parkinson’s disease: Neurobehavioral functioning before and 3 months after electrode implantation. Neurology 1997;49:1078–1083. Spreen O, Strauss E: A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary, ed 2. New York, Oxford University Press, 1998. Taylor AE, Saint-Cyr JA, Lang AE: Frontal lobe dysfunction in Parkinson’s disease: The cortical focus of neostriatal outflow. Brain 1986;109:845–883. Brown R, Marsden C: Cognitive function in Parkinson’s disease: From description to theory. Trends Neurosci 1990;13:21–29. Stebbins GT, Gabrieli JDE, Goetz C, Shannon KM, Penn RD, Goetz CG: Impaired fronto-striatal cognitive functioning following posteroventral pallidotomy in advanced Parkinson’s disease. Brain Cogn (special issue) 2000, in press. Pasquier F, Delacourte A: Non-Alzheimer degenerative dementias. Curr Opin Neurol 1998;11: 417–427. Azuma T, Bayles K, Cruz R, Tomoeda C, Wood J, McGeagh A, Montgomery E Jr: Comparing the difficulty of letter, semantic and name fluency tasks for normal elderly and patients with Parkinson’s disease. Neuropsychology 1997;11:488–497. Jacobs D, Marder K, Coˆte´ L, Sano M, Stern Y, Mayeux R: Neuropsychological characteristics of preclinical dementia in Parkinson’s disease. Neurology 1995;45:1691–1696. Taylor AE, Saint-Cyr JA, Lang AE: Memory and learning in early Parkinson’s disease: Evidence for a ‘frontal lobe syndrome’. Brain Cogn 1990;13:322–232. Owen A, Iddon J, Hodges J, Summers B, Robbins T: Spatial and non-spatial working memory at different stages of Parkinson’s disease. Neuropsychologia 1997;35:519–532.

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Aarsland D, Tandberg E, Larsen J, Cummings J: Frequency of dementia in Parkinson’s disease. Arch Neurol 1996;53:538–542. Cummings J: Depression and Parkinson’s disease: A review. Am J Psychiatry 1992;149:443–454. Marsden C, Obeso J: The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson’s disease. Brain 1994;117:877–897. Starr PA, Vitek JL, Bakay RAE: Deep brain stimulation for movement disorders. Neurosurg Clin North Am 1998;9:381–402. Kumar R, Lozano A, Kim Y, Hutchison W, Sime E, Halket E, Lang A: Double-blind evaluation of the effects of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998;51:850–855. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffman D, Benabid AL: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–1111. Lombardi WJ, Gross RE, Tre´panier LL, Lang AE, Lozano AM, Saint-Cyr JA: Relationship of lesion location to cognitive outcome following microelectrode-guided pallidotomy for Parkinson’s disease: Support for the existence of cognitive circuits in the human pallidum. Brain 2000, in press.

Jean A. Saint-Cyr, PhD, Department of Surgery, University of Toronto, Toronto, Ont. M5T 2S8 (Canada) Tel. +1 416 603 6422, Fax +1 416 603 5004, E-Mail [email protected]

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The Gamma Knife in Movement Disorder Surgery Ronald F. Young The Neurosciences Institute/Gamma Knife Center, Good Samaritan Hospital, Los Angeles, Calif., USA

Lars Leksell is generally credited with the concept of radiosurgery. In his original description of the method in 1951, Leksell [1] described the possibility of utilizing this method for the destruction of normal brain tissue and gave thalamotomy as an example of such a technique. Only a handful of patients underwent radiosurgical treatment of movement disorders until the publication by Rand et al. [2] in 1993, which described radiosurgical treatment of 18 patients with movement disorders. The remainder of this chapter will describe our technique and results in the radiosurgical treatment of movement disorders. To our knowledge, all attempts to use radiosurgical methods in recent years have employed the Leksell Gamma Unit only. We are unaware of any current usage of either linear accelerator-based or proton beam-based radiosurgery to treat movement disorders.

Technique Target Selection The most commonly utilized target for thalamotomy to treat tremor has been the ventral intermediate thalamic nucleus, although some other targets have also been recommended. As with thalamotomy, the exact target for pallidotomy is not completely agreed upon. Laitinen et al. [3] in 1992 described a target located 2–3 mm anterior to the midcommissural point about 22 mm lateral to the midline and about 6 mm below the commissural plane. This was intended to place a lesion in the internal segment of the globus pallidus (GP) posteriorly. The primary symptoms for which pallidotomy has been recommended have been bradykinesia, rigidity, and L-dopa-induced dyskinetic movements. Pallidotomy may also have an effect upon tremor, but this effect is considerably less consistent than with thalamotomy. For

Fig. 1. Gadolinium-enhanced MRI scan 6 months following left VIM thalamotomy with the gamma knife. The patient was completely free of tremor and has remained so over a follow-up period of 2 years. stereotactic pallidotomy with the gamma knife, we have utilized the target described by Laitinen et al. [3], however we have modified the stereotactic coordinates based on an assessment of each individual patient’s brain. It is our intent to place the lesion in the internal segment of the GP just anterior to the midcommissural point avoiding injury to both the optic tract and the internal capsule. Target Localization Stereotactic lesioning with the gamma knife does not allow for electrophysiological target localization and therefore stereotactic localization for gamma knife lesioning depends exclusively on magnetic resonance imaging (MRI) localization. For thalamotomy, T1 and inversion recovery MRI images are employed in the axial and coronal planes. The position of the anterior and posterior commissures is identified and the intercommissural distance and third ventricular width are measured. Adjustments in stereotactic coordinates are made based on the size of each individual patient’s basal ganglion structures. For thalamotomy, the anterior-posterior, or Y coordinate, is determined by reference to standard stereotactic atlases adjusted for the intercommissural distance and in an average brain with an intercommissural distance of 26 mm, has been placed 6–7 mm posterior to the midcommissural point. Both the lateral or X coordinate and vertical or Z coordinate are determined from examination of coronal plane images made at the intended Y coordinate. The thalamic mass and position of the internal capsule are identified. The lesion is placed in the inferolateral corner of the thalamic mass (fig. 1). This localizes the lesion to the ventral intermediate thalamic nucleus with allowance for lesion extension into the VOP.

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Fig. 2. MRI scan 18 months after left pallidotomy with the gamma knife. Contralateral dyskinesias were completely relieved within 3 months of the procedure and have remained so over a follow-up period of more than 3 years. For pallidotomy a similar procedure is utilized except that attention is turned to the location of the putamen and external and internal segments of the GP as well as the optic tract and internal capsule. The anterior/posterior or Y coordinate is determined 2–3 mm anterior to the midcommissural point. Coronal sections at this location are utilized to place the lesion in the internal segment of the GP (fig. 2). The lateral or X coordinate and vertical or Z coordinate are then measured by direct inspection of the coronal scans. Radiosurgical Technique We currently make functional lesions with the gamma knife using only a single exposure with the 4 mm collimator. The radiosurgical dose maximum is between 120 and 140 Gy. The procedures are performed under local anesthesia with minimal intravenous sedation utilized mainly for placement of the stereotactic frame. There have been no complications of any kind associated with the perioperative period and patients are discharged from the

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hospital either on the same day as the procedure or the following morning. Immediate return to normal activities is always possible.

Results Unlike radiofrequency thalamotomy or pallidotomy, the lesions made with the gamma knife develop slowly rather than immediately. Follow-up MRI scans taken about 1 month after the procedure generally show a small area of decreased attenuation at the lesion site, but without any evidence of enhancement with intravenous gadolinium. At this point in time there are generally no changes in the patient’s preoperative symptoms. By 2–3 months, the area of low attenuation increases in size and gadolinium enhancement becomes apparent. At this time, improvement in the patient’s clinical symptoms generally commences. Over the next several months the lesion will generally stabilize in size and some surrounding area of low density on T1-weighted MRI scans and increased signal attenuation on T2-weighted scans will become apparent. These perilesional changes are generally not accompanied by any neurologic symptoms. One hundred fifty-four patients have now undergone unilateral ventral intermediate/ventral lateral nucleus thalamotomy by our group for treatment of contralateral tremor using the gamma knife. Earlier results in some of these patients have been previously published [4–7]. Minimum follow-up time in these patients currently is 6 months and maximum follow-up time is more than 5 years. Thalamotomy was performed for control of primarily resting tremor in 121 patients with Parkinson’s disease. Twenty-six patients with essential/familial tremor were treated primarily for action tremor. Seven patients with tremor due to variety of other conditions – poststroke, postencephalitic and posttraumatic – were treated for combinations of resting and action tremor. For both patients with Parkinson’s disease and essential tremor 85% were either completely free of tremor or nearly completely free following treatment. A recent report on some of these patients demonstrated statistically significant improvements in the Unified Parkinson’s Disease Ratings Scale (UPDRS) items 16, 20 and 21 for measures of tremor, tremor at rest, and action tremor when comparing the same patient before and after thalamotomy [4]. Handwriting samples and spiral diagrams showed marked improvements following thalamotomy. Finger-tapping speed improved from 15 to 95%. There were also statistically significant improvements in the activities of daily living score (p>0.008), contralateral motor subscore (p>0.03), and total UPDRS scores both contralateral (p>0.05) and ipsilateral (p>0.02) to the side of the lesion when comparing the treated patients to a control group of untreated patients. Improvements in the patients with the other tremor types were much less consistent. Three of 4 patients with stroke-

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related tremor showed improvements in tremor, but none of these had complete resolution. One patient with postencephalitic tremor showed minimal improvement and 1 of 2 patients with posttraumatic tremor showed nearly complete resolution of tremor, but the other patient showed little improvement. The results were less striking for the postpallidotomy patients [4, 5]. The most consistent area of improvement was in L-dopa-induced dyskinesias where 49 of 58 (84%) showed virtual complete resolution of contralateral L-dopa-induced dyskinetic movements. Another 6 patients (10%) showed significant improvements in dyskinesias, but not complete resolution, resulting in a total complete or marked improvement in 94% of patients. For bradykinesia and rigidity the improvements were less striking following gamma knife pallidotomy. Overall, 64.7% of patients showed improvement in at least one UPDRS score. The mean magnitude of improvement ranged from a low of 19.4% for activities of daily living to a maximum of 37% for ipsilateral motor scores. Neuropsychological testing in both the thalamotomy and pallidotomy patients showed no significant changes in neurocognitive function in assessments that represented memory, information processing, and problem-solving abilities. Complications Not a single patient of the 154 total patients who underwent radiosurgical thalamotomy either at the Good Samaritan Hospital in Los Angeles, California or the Northwest Hospital in Seattle, Washington showed any neurological complication of any kind at any time after the treatment. Of the 38 patients who underwent pallidotomy at the Northwest Hospital, a single patient (2.6%) developed a contralateral homonymous hemianopsia about 10 months after the procedure. MRI scan at 9 months had shown a lesion of the expected size, located within the internal segment of the GP as planned. Subsequently however, the lesion increased markedly in size and came to include the subjacent optic tract, resulting in the homonymous hemianopsia, which has now been consistent for over 2 years without evidence of improvement. Duma et al. [8] recently reviewed their results in 18 of the 20 patients who underwent pallidotomy at the Good Samaritan Hospital in Los Angeles. Thirty-three percent of their patients showed improvements in rigidity and dyskinesia. Three patients were unchanged and 9 patients (50%) were described as showing worsening as a result of the treatment. Four of these 18 patients (22%) had visual field defects and/or speech difficulties and 3 had worsening of their gait and 1 numbness in the contralateral hemibody – all of which were felt to be related to lesions developing larger than expected. Duma et al. [8] postulated an anatomical susceptibility of the GP to infarction related to this area as a region of end arterial supply. It is interesting to note that delayed infarction has also been described following radiofrequency pallidotomy.

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Discussion For gamma knife thalamotomy for the treatment of tremor, the results are approximately comparable to those reported for open radiofrequency thalamotomy. Fox et al. [9] for instance reported 91% tremor control and Jankovic et al. [10] reported 90% tremor control. It is important to note that in the Jankovic series for instance, these results were accomplished with a 15% reoperation rate because of failure of the tremor to improve on the first operative procedure whereas the results with the gamma knife are all based on a single procedure. Regarding the complications, those for the gamma knife-treated patients appear markedly lower than has been reported for radiofrequency thalamic lesioning for treatment of tremor. For instance, Jankovic et al. [10] reported a 58% temporary complication rate and a 23% persistent complication rate. Regarding pallidotomy, the results of the patients treated in Seattle are very similar to those that have been described for radiofrequency pallidotomy. For patients treated at Good Samaritan Hospital the results are less clear, but it should be pointed out that Good Samaritan Hospital was the leader in developing the gamma knife pallidotomy procedure, and in the early work they used a variety of techniques, including multi-isocenter treatments and high maximum radiosurgical doses, which are not used currently. This may account for some of the differences. Currently we recommend that only a single isocenter be utilized with the 4-mm secondary collimator helmet and we do not recommend a maximum radiosurgical dose above 140 Gy. Utilizing these parameters we believe that both thalamotomy for the control of tremor and pallidotomy for the treatment of dyskinesia, bradykinesia, and rigidity with the gamma knife have similar success rates to thalamotomy performed using open radiofrequency methods and certainly for thalamotomy the complication rate is substantially lower. For pallidotomy the Good Samaritan Group has recommended that pallidotomy be performed using the radiofrequency method unless there is some overriding medical reason, such as the use of anticoagulants or other serious medical conditions, which make the patient an unsuitable candidate for an open radiofrequency pallidotomy [8]. It also should be pointed out that in most of the radiofrequency pallidotomy series, a maximum age of 70 years has been utilized. As described in our earlier reports, however we have treated patients up to the age of 85 with similarly good results and with no significant increase in complications using radiosurgical thalamotomy [4, 5]. Consequently, patients of advanced age may be considered for radiosurgical procedures where they might not be suitable for open radiofrequency procedures. The primary concern of those critics of radiosurgical thalamotomy and pallidotomy, namely inability to accurately localize the target, has not proven to

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be a major problem in any of the patients described in this report. No patient has sustained a complication, which has been related to inaccuracy of target localization. Presumably, at least some of the failures in the thalamotomy patients may be related to slight inaccuracies in target localization, however, the success rate, as mentioned, is comparable to radiofrequency procedures performed using electrophysiological control. Consequently, we believe that for thalamotomy performed for the treatment of tremor, the procedure can be recommended using the gamma knife as an alternative to radiofrequency thalamotomy for all patients. For pallidotomy, our tendency is to use the radiofrequency method with microelectrode control for the vast majority of patients, reserving pallidotomy for those who may be less suitable candidates for an open radiofrequency procedure. On the other hand, we believe it appropriate to inform all patients considering these procedures, of the options and allow them to participate in the final treatment decision.

References 1 2

3 4

5 6 7 8

9 10

Leksell L: The stereotactic methods and radiosurgery of the brain. Acta Chir Scand 1951;102: 316–331. Rand RW, Jacques DB, Melbye RW, Copcutt BG, Fisher MR, Levenick MN: Gamma knife thalamotomy and pallidotomy in patients with movement disorders: Preliminary results. Stereotact Funct Neurosurg 1993;61(suppl 1):65–92. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Young RF, Shumway-Cook A, Vermeulen SS, Grimm P, Blasko J, Posewitz A, Burkhart WA, Goiney RC: Gamma knife radiosurgery as a lesioning technique in movement disorder surgery. J Neurosurg 1998;89:183–193. Young RF, Vermeulen SS, Posewitz A, Shumway-Cook A: Pallidotomy with the gamma knife: A positive experience. Stereotact Funct Neurosurg 1998;70(suppl 1):218–228. Young RF: Functional disease of the brain: Treatment by gamma knife radiosurgery; in Lufkin R (ed): Minimally Invasive Therapy of the Brain. New York, Thieme, 1996, pp 225–234. Young RF, Posewitz A: Non-invasive lesioning: Functional radiosurgery; in Alexander EB III, Maciunas RM (eds): Advanced Neurosurgical Navigation. New York, Thieme, 1999, pp 507–517. Duma CM, Jacques DB, Kopyov OV, Mark RJ, Copcutt BG, Farokhi HK: Functional radiosurgery; in Alexander EB III, Maciunas RM (eds): Advanced Neurosurgical Navigation. New York, Thieme, 1998, pp 519–528. Fox MW, Ahlskog JE, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. J Neurosurg 1991;75:723–730. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for Parkinsonian, essential, and other types of tremor. Neurosurgery 1995;37:680–687.

Ronald F. Young, MD, NSI/Gamma Knife Center, Good Samaritan Hospital, 637 S. Lucas Avenue, Suite 501, Los Angeles, CA 90017–2395 (USA) Tel. +1 213 977 2234, Fax +1 213 482 2157, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 279–295

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Stereotactic Neurosurgery for Dystonia Daniel Yoshor a, Winifred J. Hamilton a, J. Michael Desaloms a, William Ondo b, Joseph Jankovic b, Robert G. Grossman a Departments of a Neurosurgery and b Neurology, Baylor College of Medicine, Houston, Tex., USA

Dystonia is characterized by involuntary sustained and patterned muscle contractions that result in twisting, spasmodic movements [1, 2]. These movements frequently involve the simultaneous contraction of agonist and antagonist muscle groups and are typically exacerbated by voluntary movements. In the United States, the estimated prevalence of primary dystonia is 32.9 per 100,000 [3]; in the United Kingdom the prevalence is estimated to be 14.3 per 100,000 [4]. The relatively large number of people affected, along with a young age at onset (from a mean of 16.7 years for generalized dystonia to 58.8 years for blepharospasm [4]) and a lack of reliably effective treatment for most forms of dystonia, exacts significant cost, in both human and economic terms [5], from its victims and society. Drugs currently used to treat dystonia include levodopa, anticholinergics, dopamine-blocking or dopamine-depleting agents, benzodiazepines, baclofen, and muscle relaxants [6]. In addition, the use of botulinum toxin to chemically denervate overactive muscles offers a useful treatment for some forms of focal dystonia [7]. However, the toxin must be administered every few months to maintain the denervation and, with repeated use, some patients develop antibodies against the serotypes currently in use [8], thereby rendering the treatment ineffective. With the exception of dopa-responsive dystonia and some focal dystonias that are well managed with botulinum toxin, however, dystonia generally responds poorly to medical therapy. The lack of effective medical therapy and the progressive nature of the disease in most patients have led to a number of attempts to utilize surgical therapies, including the sectioning of overactive muscles, peripheral denervation of dystonic muscles, and stereotactic lesions in the thalamus and basal ganglia [9], to treat dystonia.

Table 1. Classification of dystonia Etiology Primary Secondary Dystonia plus Heredodegenerative Symptom distribution Focal Segmental Multifocal Generalized Hemi-

Classification and Genetics of Dystonia Familiarity with the classification (table 1) and the genetic substrates of the various dystonia syndromes is requisite, as different forms of dystonia respond differently to a given surgical procedure. Dystonia can be classified by etiology as primary or secondary dystonia, dystonia plus, or heredodegenerative dystonia [2]; and by symptom distribution as focal (involving one body part), segmental (involving multiple contiguous regions), multifocal (involving two or more noncontiguous regions), or generalized (involving one leg and at least one other noncontiguous body part) [2]. Unilateral dystonia involving half of the body is classified as hemidystonia. Primary dystonia is characterized by dystonic movements with or without associated tremor, and without precipitating factors such as stroke or traumatic brain injury. In this form of dystonia, which may be idiopathic or inherited, magnetic resonance (MR) images of the brain are normal and other neurologic syndromes such as Wilson’s disease or dopa-responsive dystonia are, by definition, not present. Of the at least eight genes for dystonia that have been mapped [10, 11], primary dystonia genes include DYT1 (associated with early limb-onset dystonia), DYT6 (associated with early- and late-onset familial cranial and limb dystonia) [12], and DYT7 (associated with late-onset familial torticollis) [13]. The best characterized of the dystonia loci is the DYT1 gene which has been mapped to chromosome 9q34. Early limb-onset (Oppenheim’s) primary dystonia in both Ashkenazic Jewish and non-Jewish families is associated with a specific three base-pair deletion in the coding sequence of the DYT1 gene [14]. This gene, which is expressed at high levels in the substantia nigra, encodes a protein, torsinA, which exhibits homology to the family of heat-shock proteins and proteases and to the family of ATPases [15].

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The secondary dystonias are caused by identifiable insults to the nervous system, such as stroke, perinatal hypoxia, infection, exposure to dopamine receptor D2-blocking agents, or traumatic injury to the brain, spinal cord or peripheral nerves. Patients with secondary dystonia have not been found to harbor the DYT1 mutation. However, the role of genetic susceptibility to secondary dystonia is poorly understood and may ultimately be important in explaining why many patients can sustain a cerebral or peripheral insult but only a few develop secondary dystonia [16]. Dystonia-plus syndromes encompass disorders that include a clinical phenotype of both dystonia and additional neurologic features [2]. They can be idiopathic or due to an identifiable etiology. Examples in this category include the DYT5-linked dystonic-parkinsonism syndrome of dopa-responsive dystonia, and the hereditary, but as yet unmapped, autosomal dominant dystonia-myoclonus syndrome. The heredodegenerative dystonias are neurodegenerative diseases that include dystonia as well as other neurologic symptoms. These diseases are frequently the result of genetic abnormalities and include autosomal dominant disorders such as spinocerebellar degeneration, the X-linked recessive dystoniaparkinsonism syndrome lubag (linked to the DYT3 locus), and the autosomal recessive Wilson’s disease.

Pathophysiology of Dystonia Abundant evidence exists to demonstrate that dystonia is rooted in the central nervous system rather than in the muscles or peripheral nerves [17]. Studies using positron emission tomography (PET), magnetoencephalography, and functional MRI have further localized the dysfunctional circuitry of primary dystonia to the basal ganglia [17, 18]. Anatomic and imaging studies of the brains of patients with secondary dystonia demonstrate a variety of focal lesions in the basal ganglia and thalamus [19–21]. Interestingly, the sites of these focal lesions include the pallidum and the ventrointermedius (Vim) nucleus of the thalamus, structures which, when surgically lesioned, ameliorate dystonia. The model of corticobasal ganglia-thalamocortical interactions commonly used to explain the aberrant neurologic activity found in hypokinetic and in hyperkinetic movement disorders posits that in PD, a largely hypokinetic movement disorder, loss of dopaminergic neurons leads to reduced dopaminergic input to the striatum which in turn results in decreased inhibition of the major output nuclei of the basal ganglia, the globus pallidus interna (GPi) and the substantia nigra pars reticulata (SNr), thereby leading to their overactivity. The increased inhibitory outflow of these nuclei in turn decreases

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activation of the excitatory thalamocortical projections to the motor cortex. Conversely, classic hyperkinetic disorders, such as dystonia, ballism and Huntington’s chorea, are characterized by underactivity of basal ganglia inhibitory output that ultimately results in excessive activation of the motor cortex. The results of recent PET studies of patients with primary dystonia are consistent with this model of GPi underactivity in dystonia. Using [18F]fluorodeoxyglucose PET scans, Eidelberg et al. [16] found evidence for overactivity of the direct inhibitory projections from the putamen to the GPi and increased metabolic activity of the ventral thalamic nuclei and supplementary motor cortex. They argue that, in dystonia, increased activity of the inhibitory direct putamenopallidal pathway leads to reduced GPi activity which in turn causes hyperactivity of the thalamic relays and of the motor cortex. Microelectrode recordings in dystonia patients support this concept, demonstrating a reduction in the firing rate of GPi units in dystonia patients relative to that seen in normal primates or patients with PD [22, 23]. In PD, lesions of the GPi are thought to ameliorate rigidity and bradykinesia by reducing the inhibitory output of the basal ganglia. This model, however, is problematic when applied to dystonia, a hyperkinetic disorder that improves following stereotactic lesioning of the GPi. If hyperkinetic disorders like dystonia are characterized by reduced pallidal output and increased cortical activation, pallidotomy would be predicted to exacerbate the disorder. Furthermore, the reduced pallidal inhibition posited in the model should lead to increased activity of the ventro-oralis anterior (Voa) and ventro-oralis posterior (Vop) nuclei of the thalamus, other key stereotactic targets for treatment of dystonia. However, Lenz et al. [23] found Vop neuronal activity in dystonia patients to be reduced [23]. How can a lesion of possibly underactive neurons (in the GPi or Voa/ Vop) exert a beneficial effect on dystonia? How can an injury to the pallidum or thalamus cause secondary dystonia while a surgical lesion in these same areas can ameliorate dystonia? One possible explanation, put forth by Vitek et al. [22], is that dystonia results from a combination of decreased discharge rates, and altered patterns and GPi neuronal responses. According to this hypothesis, stereotactic lesions placed in the GPi or Voa/Vop disrupt rather than correct this abnormal corticobasal ganglia-thalamocortical activity, thereby alleviating the movement disorder.

Surgical Management of Dystonia Early surgical therapy for dystonia focused on sectioning the overactive muscles of focal cervical dystonia (torticollis). These procedures were gradually

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replaced by denervation of the most affected muscles, with the most commonly utilized techniques being anterior cervical rhizotomy, cervical dorsal ramisectomy, and sectioning of the spinal accessory nerve [24, 25]. Peripheral facial neurectomy and myectomy have been similarly used to treat intractable blepharospasm [26], although chemical denervation using botulinum toxin is now often the first treatment option for focal dystonia. In addition, several recent reports have noted significant improvement of torticollis following microvascular decompression (MVD) of the entry zone of the 11th cranial nerve [27, 28]. These and other surgical procedures for torticollis are reviewed in chapter 22 of this volume. Other more globally directed surgical procedures, including stimulation of the spinal dorsal column or cerebellum, have met with little success in the treatment of dystonia [29, 30]. Since the 1940s, a variety of stereotactic procedures have been used to treat both focal and generalized dystonia. The majority of these procedures have targeted the thalamic nuclei. Although interpretation of these early series is hindered by the heterogeneity of the patient populations, variations in the lesioning technique and target selected, an inability to determine precisely the lesion site in vivo in the era before MRI, and the use of ambiguous outcome measures, a review of the literature, coupled with our own experience, supports the view that thalamotomy offers meaningful improvement for some patients with dystonia. In the 1990s, a resurgence of pallidotomy for Parkinson’s disease has created new interest in applying this procedure to dystonia and several centers, including our own, have reported dramatic improvement in some patients with dystonia following stereotactic pallidotomy. The lack of other consistently effective treatments for most forms of dystonia makes it important to consider pallidotomy, as well as thalamotomy, as a practical therapeutic option.

Thalamotomy The largest reported series on stereotaxy for the treatment of dystonia is that of Irving Cooper [31, 32]. Beginning in the 1950s, Cooper performed thalamotomies (including 122 bilateral procedures) in over 200 patients with dystonia muscularum deformans (DMD), the term formerly used to describe primary generalized dystonia. Thalamic targets within his series varied and included the Voa, Vop, Vim, centralis medialis (CM), pulvinar, and portions of the ventralis posterolateralis (VPL) and ventralis posteromedialis (VPM) nuclei. Cooper observed marked improvement in 24.5% and mild to moderate improvement in 45.2% of dystonia patients who underwent thalamotomy after a mean follow-up of 7.9 years (table 2). Greater improvement was noted in Jewish patients with a positive family history (presumably patients with a

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Table 2. Late outcome from published series of thalamotomies for dystonia Series

Type of dystonia

Cooper, 1976 [32]

Dystonia musculorum deformans 208

701

NA

Gros, 1976 [34]

Juvenile dystonia/dyskinesia

14

50

164

Andrew, 1983 [33]

Generalized Hemidystonia Focal/segmental

16 25 12 100 27 62

475

Tasker, 1988 [36]

Generalized (all) Primary Secondary

563 20 29

342 352 342

21 25 25

Cardoso, 1995 [35]

All Generalized Hemidystonia Segmental Primary Secondary

17 5 9 3 7 10

47 80 33 33 43 50

6 0 0 33 0 10

130 61 69 83 47

59 57 62 60 59

Sungurov, 1998 [38] All Generalized Focal Primary Secondary

N

% moderate % persistent or marked complications improvement

3 (12)6

N>Number of patients; NA>not available; 1>includes mild improvement; 2>?50% improvement in contralateral limb symptoms; 3>includes 7 patients of unknown etiology; 4>all cases (n>25) including other lesion sites; 5>18% ‘significant’; 6>complications in 278 patients; ( ) > bilateral.

DYT1 mutation), in patients with limb symptoms, and in patients between 11 and 16 years of age. A number of smaller series, including our center’s experience, have confirmed that thalamotomy produces meaningful functional improvement in a significant percentage of dystonia patients (table 2) [33–38]. Several points of clinical importance are worth noting. Although Cooper stated that patients with primary dystonia responded better to thalamotomy than did patients with secondary dystonia, other series have generally found little or no difference [38] or that that patients with secondary dystonia do somewhat better than patients with primary dystonia following thalamotomy [35, 36]. Tasker et al.

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[36], for example, reported 25% or greater improvement in contralateral limb symptoms in 69% of patients with secondary dystonia (n>29), whereas 50% of primary dystonia patients were similarly improved. Cardoso et al. [35], reported moderate or marked improvement in 50% of secondary dystonia patients (n>10), whereas 43% of primary dystonia patients (n>7) were similarly improved following thalamotomy. In our experience and in that of others, improvement following thalamotomy may deteriorate over time [34–36, 38], especially in patients with primary dystonia. This may reflect the continued progression of the disease. In separate studies, Tasker’s group and our group have reported that 65 and 43%, respectively, of primary dystonia patients who improved initially after thalamotomy did not maintain the full benefits of surgery; similar deterioration was noted in only 31 and 33%, respectively, of patients with secondary dystonia [36]. Occasional patients were noted to improve over time. Most thalamotomy series have reported better results for segmental dystonia than for generalized dystonia. Tasker et al. [36], for example, have noted that appendicular dystonia responds better to thalamotomy than does axial dystonia. In their series, 34% of limb dystonia symptoms improved markedly, whereas only 13% of neck and trunk dystonia symptoms exhibited similar improvement. One important factor in obtaining amelioration of axial symptoms may be the use of bilateral thalamotomies. Torticollis in particular appears to respond better to a bilateral procedure. Andrew et al. [33], for example, found that bilateral thalamotomies were highly effective in 67% of patients with cervical dystonia, whereas unilateral thalamotomy was ineffective in all 5 patients in whom it was performed. Our technique for stereotactic thalamotomy for dystonia has been previously described in detail [39]. The Leksell G frame is employed in conjunction with 1-mm axial CT scans with sagittal and coronal reconstructions. A line connecting the anterior and posterior commissures (the AC-PC line) is defined in relation to the center of the Leksell frame. In the majority of patients, we initially target the junction of the Voa and Vop nuclei (fig. 1). The coordinates of this target relative to the AC-PC line are typically 12 mm lateral and 1 mm superior to the AC-PC line, and 2 mm posterior to the midpoint of the AC-PC line. In young patients or patients with symptom severity that prohibits an awake procedure, we have performed the surgery under general anesthesia with localization based either solely on stereotactic imaging or with the aid of intraoperative microelectrode recordings. In cases performed on cooperative patients under local anesthesia, target localization is aided by macroelectrode stimulation. A single radiofrequency lesion or two overlapping lesions are then fashioned at the target site by heating the 3-mm bare tip of a 2.1-mm diameter electrode to 75 ºC for 60 s.

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Fig. 1. Typical stereotactic target for thalamotomy for dystonia: 12 mm lateral and 1 mm superior to the AC-PC line, and 2 mm posterior to the midpoint of the AC-PC line. Lesion and external labels added to art reproduced, with permission, from Schaltenbrand and Wahren [56]. The brain section depicted is 12 mm lateral to the midsagittal plane. Exterior abbreviations: A>anterior; AC>anterior commissure; P>posterior; PC>posterior commissure. Selected interior abbreviations: Cd>caudate nucleus; Cp.ip>capsula interna (internal capsule); P.l.>Pallidum laterale (>globus pallidus externus); P.m.>pallidum mediale (>globus pallidus internus); Sth>subthalamic nucleus; Th>thalamus; V.i.m.i> ventrointermedium internus nucleus of the thalamus; V.o.a>ventro-oralis anterior nucleus of the thalamus; V.o.p>ventro-oralis posterior nucleus of the thalamus; Z.i>zona incerta; II>tract of the optic nerve. Bar>1 cm.

Potential complications of thalamotomy include dysarthria, hemiplegia, and pseudobulbar palsy. The incidence of serious complications, however, has decreased with recent improvements in imaging and stereotactic techniques. Although earlier studies reported persistent complications in 16 to 47% of patients [32–34, 36], two series published in the 1990s noted complication

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rates of 6 and 3%, respectively [35, 38]. The higher complication rate in the earlier series is inflated, however, due to the presence of significant numbers of bilateral procedures. Complications, especially dysarthria, are significantly more common following bilateral thalamotomies. Andrew et al. [33] described a 56% incidence of dysarthria after bilateral thalamotomies compared with an 11% incidence after unilateral thalamotomy. Thus the benefit of bilateral thalamotomies for axial dystonia is tempered somewhat by the higher incidence of complications. Unilateral thalamotomy combined with a contralateral thalamic deep brain stimulator (DBS) or bilateral DBS may be a safe and effective alternative. Our group and others have experienced excellent results with bilateral thalamic DBS for tremor and bilateral GPi DBS for parkinsonian symptoms, although the effectiveness of DBS for dystonia is still unclear [40, 41].

Pallidotomy One of the most striking and consistent areas of improvement in PD patients after stereotactic pallidotomy is the resolution of levodopa-induced dyskinesias, including dystonia [42–45]. This observation, combined with the paucity of serious complications associated with bilateral pallidotomies, has led several centers to apply pallidotomy to the treatment of dystonia. In Cooper’s series of more than 200 patients who underwent stereotactic surgery for dystonia, only 14 patients underwent pallidotomy; 2 were reported in detail [32]. Of these 2 patients, 1 derived no benefit from a unilateral pallidotomy. The second patient, who was treated with bilateral pallidotomies, improved dramatically. In the few case reports published between 1960 and 1985, the results of pallidotomy for dystonia were inconsistent and usually unfavorable [34, 46–50]. However, the current pallidal target of choice, the posteroventral GPi, was not generally employed until the 1990s. In the earlier reports, the lesions, although inconsistent in location, were most frequently placed in the lateral and dorsal aspect of the pallidum to avoid damage to the optic tract and the internal capsule. Subsequent to 1992, when Laitinen et al. [45] reported good results for parkinsonism and levodopa-related dyskinesias using a stereotactic lesion placed in the posteroventral pallidum, neurosurgeons have almost universally targeted this portion of the GPi. In 1996, Iacono et al. [51] published an account of striking improvement following bilateral pallidotomies in a 17-year-old male with primary generalized dystonia, and have subsequently reported results of pallidotomy in 4 additional dystonia patients [52]. Marked improved was noted in a 59-yearold patient with craniocervical dystonia who underwent bilateral pallidoto-

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mies, and in a 47-year-old patient with primary focal cervical dystonia who underwent a left pallidotomy. A 48-year-old patient with primary spasmodic dysphonia and left lower extremity dystonia experienced moderate improvement in leg dystonia, but no change in dysphonia following right pallidotomy. A 24-year-old patient with secondary generalized dystonia, primarily appendicular in distribution, was noted to have no improvement following unilateral pallidotomy. Improvement in all cases occurred gradually, typically over weeks to months postoperatively. Vitek et al. [22] have reported on 3 patients with generalized dystonia who underwent microelectrode-guided unilateral posteroventral pallidotomy. Postoperatively, there was marked improvement in contralateral dystonic symptoms, with a mean reduction in disability on the Fahn-Marsden Dystonia Movement Scale and the Disability Scale of 80 and 72%, respectively. Comparison of pre- and postoperative surface EMG studies of overactive muscle groups revealed decreased coactivation of agonist-antagonist muscle groups during movement, and a dramatic reduction in resting EMG activity following pallidotomy. One year after surgery, 2 patients with predominantly appendicular symptoms had maintained their excellent improvement, whereas 1 patient with mostly axial symptoms, although still markedly improved from his preoperative state, experienced some return of truncal dystonia at 8 months postoperatively. Vitek et al. [22] speculated that axial symptoms may be more optimally treated with bilateral pallidotomies. Two other groups with extensive experience with pallidotomy for PD have recently applied the procedure to patients with dystonia. Lozano et al. [53] have reported remarkable improvement in an 8-year-old Ashkenazic boy with familial (DYT1-negative) primary generalized dystonia following simultaneous bilateral pallidotomies. After being wheelchair-bound for 6 months preoperatively, the patient was able to walk independently and ride a bicycle 3 months after surgery. Lin et al. [54] observed progressive postoperative improvement leading to an excellent functional outcome after staged bilateral pallidotomies in a 36-year-old woman with severe secondary generalized dystonia. Her postoperative course was complicated by transient right facial weakness. Our group at Baylor College of Medicine has previously reported 59 and 62.5% improvement in the Burke-Marsden-Fahn and in the United Dystonia Rating Scales scores, respectively, following pallidotomy in 8 patients with dystonia [55]. A total of 11 patients with dystonia have now undergone unilateral or bilateral pallidotomies at our center. Bilateral lesions were employed in those patients with a bilateral or axial distribution of symptoms. Five of the patients had primary dystonia, and 6 patients had secondary dystonia. The mean age at surgery was 23 years (range 8–57). There were 5 females and 6 males. General anesthesia (2.5% desfluorane and cisatracurium) was used in 9 of the 11 patients

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Fig. 2. Typical stereotactic target (solid oval) for pallidotomy for dystonia: 20 mm lateral and 4 mm inferior to the AC-PC line, and 2–3 mm anterior to the midpoint of the AC-PC line. Lesion and external labels added to art reproduced, with permission, from Schaltenbrand and Wahren [56]. The brain section depicted is 20 mm lateral to the midsagittal plane. External abbreviations: A>anterior; AC>anterior commissure; P>posterior; PC>posterior commissure. Selected internal abbreviations: An.l>ansa lenticularis; Cp.ip>capsula interna (internal capsule); P.l.>Pallidum laterale (globus pallidus externus); P.m.i. and P.m.e>internal and external portions of the pallidum mediale (>globus pallidus internus); Put>putamen; Th>thalamus; II>tract of the optic nerve. Bar>1 cm.

due to the severity of their dystonia. The posteroventral GPi was localized using the Leksell G stereotactic frame and 1-mm axial CT scans with sagittal and coronal reconstructions. An initial target point was chosen at 19–21 mm lateral and 4 mm inferior to the AC-PC line, and 2–3 mm anterior to the midpoint of the AC-PC line (fig. 2). Final localization of the sensorimotor GPi was guided by extracellular microelectrode recordings, impedance measurements, and by monitoring motor, sensory, and visual responses to electrode stimulation. In

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Table 3. Global Outcome Scale (GOS) scores, by patient (n>21), from published series of pallidotomies for dystonia GOS 1 (4 is best)

4 3 2 1 0

Iacona et al. 1998 [52]

Lin et al. 1998 [54]

Vitek et al. 1998 [22]

Lozano et al. 1997 Yoshor (1999) 2 [53]

Prim

Prim

Sec

Prim

Prim

1

3

Sec

3 1

Sec

1

Sec

Prim

Sec

4

2 1 1 2

1 1

1 4>Marked improvement in movement disorder and function; 3>moderate improvement in movement disorder and function; 2>moderate improvement in movement disorder but minimal or no improvement in function; 1>mild improvement in movement disorder but no improvement in function; 0>no effect. 2 Series reported in text.

cases performed under general anesthesia, microelecrode recordings were especially critical for safely and accurately determining the optimal target. Five patients underwent bilateral pallidotomies performed at one operative session, 3 patients underwent bilateral pallidotomies performed in two stages, and 2 patients underwent unilateral pallidotomy exclusively. In order to better compare patients from our series with cases reported in the English literature since 1995, patients were graded postoperatively according to a global outcome scale (4, marked improvement in movement disorder and function; 3, moderate improvement in movement disorder and function; 2, moderate improvement in movement disorder but minimal or no improvement in function; 1, mild improvement in movement disorder but no improvement in function; 0, no effect). Comparison of our results with reported results of pallidotomy for dystonia since 1995 revealed strikingly similar outcomes (table 3). When the recently published reports on pallidotomy are combined with our own experience, a statistically significant difference (p=0.02, two-sample Wilcoxon rank-sum test) in mean outcome after pallidotomy was observed between primary (mean GOS 3.77, n>13) and secondary dystonia patients (mean GOS 2.38, n>8), suggesting that primary dystonia patients benefit more from pallidotomy than do secondary dystonia patients. Among the 11 patients who underwent pallidotomy for dystonia at our center, 2 experienced transient complications, including lethargy and subgaleal effusion. An additional 2 patients experienced mild but persistent dysarthria and hypophonia.

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Table 4. Global Outcome Scale (GOS) scores for patients who underwent thalamotomy or pallidotomy at The Methodist Hospital, Houston, Texas, between February 1981 and December 1998, by etiology, at most recent follow-up visit GOS 1 (4 is best)

4 3 2 1 0

Thalamotomy (n>18) (mean FU 39.6 months)

Pallidotomy (n>11) (mean FU 14.5 months)

primary (n>7)

secondary (n>11)

primary (n>5)

secondary (n>6)

1 2 1 0 3

1 5 1 1 3

4 (80%) 0 1 (20%) 0 0

2 1 1 2 0

(14%) (29%) (14%) (43%)

(9%) (46%) (9%) (9%) (27%)

(33%) (17%) (17%) (33%)

FU>Follow-up. 1 4>Marked improvement in movement disorder and function; 3>moderate improvement in movement disorder and function; 2>moderate improvement in movement disorder but minimal or no improvement in function; 1>mild improvement in movement disorder but no improvement in function; 0>no effect.

Comparison of Thalamotomy and Pallidotomy In the absence of any existing guidelines for choosing one stereotactic procedure over another for dystonia, we have compared global outcome scale scores from our series of dystonia patients treated with thalamotomy (n>18) with our series of dystonia patients treated with pallidotomy (n>11) (table 4). These comparisons, however, need to be viewed with caution due to the small number of patients, and differences in the patient populations, follow-up, and surgical technique. Although there was no significant difference between the outcomes following pallidotomy and thalamotomy for secondary dystonia, generalized dystonia, or hemidystonia, the long-term mean GOS score following pallidotomy for primary dystonia (3.6×0.89, n>5) was statisically superior to that following thalamotomy for primary dystonia (1.7×1.7, n>7) (p>0.05, two-sample Wilcoxon rank-sum test) (fig. 3).

Conclusion For dystonia patients in whom drug therapy and denervation (using botulinum toxin or surgery) are ineffective, stereotactic surgery offers the hope of meaningful functional improvement. The wide range of etiologies for dystonia,

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Fig. 3. Mean short-term (immediate postoperative) and long-term (last follow-up) Global Outcome Scale (GOS) scores in patients with primary dystonia who underwent thalamotomy (n>7; mean follow-up 39.6 months) or pallidotomy (n>5; mean follow-up 14.4 months) at The Methodist Hospital, Houston Texas, between February 1981 and December 1998.

however, including multiple distinct genetic mutations, implies the possibility of significant variability in response to specific surgical approaches and therefore the stereotactic target for specific forms of dystonia remains unclear. Nevertheless, a review of the literature and our own experience suggest that pallidotomy is the optimal surgical therapy for most patients with primary dystonia, especially for those with early-onset primary generalized dystonia. For treatment of secondary dystonia, the outcomes following pallidotomy or thalamotomy do not appear to be significantly different. Further studies, currently in progress, will help determine the relative efficacy of various stereotactic procedures, such as pallidotomy and deep brain stimulation of the GPi or other subcortical nuclei, in ameliorating the different forms of dystonia.

References 1 2 3

Jankovic J, Fahn S: Dystonic disorders; in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders, ed 3. Baltimore, Williams & Wilkins, 1998, pp 513–551. Fahn S, Bressman SB, Marsden CD: Classification of dystonia; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 1–10. Nutt JG, Muenter MD, Melton LJ 3rd, Aronson A, Kurland LT: Epidemiology of dystonia in Rochester, Minnesota; in Fahn S, Marsden CD, Calne DB (eds): Advances in Neurology: Dystonia 2. New York, Raven Press, 1988, vol 50, pp 361–365.

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292

4

5

6 7 8 9 10 11

12

13

14

15

16

17 18

19 20 21 22

23

Duffey PO, Butler AG, Hawthorne MR, Barnes MP: The epidemiology of the primary dystonias in the north of England; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 121–125. Butler AG, Duffey PO, Hawthorne MR, Barnes MP: The socioeconomic implications of dystonia; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 349–358. Jankovic J: Medical therapy and botulinum toxin in dystonia; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 169–183. Jankovic J, Brin MF: Botulinum toxin: Historical perspective and potential new indications. Muscle Nerve 1997;6(suppl):129–145. Hanna PA, Jankovic J, Vincent A: Comparison of mouse bioassay and immunoprecipitation assay for botulinum toxin antibodies. J Neurol Neurosurg Psychiatry 1999;66:612–616. Lang AE: Surgical treatment of dystonia; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 185–198. Warner TT, Jarman P: The molecular genetics of the dystonias. J Neurol Neurosurg Psychiatry 1998;64:427–429. Bressman SB, de Leon D, Raymond D, Ozelius LJ, Breakefield XO, Nygaard TG, Almasy L, Risch NJ, Kramer PL: Clinical-genetic spectrum of primary dystonia; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 79–91. Almasy L, Bressman SB, Raymond D, Kramer PL, Greene PE, Heiman GA, Ford B, Yount J, de Leon D, Chouinard S, Saunders-Pullman R, Brin MF, Kapoor RP, Jones AC, Shen H, Fahn S, Risch NJ, Nygaard TG: Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol 1997;42:670–673. Leube B, Hendgen T, Kessler KR, Knapp M, Benecke R, Auburger G: Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe. Am J Med Genet 1997;74: 529–532. Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, Fahn S, Risch NJ, Buckler AJ, Gusella JF, Breakefield XO: The earlyonset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997;17:40–48. Augood SJ, Penney JB Jr, Friberg IK, Breakefield XO, Young AB, Ozelius LJ, Standaert DG: Expression of the early-onset torsion dystonia gene (DYT1) in human brain. Ann Neurol 1998;43: 669–673. Eidelberg D, Moeller JR, Antonini A, Kazumata K, Nakamura T, Dhawan V, Spetsieris P, de Leon D, Bressman SB, Fahn S: Functional brain networks in DYT1 dystonia. Ann Neurol 1998;44: 303–312. Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD: The pathophysiology of primary dystonia. Brain 1998;121:1195–1212. Perlmutter JS, Stambuk MK, Markham J, Black KJ, McGee-Minnich L, Jankovic J, Moerlein SM: Decreased [18F]spiperone binding in putamen in dystonia; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 161– 1688. Hartmann A, Pogarell O, Oertel WH: Secondary dystonias. J Neurol 1998;245:511–518. Jankovic J: Post-traumatic movement disorders: Central and peripheral mechanisms. Neurology 1994;44:2006–2014. Marsden CD, Obeso JA, Zarranz JJ, Lang AE: The anatomical basis of symptomatic hemidystonia. Brain 1985;108:463–483. Vitek JL, Zhang J, Evatt M, Mewes K, DeLong MR, Hashimoto T, Triche S, Bakay RA: GPi pallidotomy for dystonia: Clinical outcome and neuronal activity; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 211–219. Lenz FA, Suarez JI, Metman LV, Reich SG, Karp BI, Hallett M, Rowland LH, Dougherty PM: Pallidal activity during dystonia: Somatosensory reorganisation and changes with severity. J Neurol Neurosurg Psychiatry 1998;65:767–770.

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24 25 26 27 28 29 30 31 32

33 34 35 36 37 38

39 40

41 42 43

44

45 46 47 48

Krauss JK, Toups EG, Jankovic J, Grossman RG: Symptomatic and functional outcome of surgical treatment of cervical dystonia. J Neurol Neurosurg Psychiatry 1997;63:642–648. Bertrand CM: Selective peripheral denervation for spasmodic torticollis: Surgical technique, results, and observations in 260 cases. Surg Neurol 1993;40:96–103. Bates AK, Halliday BL, Bailey CS, Collin JR, Bird AC: Surgical management of essential blepharospasm. Br J Ophthalmol 1991;75:487–490. Aksik I: Microneural decompression operations in the treatment of some forms of cranial rhizopathy. Acta Neurochir (Wien) 1993;125:64–74. Jho HD, Jannetta PJ: Microvascular decompression for spasmodic torticollis. Acta Neurochir (Wien) 1995;134:21–26. Fahn S: Lack of benefit from cervical cord stimulation for dystonia. N Engl J Med 1985;313:1229. Fraioli B, Baldassarre L, Refice GM: Chronic paleocerebellar stimulation in dystonia and athetosis. Report of two cases. J Neurosurg Sci 1980;24:99–103. Cooper IS: Neurosurgical treatment of the dyskinesias. Clin Neurosurg 1977;24:367–390. Cooper IS: 20-year follow-up study of the neurosurgical treatment of dystonia musculorum deforans; in Eldridge R, Fahn S (eds): Advances in Neurology: Dystonia. New York, Raven Press, 1976, vol 14, pp 423–452. Andrew J, Fowler CJ, Harrison MJG: Stereotaxic thalamotomy in 55 cases of dystonia. Brain 1983; 106:981–1000. Gros C, Frerebeau PH, Perez-Dominquez E, Bazin M, Privar JM: Long term results of stereotaxic surgery for infantile dystonia and dyskinesia. Neurochirurgia (Stuttg) 1976;19:171–178. Cardoso F, Jankovic J, Grossman RG, Hamilton WJ: Outcome after stereotactic thalamotomy for dystonia and hemiballismus. Neurosurgery 1995;36:501–508. Tasker RR, Doorly T, Yamashiro K: Thalamotomy in generalized dystonia; in Fahn S, Marsden CD, Calne DB (eds): Advances in Neurology: Dystonia 2. New York, Raven Press, 1988, vol 50, pp 615–631. Yamashiro K, Tasker RR: Stereotactic thalamotomy for dystonic patients. Stereotact Funct Neurosurg 1993;60:81–85. Sungurov EB, Peresedov VV, Markova ED, Ivanova-Smolenskaia IA, Rebrova O, Tiurnikov VM: The surgical results in patients with different forms of torsion dystonia. Zh Vopr Neirokhir Im N N Burdenko 1998;Oct-Dec:21–24. Krauss JK, Grossman RG: Surgery for Hyperkinetic Movement Disorders: Parkinson’s Disease and Movement Disorders, ed 3. Baltimore, Williams & Wilkins, 1998, pp 1017–1047. Ghika J, Villemure JG, Fankhauser H, Favre J, Assal G, Ghika-Schmid F: Efficiency and safety of bilateral contemporaneous pallidal stimulation (deep brain stimulation) in levodopa-responsive patients with Parkinson’s disease with severe motor fluctuations: A 2-year follow-up review. J Neurosurg 1998;89:713–718. Starr PA, Vitek JL, Bakay RA: Deep brain stimulation for movement disorders. Neurosurg Clin North Am 1998;9:381–402. Brophy BP: Surgical palliation of dyskinesiae in Parkinson’s disease. Stereotact Funct Neurosurg 1998;70:107–113. Desaloms JM, Krauss JK, Lai EC, Jankovic J, Grossman RG: Posteroventral medial pallidotomy for treatment of Parkinson’s disease: Preoperative magnetic resonance imaging features and clinical outcome. J Neurosurg 1998;89:194–199. Krauss JK, Desaloms JM, Lai EC, King DE, Jankovic J, Grossman RG: Microelectrode-guided posteroventral pallidotomy for treatment of Parkinson’s disease: Postoperative magnetic resonance imaging analysis. J Neurosurg 1997;87:358–367. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Burzaco J: Stereotactic pallidotomy in extrapyramidal disorders. Appl Neurophysiol 1985;48:283– 287. Handa H, Araki C, Mori K: Spasmodic torticollis treated by chemothalamotomy and chemopallidotomy. Confin Neurol 1960;22:393–396. Hassler R, Reichert T, Mundinger F, Umbach W, Ganglberger JA: Physiological observations in stereotaxic operations in extrapyramidal motor disturbances. Brain 1960;83:337–350.

Yoshor/Hamilton/Desaloms/Ondo/Jankovic/Grossman

294

49 50 51 52

53 54 55 56

Krayenbuhl H, Siegfried J: Dentatotomies or thalamotomies in the treatment of hyperkinesia. Confin Neurol 1972;34:29–33. Tasker RR: Surgical treatment of the dystonias; in Gildenberg P, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1996, pp 1015–1032. Iacono RP, Kuniyoshi SM, Lonser RR, Maeda G, Inae AM, Ashwal S: Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans. Pediatr Neurol 1996;14:145–148. Iacono RP, Kuniyoshi SM, Schoonenberg T: Experience with stereotactics for dystonia: Case examples; in Fahn S, Marsden CD, DeLong MR (eds): Advances in Neurology: Dystonia 3. Philadelphia, Lippincott-Raven, 1998, vol 78, pp 221–226. Lozano AM, Kumar R, Gross RE, Giladi N, Hutchison WD, Dostrovsky JO, Lang AE: Globus pallidus internus pallidotomy for generalized dystonia. Mov Disord 1997;12:865–870. Lin JJ, Lin SZ, Lin GY, Chang DC, Lee CC: Application of bilateral sequential pallidotomy to treat a patient with generalized dystonia. Eur Neurol 1998;40:108–110. Ondo WG, Desaloms JM, Jankovic J, Grossman RG: Pallidotomy for generalized dystonia. Mov Disord 1998;13:693–698. Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Chicago, Year Book Medical, 1977. Robert G. Grossman, MD, Department of Neurosurgery, Baylor College of Medicine, 6560 Fannin Street, Suite 944, Houston, TX 77030 (USA) Tel. +1 713 798 4696, Fax +1 713 798 3739, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 296–330

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Surgery for Spasmodic Torticollis Alan T. Villavicencio, Allan H. Friedman Division of Neurosurgery, Duke University Medical Center, Durham, N.C., USA

Spasmodic torticollis (ST) is an adult-onset, involuntary, focal or segmental dystonia of the neck manifested by patterned, repetitive, clonic (spasmodic) or sustained (tonic) movements. Also known as idiopathic cervical dystonia (ICD), patients with ST have individually stereotyped postures characterized by a variable combination of neck flexion, extension, rotation or tilting (fig. 1). These dystonic postures are present at rest, worsen with action or stress, and improve or completely resolve with sleep [97, 123] and are frequently painful [117]. ST may occur in isolation or may be the predominant feature of a generalized dyskinesia [8]. Although numerous medical and surgical therapies have been aimed at treating theoretical pathophysiology or resultant symptoms, so far no definite solution has been found.

Incidence and Etiology Spasmodic torticollis is the most common form of adult-onset focal dystonia [46, 60]. The overall incidence has been estimated at 1.2/100,000 personyears with a female:male ratio of approximately 4:1 [39]. Although numerous reports have attempted to relate ST to an underlying cause (table 1), most cases occur spontaneously and only rarely is there a temporally related inciting factor. There is a natural tendency to relate the appearance of abnormal posturing to recent trauma. However, it appears that in most cases early symptoms were actually present before the trauma [66, 146]. The pathologic literature has not significantly contributed to our understanding of this disorder. Light and electron microscopy reveal several abnormalities such as prominent, numerous Renaut bodies (evidence of demyelination and remyelination) and disproportionately thin myelin sheaths with

Fig. 1. Drawings derived from photographs of patients with ST before and after undergoing intradural rhizotomy. Note the variations in head posture and postoperative improvement. The following conditions are depicted: pure rotational torticollis (A); pure laterocollis (B); pure retrocollis (C ); rotational and retrocollis (D); rotational and retrocollis (E ): and rotational and laterocollis (F ) [from 70, fig. 2].

endoneurial edema and thickening of the perineurium. This is suggestive of a compression neuropathy. A disorder of muscle spindle afferent processing has been suggested by evidence of abnormalities in perception of the tonic vibration reflex which are remote from the clinically affected site [80]. There has been a recent interest in the possibility that disorders of the basal ganglia and thalamus underlie ST. Several neuroradiological studies have attempted to evaluate this hypothesis [71, 125, 140]. 123I SPECT [140] has demonstrated dopaminergic dysfunction in idiopathic ST. Evaluation of regional cerebral glucose metabolism has demonstrated ‘a significant hypermetabolism in the basal ganglia, thalamus, premotor-cortex and cerebellum’ [125]. Proton nuclear magnetic resonance spectroscopy shows a significant, therapyresistant decrease of basal ganglia N-acetyl-L-aspartate (NAA)/choline (Cho). Clinical significance of these changes to the actual etiology of ST remain unclear. Bertrands [18] and others [61, 63, 128] have commented that ST may be a limited manifestation of the same process that causes adult-onset dystonia.

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Table 1. Classification of torticollis by etiology Idiopathic adult-onset torticollis Infantile torticollis (Pure) Psychogenic torticollis Torticollis associated with specific abnormality Abnormalities in the rostral brainstem and basal ganglia [100, 138] Arterial compression of spinal accessory nerve [112] Cervical-spine subluxation Dystonia musculorus deformans Electrical injury [25, 40] Hiatal hernia (thought to result from attempts to alleviate gastrointestinal symptoms) Hydrocephalus Infection [136] Cervical tuberculosis (and other low-grade spinal infections) Cervical epidural abcess Cervical osteomyelitis Previous encephalitis Retropharyngeal abscess [86] Inflammatory lesions of the C-spine Intervertebral disk calcification [37] Medications [31, 62, 98] Dopaminergic Antidopaminergic drugs (tardive dystonia) [52] Metabolic disorders Ceroid lipofuscinosis GM1 gangliosidosis Multiple sclerosis [81, 92, 113, 129, 148] Neurodegenerative disorders involving the basal ganglia Huntington’s disease [9] Wilson’s disease Ocular pathology [109, 189] Pneumomediastinum [50] Previous thalamotomy Rheumatoid arthritis [187] Steele-Richardson-Olszewski syndrome [22] Tumors of the neck Tumors of the posterior fossa [24, 36, 82, 116] Tumors of the spine [34, 144] Tumors of the supratentorial compartment [170] Stroke [138] Trauma [21, 95, 126, 143] Upper respiratory tract symptoms [70, 146]

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Extracervical dystonia can be found in up to 20% of ST patients [46]. Five of Bertrands 118 patients with rotational or laterocollis later went on to develop a more generalized dystonia with marked scoliosis of the cervicothoracic spine [18, 19, 176]. Other authors [43, 73] have noted a personal or familial predisposition to essential tremor or involvement of the facial musculature in some patients with torticollis. There may be a small subset of patients who have a genetic predisposition to ST [101].

Natural History of Spasmodic Torticollis The clinical course of patients with ST has been described by several reports. Although not in complete agreement, some reliable trends can be derived. ST is not limited to any age, though it usually begins in young or mid-adult life between 30 and 40 years of age. The onset of ST is almost never abrupt, most patients experience a recognized prodrome. Usually noted is a ‘crick in the neck’, neck muscle tightness, or a pulling sensation in the neck in the months before any malposition becomes apparent. The head turning is most often initially intermittent, later becoming constant and abating only during sleep. Symptoms may progress rapidly over several weeks or gradually over several years until a plateau is typically reached 3–5 years after the initial manifestations [75, 135]. Temporary spontaneous remission has been reported to occur in anywhere from 5 to 30% of patients with torticollis [46, 69, 92, 123, 135, 145]. When spontaneous remission occurs, it usually happens within the first year of the disease when head-turning is intermittent [69, 130]. However, remissions are usually transient with nearly all patients eventually relapsing [97]. Other patients will be noted to have a spontaneous diminution but not complete resolution of their disease [92, 123, 145].

Evaluation of the Patient with Torticollis ST must be differentiated from other forms of torticollis. Bony or softtissue abnormalities and other conditions leading secondarily to torticollis which should be ruled out from the start are listed in table 1. Patients should be examined for concomitant movement disorders such as benign essential tremor and writer’s cramp. Patient’s dystonic posturing may be hidden during lack of activity. Writers should be observed while writing, typists while typing, musicians while performing, and so on. Involvement of muscles other than the neck may imply a diagnosis of dystonia musculorus deformans.

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Physical Examination The major muscles involved in head-turning include the sternocleidomastoid (SCM), the trapezius, and the four layers of muscles posterior to the spine (primarily the rectus capitus posterior major, the inferior capitus oblique, the semispinalis capitus, and the splenius capitus) [1]. The SCM rotates the head obliquely to the opposite side. Bilateral activation of the SCMs flex the neck and extend the head. The trapezius, although infrequently involved in abnormal movements [18] rotates the scapula, draws the dorsum of the head to the ipsilateral side and rotates the face to the contralateral side. Bilateral activation of the trapezius results in neck extension. Unilateral activation of the splenius capitus draws the head backward and rotates the face to the same side. The semispinalis capitus similarly rotates and draws the head backward. The inferior capitus oblique functions to rotate the atlas, turning the face to the same side, while the rectus capitus major rotates the face to the ipsilateral side and extends the head. The anterior cervical group of muscles contribute little to abnormal head and neck movements. The neck musculature involved in ST are generally hypertrophied and tense. In rotational cases of torticollis, the SCM muscle on the side opposite to that which the chin turns is nearly always enlarged. The head may be rotated to one side or the other so much that the chin approximates that shoulder [75]. Less commonly, the head may tilt so that the ear and ipsilateral shoulder approximate each other (laterocollis). By convention, torticollis is named for the SCM muscle that is in contraction (a patient turned to the left has right torticollis). There may be forced hyperextension of the neck, with or without rotation or tilting. This is termed retrocollis, whereas forced flexion is more rare, and has been referred to as antecollis. Flexion with inclination of the head to the left and rotation to the right may be caused by involvement of the left SCM and the ipsilateral semispinalis capitus or splenius capitus, whereas rotation to the right with slight inclination and extension of the occiput to the right suggests involvement of the left SCM combined mostly with the right splenius capitus [18]. The contralateral semispinalis may be involved in a patient with lateroretrocollis and pronounced extension. Bilateral muscular involvement is almost always present and occurs most often in the SCM muscles. Electromyography In patients without torticollis, the two SCM muscles normally demonstrate reciprocal inhibition. Patients with rotary torticollis frequently demonstrate impaired reciprocal inhibition, especially when rotating their chins toward the most affected SCM muscle. EMG will generally demonstrate varying evidence of involuntary suprasegmental hyperactivity, with the most

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common being bursts of suprasegmental spontaneous electrical activity [70]. In mildly affected patients, involuntary muscle activity may be difficult to detect while the patient is at rest. As the severity of the disease increases, spontaneous intermittent electrical activity is seen along with excessive muscle activity and simultaneous contraction of agonist and antagonists. Spontaneous involuntary EMG activity may be seen bilaterally throughout the neck musculature [70, 75, 149]. In the most severe cases, bursts of spontaneous activity interrupt increasingly short periods of electrical silence. These abnormalities are absent only during sleep. A rhythmic tremor is frequently visualized on EMG by alternating discharges of the antagonists. Surgery is less likely to relieve this problem. Temporary Blocks Injection of up to 20 cm3 of 1% lidocaine without epinephrine may be used to determine the relative importance of involved muscles in the abnormal head movement. In the case of laterocollis, this technique may be used to evaluate the contribution of the left SCM muscle versus the right posterior cervical group, or the right SCM versus the left posterior cervical group in the case of rotational torticollis. Radiologic Evaluation A variety of cervical spine abnormalities can result in head malposition in a patient with nonspasmodic torticollis (table 1). Routine cervical-spine radiographs may demonstrate severe degenerative disease, unilateral jumped facets, or an unsuspected fracture. Children with rotary subluxation of the atlas on the axis may present with a ‘cock-robin’ appearance. AP and lateral chest roentgenograms frequently demonstrate compensatory scoliotic and kyphotic curves of the thoracic spine associated with long-standing ST. The degree of scoliosis and spondylotic change in the spine may be striking. MRI or postmyelogram CT can be potentially useful tests in patients with severe degenerative cervical spine disease or myelopathy. Fluoroscopic evaluation of patients with ST demonstrate swallowing abnormalities in approximately 65% of patients [70]. Mild aberrations include lateralization of the pharyngeal transient, abnormal postures and delayed swallowing reflexes. Frank aspiration is more rarely identified.

Nonoperative Management Nonoperative management of ST varies widely. Common nonsurgical attempts at treating torticollis are summarized in table 2. Physical therapy

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Table 2. Nonsurgical therapies in the treatment of ST Acupuncture Biofeedback Botulinum toxin Cervical braces Hypnosis Intramuscular phenol injection Pharmacotherapy Amanboline Amantadine hydrochloride Anticholinergics (trihexyphenidyl, ethopropazine) Anticonvulsants (carbamazepine) Antidepressants Anxiolytics Dopamine receptor antagonists c-Aminobutyric acid (GABA)-enhancing agents Muscle relaxants (diazepam, lorazepam, clonazepam) Pain medications Physical therapy and relaxation techniques Psychotherapy Transcutaneous nerve stimulation

and relaxation techniques are of limited benefit to patients with torticollis, but may be useful in preventing permanent contractures [99]. Pharmacotherapy Although the literature is filled with reports of medications alleviating dystonic conditions, these therapeutic triumphs are rarely corroborated by further study. Ultimately, pharmacotherapy may provide some benefit in up to 50% of patients suffering from torticollis, but the reduction in neck spasms is usually not sufficient to improve the patient’s function and control of neck movement [99]. Medications are primarily useful for short-term symptomatic relief in select patients. The most frequent medications administered are aimed at stimulating GABAergic or inhibiting cholinergic receptors, respectively. The anticholinergic agent trihexyphenidyl is the most frequently used mediation [99] and is also probably the most effective [32, 79]. Anxiolytics, antidepressant medications, dopamine receptor-blocking agents, amanboline, and GABA-enhancing regimens have also all been reported to be of some benefit in treating ST (table 2) [119, 127].

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Botulinum Toxin Type A Most patients who fail to respond to medical therapies are treated with botulinum toxin injections. Type A botulinum toxin acts by rapidly and strongly binding at the neuromuscular junction to prevent the release of acetylcholine from the presynaptic nerve terminal [45, 131, 168, 169]. When injected into the abnormally contracting muscle, botulinum toxin reduces involuntary dystonic movements [61–63]. The belly of the SCM is initially injected followed by other muscles selected through preoperative exam and EMG studies. Following each injection, patients are examined within 1–2 weeks in order to determine the early beneficial or adverse effects. There are three possible results of each injection: (1) The injection is not effective enough and the same abnormal movements and postures remain. In this case, the same muscles may be reinjected. (2) The injection is effective and the patient’s condition improves. In this case, the patient is not injected again until the effects of the toxin wear off. (3) The injection is effective for the target muscle but the involuntary movement persists or is slightly different. In this case the muscles responsible for the residual torticollis are injected. If there is no improvement after multiple injections, concentrations may be increased in steps until symptoms improve. Roughly 75% of patients show clinical improvement following the initial injection [46]. There is commonly a 30–60% improvement which lasts approximately 13–15 weeks, with a total duration of improvement about 6 weeks longer [104, 173, 184]. Average latency between the injection time and onset of improvement (usually associated with muscle atrophy) is approximately 1 week. Patients report a subjective lessening of cramping, discomfort, and tension, which is associated with temporary weakness in those muscles injected. It is usually necessary to achieve an equilibrium in each patient between muscle spasm and disabling weakness. Comparison of EMG recordings before and after successful treatment with botulinum toxin usually does not show changes in muscle firing pattern. There is continued prolonged bursts of muscle activity and loss of reciprocal inhibition. However, the amplitude of recordings from injected muscles is lower than before treatment. Therapy does not usually eliminate the spasms, but prolonged EMG bursts in a weak muscle do not lead to clinical spasms in the weakened muscles. If beneficial, injections may continue as long as satisfactory results are obtained. Eventually the treatment becomes ineffective, as steadily increasing doses are required for relief of symptoms. Resistance to the effects of subsequent injections has been correlated with the presence of antibodies to botulinum toxin in some patients [160]. It is also well known that patients with long-standing dystonia tend to respond less well than those who are treated relatively early in

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Table 3. Surgical procedures for torticollis Extraspinal nerve cutting (neurectomy) High cervical dorsal column stimulation Intraspinal (rhizotomy) Iontophoresis Microvascular decompression Myotomy Stereotactic lesions (thalamic, subthalamic, globus pallidus, corticocapsular)

the course of the disease [160]. This resistance to treatment is possibly related to the formation of contractures after prolonged dystonic posturing.

Surgery Indications Surgical treatment of torticollis should be reserved for patients who are disabled by their symptoms. The potential benefits of the proposed surgery must outweigh the risks. Reporting on 41 cases of ST, 17 of which underwent surgery, Meares [135] underlined certain complications following rhizotomies or thalamotomies. He concluded that patients treated conservatively fared better, particularly when they expressed high anxiety levels and neurotic traits. This is in sharp contrast to many other reports which promote surgical intervention [51, 85, 87, 89, 131, 132, 139, 141, 154]. However, patients are being referred for surgical evaluation and possible correction with increasing frequency [104, 105], and it should be made clear to the patient that improvements can be incomplete or associated with undesirable effects [175]. Surgical approaches that are presently advocated for the treatment of ST can be divided into seven different types of procedures: resection of the involved abnormally contracted muscles, stereotactically placed lesions in the diencephalon, spinal cord stimulation, iontophoresis, microvascular decompression, selective peripheral denervation, and intradural rhizotomy (table 3). Myotomy The Ancient Greeks are reported to have severed an SCM muscle for the treatment of torticollis [96]. Finney and Hughson [64] reported that a German physician treated torticollis in 1641 by sectioning that same muscle, and Dupuytren performed a sternomastoid tenotomy for torticollis in 1812 [180]. This form of therapy has recently been revisited by a number of Chinese colleagues.

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In 1981, Xinkang [191] reported on the results of 30 patients followed for more than 1 year following selective resection of selected posterior cervical muscles in conjunction with sectioning of the spinal accessory nerve in some patients. The muscles resected varied according to the type of torticollis and the results of preoperative EMG studies. Eighty-three percent of 60 patients were reported to experience either complete recovery or were markedly improved postoperatively. However, only 50% of patients had long-term followup (more than 12 months), and only 4 of 60 patients (less than 7%) were followed for more than 5 years. Chen et al. [38] reported successful treatment of bilateral retrocollis by selective resection of specific posterior cervical muscles in 15 patients. This included partial resection of the upper part of the trapezius, part of the splenius muscles, and portions of the semispinalis capitus, and semispinalis cervicus muscles bilaterally. Abnormal movements were reported to be abolished completely or greatly diminished in 13 patients (87%) while preserving the normal posture and mobility with postoperative follow-up ranging from 3 to 10 years. Despite these results, myotomy for the treatment of torticollis is rarely performed outside of China. Stereotactic Surgery The anatomico-pathologic substrate for ST is not definitively known. Thus, although there is theoretical basis for stereotactic methods in the treatment of ST (fig. 2), physiologic evidence for use of these techniques is lacking (see etiology, above). The rapid development of stereotactic neurosurgery along with good results following use of stereotactic methods for treatment of generalized dystonia encouraged an initial enthusiastic use of these techniques for ST. Riechert [153] first reported using stereotactic pallidotomy to treat ST in 1953. Since then, several other targets have been utilized for the stereotactic treatment of torticollis (see below and table 4). Overall, satisfactory results are reported to have been obtained in approximately two-thirds of patients undergoing such stereotactic procedures (table 4). Stereotactic lesions for ST are currently only being performed by a few surgeons.

Thalamotomy and Pallidotomy In 1954, Hassler and Hess [89] defined the ventralis oralis internus (VOI) of the thalamus as the primary target for torticollis because of its head and face representation. Shortly thereafter, Hassler and Dieckmann [87] suggested adding a lesion of the H1 bundle of Forel because of its influence on headturning in experimental animals. The latter are afferent fibers originating from

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Fig. 2. Vestibulo-interstitio-thalamocortical pathway, the circuit subserving rotation of the head. Schematic illustration includes the efferent pathways from the vestibular nucleus to the interstitial nucleus of Cajal to VOI in the contralateral thalamus and from there to Broadman’s area 8 [from 14].

the interstitial nucleus of Cajal, or ‘the pallido-thalamic fibers representing the contraversive movement of the head and body’ [87]. In Hassler and Dieckmann’s experience, 9 of 16 patients (53%) with ST in whom the head rotated horizontally to the side of the lesion did well when the VOI lesion was exended into H1 in the subthalamus. Several other authors have reported making stereotactic lesions in the ventral medial thalamus or the adjacent fields of Forel [15, 167]. Based on the theory that the dentarubrothalamic pathway subserved, at least in part,

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Table 4. Results following stereotactic surgery for the treatment of ST Group (first author) Andrew Siegfried

Ref.

Year

Patients, n

Results, n (%) 1

Target

excellent good/fair 6 7

1983 1974

21 6

167

1983

German

Vim, Vce-Vci of thalamus 3 above plus CM

9 (43) 0 (0)

172

1981

107

(24)

(29)

von Essen

192

1980

17

VOI

1 (6)

12 (71)

4 (23)

Bertrand 5

14 20

1978 1975

12 13

Posterointernal VOI 6 VOI or subthalamotomy

6 (50) 1 (8)

4 (33) 6 (46)

2 (17) 6 (46)

118

1977

7

(0)

(0)

7 (100)

Cooper Dieckmann

42 41

1977 1964

160

51

(47)

NO 2 3 (50) 4

Stejskal

Laitinen

Internal capsule

12 (57) 3 (50)

poor

VOI VL, VPM and CM

7

(60)

1976

70

Forel’s thalamic bundle

(47)

Driollet

53

1975

13

–

(14)

Nitter

141

1974

4

Mazars

132 131

1974 1968

45

French

Sano

154 155 156

1972 1970 1967

12

Interstitial nucleus of Cajal or upper MLF 8

Mundinger

139 193

1972 1970

52

Zona incerta or ventral oral thalamus

Hassler

87

1970

16

VOI and H1 bundle of Forel

Interstitial nucleus of Cajal

NO (29)

(40) (24) (86)

3 (75)

NO

1 (25)

(87)

NO

(13)

4 (33)

4 (33)

4 (33)

(61) (39)

NO NO

(39) (41)

9 (57)

NO

7 (43)

1

Results: Excellent>subjectively rid of torticollis, free of spontaneous muscle spasms, suffered no or minimal pain, had normal or almost normal head position, and had no complications from surgery; Good/ fair>improved but still in pain or with significantly abnormal neck posture at rest; Poor>persistent nuchal muscle spasms, severe neck pain, worsening of nuchal posture, or a persistent untoward effect from surgery. 2 NO: the authors in these series made no clear distinction between those patients who did excellent versus those who did fair. 3 Vim>ventralis intermedius of thalamus; Vce>ventralis caudalis externus of thalamus; Vci>ventralis caudalis internus of thalamus. 4 Complete but temporary relief only. 5 In 4 of these patients peripheral denervation was also performed. 6 VOI>nucleus ventralis oralis internus, a vestibulo-interstitial-thalamocortical circuit of head turning. 7 VL>ventrolateral nucleus; VPM>ventroposteromedial nucleus; CM>centromedian. 8 MLF>medial longitudinal fasciculus.

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the pathophysiological mechanism of torticollis, Cooper [42] performed thalamotomies in 160 patients over 25 years. Cooper [41] initially carried out unilateral and bilateral pallidal or ventrolateral thalamus lesions. The reported effect of these lesions upon torticollis were often negative or, if favorable, transient. Bilateral lesions of the thalamus were more lasting but still did not completely abolish symptoms. Cooper [42] reported that when extended posteriorly into the ventroposterolateral, ventroposteromedial and centrum medianum nuclei, in order to interrupt all of the afferent fibers arriving via the brachium conjunctivum, bilateral lesions had a more profound, persistent effect. Sixty percent of Cooper’s patients (exact numbers were not reported) who underwent bilateral lesions achieved satisfactory alleviation of their previously incapacitating symptoms [42]. Twenty percent of patients developed permanent dysphonic symptoms postoperatively. Cooper’s group [42] were unable to arrive at any satisfactory explanation for the success of the procedure in some cases and its failure to achieve a therapeutic result in the remainder. In view of these results, Cooper felt that ‘unless the patient is in great distress and feels that he cannot live with the symptoms, I do not advise this approach.’ Driollet et al. [53] found stereotactic surgery unsatisfactory for the treatment of ST and reported 86% poor results using VOI as a target. Likewise, Laitinen and Vilkki [118] reported that although the immediate clinical effects of VOI thalamotomy on ST was good in 1 patient and fair in 6, at an average follow-up of 8 months, none of 7 patients regarded the effect as good. Two patients had some long-lasting improvement and regarded the results as fair, but in 5 the result was nil. Dieckmann [51] on the other hand reported good results in 47% of 70 patients after lesioning Forel’s thalamic bundle. At least some improvement occurred in another 29% of patients. Bertrand [19] reported a 70% rate of satisfactory results after stereotactic lesions in the subthalamus in a mixed group of patients suffering from ST and primary dystonia. Andrew et al. [6, 7] had satisfactory results following combined bilateral thalamic lesions in: (1) Vim (ventralis intermedius), and (2) Vce (ventralis caudalis externus) to Vci (ventralis caudalis internus). These sites were based on other previous results with parkinsonism [88] and were defined according to a modification of Hassler’s teminology [88] where the posterior boundary of Vim lies immediately anterior to Vce (the sensory relay nucleus for the limbs and trunk) and is in the same coronal plane as the anterior limit of Vci (the sensory relay nucleus for the face) [6]. Andrew et al. [6] reported good results in 62% of 16 patients who underwent bilateral thalamotomy, but with a 19% rate of relapse and 56% incidence postoperative dysphonia. Two of 5 patients (40%) who underwent unilateral thalamotomies were improved postoperatively.

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Other Stereotactic Procedures Including DBS Mundinger et al. [139] reported complete resolution or significant improvement in 61% of 52 patients following lesioning of the zona incerta. There was an 8% incidence of postoperative complications. Sano et al. [154–156] reported that 8 of 12 patients improved following lesions of the nucleus of Cajal or the adjacent areas including the upper part of the medial longitudinal fasciculus. Mazars et al. [131, 132] reported an 87% success in treating 45 patients with torticollos by stereotactic interruption of the corticocapsular adversive fibers adjacent to the caudate nucleus in the anterior limit of the internal capsule. Stejskal et al. [172] reported good or fair results for an unspecified period of time in 71% of 20 patients lesioned in this same region. Lesions in the anterior limb of the internal capsule seemed to have been abandoned because of the risk of dysphonia and dysphasia. There has been a recent exciting report of bilateral globus pallidus internus chronic stimulation for the treatment of cervical dystonia [194]. Iontophoresis The thalamic relay of the vestibulo-interstitio-thalamo-cortical circuit of head-turning movements and its afferent pathways became a target after the suggestion by Svien and Cody [174] that the vestibular afferents play a major role in the maintenance of tonic neck posture. The treatment was based on the theory that excessive input to the lateral vestibular (Deiter’s) nucleus from the macula utriculi or a lesion in the mesencephalic reticular formation caused a disinhibition of the vestibular nuclei, resulting in an imbalance of the vestibular system. This imbalance was thought to result in excessive vestibular stimulation to the cervical spinal cord causing torticollis [48]. Svien and Cody [174] initially reported excellent results in 6 patients following iontophoresis of the middle ear employing a mixture of hyaluronidase and tolazoline (Priscoline). Duane and Svien [54] reported preliminary results of this treatment in 133 patients in 1972. Objective improvement was observed in 32% of the patients while subjective improvement was reported by 50% of patients. Tympanic membrane perforation complicated the procedure in 52% of patients. Although there was thought to be a suggestion of some benefit, Duane [54] felt the results were inconclusive in the absence of randomized, controlled studies. Such studies were apparently never performed due to the untimely death of Dr. Svien [48]. Since 1969, 223 patients with ST have been treated at the Mayo Clinic by this procedure. Davis et al. [48] contacted by phone 88 of these patients (39%) in a recent follow-up. Fifty-six patients (25% of total, 64% of those contacted by phone) returned a survey regarding their condition. Twenty-

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eight patients (13% of total, 32% of those contacted by phone, and 50% of those responding to the survey) enjoyed an initial period of improvement. Of these, 16 patients (7% of the total, 18% of those located, 29% of those responding, and 51% of those with initial improvement) reported sustained improvement through the time of the survey (median length of follow-up not reported). However, 5 of these patients had additional treatment with botulium toxin or selective denervation. The authors concluded that the long-term effectiveness of iontophoresis treatment in the course of torticollis is minimal. Microvascular Decompression Based on the clinical similarities between ST and hemifacial spasm, some surgeons have investigated treating torticollis with microvascular decompression or neurolysis of the spinal accessory nerve [68]. Freckman et al. [67] reported improvement in 84% of 33 patients following neurolysis of the spinal accessory nerve bilaterally and limited dorsal C1 and C2 nerve rootlet section. There was 1 death from postoperative respiratory failure and 2 patients developed paresis of the eleventh nerve musculature. Several other investigators have also postulated that vascular compression of the spinal accessory nerve was responsible ST [142, 166]. Jho and Jannetta [107, 108] reported that 13 of 20 patients (65%) who underwent microvascular decompression of the spinal accessory nerve at the brainstem were largely cured of ST. An additional 4 patients (20%) improved with minimal subsequent spasm, and 2 (10%) improved minimally or were unchanged. The most common compressing blood vessels were the vertebral artery and/or the posterior inferior cerebellar artery. No nerve sections were performed. The majority of their patients did not note a dramatic postoperative remission but rather improved gradually over a 2-year period following surgery. Shima et al. [166] postulated that ST may be the result of multiple etiologies and only the subset of patients whose condition worsened at rest are likely helped by microvascular decompression. This group decompressed the eleventh nerve from contact with the vertebral artery in 6 patients and with the posterior inferior cerebellar artery in one (one of these was bilaterally). Cervical nerve anastamoses were severed if necessary to achieve decompression. They reported a 43% rate of cure (3 patients) and 29% improved. Clinical improvement evolved over a 5-week postoperative interval. Bertrand’s Selective Peripheral Denervation The Russian surgeon Buyalski first reported ligating the spinal accessory nerve in 1834 for the treatment of torticollis [145]. Several years later, Morgan performed the same operation as proposed by Romberg, and in 1890 Collier clipped the accessory nerve with a silver wire [110]. Realizing that there was

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more widespread involvement of the cervical muscles of rotation, Wier Mitchell advised Keen [111] in 1891 to divide the posterior rami of C1–C3 at their points of emergence from the vertebrae. Keen’s operation was not very effective and resulted in severe atrophy of the neck muscles. Building on Keen’s operative procedure, Finney and Hughson [64] reported performing bilateral extraspinal neurectomies of C1–C3 along with bilateral ligation of the spinal accessory nerve at the posterior border of the SCM muscle in 31 patients. Twelve patients (39%) were reportedly cured by this procedure and an additional 16 (51%) were markedly improved; 3 patients had no benefit. Bertrand et al. [18, 19] have described a technique of identifying the specific muscles involved in the pathological neck rotation in a given patient prior to neurectomy. The procedure is then customized intraoperatively to denervate the involved muscles [14, 18]. It has been noted that rootlets below C4 often contribute to the torticollis [180]. EMG studies have shown involvement of muscles supplied by posterior rather than anterior rami levels as low as C7 [180]. Whereas anterior intradural rhizotomies below C4 and possibly even C3 would interfere with motor function in the arms, posterior rami sections at these levels are feasible. Bertrand plans his surgery by performing EMG studies at rest and during active movement, paying particular attention to the sternomastoid, splenius capitus, trapezius, semispinatus capitus, and capitus oblique. Nerve blocks are then done to evaluate the roles of various roots and their respective muscles, and the levator scapulae muscle is evaluated for its ability to substitute for the trapezius should it require denervation. The involved muscles are then denervated selectively under general anesthesia in the absence of muscle paralysis to allow for intraoperative stimulation (fig. 3). For rotary torticollis, the nerves innervating the sternomastoid are divided on one side and the posterior rami of C1–C6 are divided on the other in conjunction with avulsion of the peripheral portions of the respective nerves in order to discourage recurrence. Bertrand et al. [13] reported very satisfactory results of suppression of abnormal movements with preservation of posture and mobility in 88% of 131 patients treated exclusively by selective denervation over a 10-year period. This group [13] reported a 0% incidence of complications or serious sequelae, although there was ‘a few cases’ of transitory pain in the area of the trapezius, ‘which has been persistent in a few cases’. Bertrand [12, 17, 18] has more recently updated his experience. Of 260 consecutive cases operated on for ST or the cervical component of adult-onset dystonia, 106 patients (40%) were classified as having excellent results, and 124 (48%) a very good result (slight residual symptoms), for a total of 238, or 88% having satisfactory outcomes. Mean follow-up was not reported. However, of

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Fig. 3. Schematic illustration of the surgical exposure for a right posterior cervical ramisectomy, or selective peripheral denervation of the SCM. The small sketch to the left shows the incision beneath and posterior to the left ear for exposure of the left spinal accessory nerve and the posterior midline inverted L-shaped incision for the right posterior ramisectomy. In the main diagram, C1 is shown emerging underneath the vertebral artery on the right. In the upper circle the vertebral artery has been elevated to show the root of C1 as it divides in its lateral and posterior branches. Below this in the main diagram, the root of C2 is shown between the posterior arches of C1 and C2. The posterior primary divisions (rami) of C3–C6 are seen below this as they emerge form the intervertebral foramen and course posteriorly to innervate the posterior cervical musculature. The bottom circle demonstrates the root of C3 and its fine collateral branches immediately penetrating the muscles [from 17].

this group of patients, 167 had been operated on more than 5 years prior and 64 more than 10 years, so that the benefit was considered to be permanent. It is not clear how closely or by what method these patients have been followed. Three patients in Bertrand’s series [17] have experienced an occasional sudden tic-like pain, which subsided a few weeks. There is a marked atrophy of the posterior cervical group which is reportedly not that apparent [17], and the contour of the neck is not modified appreciably if the aponeurosis of the SCM is sutured after sectioning the muscle. There is anesthesia in the territory of the greater occipital nerve following selective peripheral denervation in an unreported number of cases. Also noted by Bertrand [17], ‘a few’ patients complain of a sensation of tightness or fullness in the neck postoperatively. Davis et al. [47] reported results on 9 patients who had undergone selective peripheral denervation for ST and had been followed for at least 13 months.

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Although all patients had improvement immediately after surgical intervention, this was maintained in only 5 patients. More recently, Braun and Richter [26] have reported significant improvement in 37 (76%) of 49 patients following a slightly modified version of Bertrand’s selective peripheral denervation. In this approach [26], the skin incision in the neck was straight instead of an inverted ‘L’. The natural planes of cleavage between the neck muscles were then used, so that there was no need for the detachment of the trapezius muscle from the occiput, or for the sectioning or removal of any other muscle. Reduced muscle bleeding and the added use of the surgical microscope was felt to afford better visibility and a decreased likelihood of leaving any intact nerves behind. Similar to Bertrand [18], this group [26] emphasized the importance of sectioning all the posterior branches of C1–6, in addition to the SCM branch of the spinal accessory nerve. Taira et al. [177] evaluated the results of selective peripheral denervation of cervical posterior rami and/or the accessory nerve for ST. Five patients underwent seven operations in total. The results were compared with those reported for botulinum toxin injections. This group reported excellent results in 4 patients and good results in one. Taira et al. [177] also claimed superior outcomes over botulinum toxin injections in similar patients with respect to control of symptoms in ST. However, 2 patients developed what is called the ‘mole-hitting game phenomenon’, in which muscles not appearing to contribute to the ST become important mediators of ST following the initial denervating operation, resulting in the requirement for further operations. After selectively denervating the C1 and C2 roots and C3–C6 spinal posterior rami in 1 patient with excellent results, Taira et al. [178] argued that an intradural approach might be more simple for sectioning the C1 and C2 roots. This was related to substantial bleeding encountered from venous plexi and the proximity of the vertebral artery. They also stressed the importance of dynamic EMG testing and thorough review of videorecording for identifying the involved neck muscles. Selective peripheral denervation has certain potential advantages, and may offer relief to carefully selected patients, but results vary considerably and some patients eventually relapse [17]. More widespread use of this technique in the future may give better insight as to long-term results. Intradural Rhizotomy Intraspinal surgery for the treatment of torticollis has slowly evolved over the first half of this century. In 1915, Taylor [182] described treating ST with unilateral intraspinal posterior rhizotomies of the upper four cervical rootlets as well as resection of the accessory nerve. Working with Cushing in 1923, McKenzie [133] modified this technique by unilaterally sectioning the spinal

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Fig. 4. Foerster-Dandy operation for ST: intradural cutting of the three superior anterior and posterior cervical roots and accessory nerves bilaterally [from 110].

accessory nerve in addition to the motor and sensory rootlets of the upper three cervical roots intradurally. In 1926, Foerster reported that sectioning of five anterior and posterior roots on one side yielded satisfactory results for ST. Frasier cut the first three posterior roots bilaterally while also sectioning the accessory nerves intradurally in 4 patients. Dandy [44], and later Olivercrona in 1931 performed bilateral intradural section of the motor and sensory roots of C1–C3 as well as intradural section of the accessory nerve roots on both sides of the foramen magnum (fig. 4). At a second stage, Dandy also performed Buyalsky’s operation – section of the accessory nerve in the neck – in all patients. Dandy reported complete cessation of involuntary head movements in 5 of 8 patients (63%) and partial symptomatic relief in an additional 2 patients (25%). Since then, surgeons have sectioned the anterior roots of C1–C3 and selectively denervated the SCM muscles. Some authors have sectioned C1–C3 intradurally while extraspinally sectioning only the branches of the spinal accessory nerve that innervate the

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SCM muscle [75, 175]. Perot [147] reported that peripheral sectioning of SCM muscle innervation did not afford lasting relief of symptoms and proposed intradural stimulation and selective sectioning of the spinal accessory nerve rootlets that innervated the SCM muscle. Based on this work, some surgeons have sectioned the anterior roots of C1–C3 bilaterally and the rootlets of the spinal accessory nerve innervating the SCM muscle intradurally [70, 75, 85]. Because the trapezius muscle is usually not involved in ST, denervation of this muscle is not necessary in the majority of cases.

Surgical Procedure and Relevant Anatomy The goal is an intradural sectioning of the ventral roots of C1–C3 and the rootlets of the spinal accessory nerve mediating SCM contraction. The operation is performed with the patient under general anesthesia without the use of muscle-relaxing agents. Although the patient may be in the sitting position, the authors prefer the prone position with the head fixed in a Mayfield head-holder. This lowers the risk of venous air embolism. Electrodes are placed over the trapezius muscle, SCM muscle, posterior cervical muscles and pharyngeal muscles bilaterally to detect evoked electrical activity of nerves. The suboccipital and nuchal muscles are detached at the midline, and the posterior rim of the foramen magnum and the upper three cervical lamina are removed. When the dura is opened, the upper four cervical nerve roots, the upper cervical spinal cord, the medulla, the cerebellar tonsils and the spinal accessory nerves are inspected using the operating microscope (fig. 5). The spinal accessory nerve courses parallel to the cervical spinal cord, ventral to the dorsal roots, and dorsal to the dentate ligament, passing over the vertebral artery and exiting through the jugular foramen (fig. 5). Nerve rootlets contributing to the spinal accessory nerve innervating the SCM, trapezius, and pharyngeal muscle are differentiated by electrical stimulation. Each rootlet is stimulated with 0.1–0.3 V using a bipolar stimulator. Resultant contractions of the SCM, trapezius, and paratracheal muscles monitored by computer-enhanced EMGs are monitored via surface electrodes. Only those rootlets mediating SCM contraction are severed. The ventral rootlets of the rostral three cervical spinal nerves are stimulated and then divided bilaterally. Contractions of the diaphragm are monitored by respiratory spirometry. The ventral root of C1 is often difficult to isolate as it is hidden beneath the attachments of the upper dentate ligament and lies in close proximity to the vertebral artery. Caution is taken to preserve any radicular artery that accompanies the nerve rootlets.

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Fig. 5. Anatomical drawing of the cervicomedullary junction demonstrating the rootlets of the spinal accessory nerve rostral to the vertebral artery and the rarely encountered McKenzie root (refer to text), which originates rostral to the vertebral artery and descends and exits with the C1 ventral root [from 70, fig. 1].

The upper cervical nerve rootlets are found to innervate the posterior paraspinal muscles but not the trapezius or SCM muscle. Special efforts are directed toward dividing the anastomotic branches between the C1 rootlets and the spinal accessory nerve. Unlike the spinal rootlets, these anastomotic nerves are frequently found to cause strong SCM muscle contraction when stimulated.

Results McKenzie [134] reported a rootlet that originated from the spinal accessory nerve and joined the C1 ventral root (fig. 5). He reported that this root was present in 5 of 10 patients and that failure to section the rootlet resulted in an incomplete clinical effect on the SCM muscle. This rootlet is considerably more rare than originally thought. McKenzie’s rootlet was noted only twice in the author’s series of 58 patients. Patients with pure retrocollis may be treated with ventral rhizotomy without concomitant selective spinal accessory nerve rhizotomy. Unilateral partial

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Table 5. Long-term results following ventral rhizotomies for ST Group Ref. Year Patients Spinal accessory (first author) n neurectomy

Results, n (%) 1

Friedman

Selective bilateral intradural section

33 (57)

16 (28)

146 1992 50

Unilateral intradural section

39 (77)

NO 2

Fabinyi

57 1980 20

Unilateral intradural section

12 (60)

Tasker

181 1976 21

Peripheral denervation of SCM muscle

17 (81)

Arseni

8 1971 54

Wycis

190 1969 26

Perot

Hamby

70 1993 58

excellent good/fair poor

6 (30) NO

Bilateral intradural section 23 (40)

20 (34)

Intradural section

NO

22 (84)

9 (15) 11 (23) 2 (10) 4 (19) 11 (26) 4 (16)

85 1969 50

Bilateral intradural section

4 (8)

36 (72)

10 (20)

Sorensen

171 1966 41

Intra- or extradural section

8 (20)

29 (71)

4 (10)

McKenzie

134 1955 12

Peripheral denervation of SCM muscle

10 (83)

NO

2 (7)

Putnam

152 1949 18

Intradural and sometimes extradural section

5 (28)

9 (50)

4 (22)

1

Results: Excellent>subjectively rid of torticollis, free of spontaneous muscle spasms, suffered no or minimal pain, had normal or almost normal head position, and had no complications from surgery; Good/fair>no spasmodic muscle contractions but still in pain or had a significantly abnormal neck posture at rest; Poor>persistent nuchal muscle spasms, severe neck pain, worsening of nuchal posture, or a persistent untoward effect from surgery. 2 NO>The authors in these series made no clear distinction between those patients who did excellent versus those who did fair.

C4 rhizotomies can be carried out to further denervate the most affected posterior spinal muscles. It is important to stimulate each of the C4 rootlets prior to sectioning, as the most inferior rootlets of C4 usually innervate the diaphragm. Table 5 [8, 57, 70, 85, 134, 146, 152, 171, 181, 190] reviews the literature regarding the treatment of torticollis with intradural selective rhizotomies. Overall, more than 80% of patients improved following ventral cervical rhizotomy when performed in conjunction with spinal accessory neurectomy. The author’s surgical results were rated based on patient satisfaction with the

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Fig. 6. Preoperative and postoperative photos of a patient with severe rotary torticollis. This patient was subjectively rid of her torticollis, free of spontaneous muscle spasms, and suffered no or minimum neck pain. Postoperatively there was almost normal head position, and she had suffered no untoward effects from surgery [from 188, fig. 107-2, p. 1047].

surgery, residual cervical pain, muscle spasms, abnormal head posture, and complications directly associated with the operation. Patients were considered to have an excellent result if they were subjectively rid of torticollis, free of spontaneous muscle spasms, suffered no or minimum neck pain, had normal or almost normal head position, and had no untoward effects from surgery (fig. 6). Patients were considered to have a fair result if they no longer had spasmodic muscle contractions but were still in pain or had a significantly abnormal neck posture at rest. Patients with persistent nuchal muscle spasms, severe neck pain, worsening of nuchal posture, or a persistent untoward effect from surgery were considered to have a poor result.

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Table 6. Results of intradural rhizotomy in 58 patients treated with ST

Result

Cases, n (%)

Excellent Fair Poor

33 (57) 16 (28) 9 (16)

Total

58

Table 7. Symptom resolution after selective rhizotomy in patients with ST Symptom

Spontaneous muscle spasm Pain Resting head position 1

Cases, n

58 47 58

Results 1, % excellent

fair

poor

72 64 59

17 17 16

10 19 26

See table 5 for a definition of each result.

Using these criteria [70] 84% of patients enjoyed a significant improvement overall; 33 of 58 patients (57%) were considered to have attained an excellent result, 16 (28%) a fair result, and 9 (15%) a poor result (table 6). All patients had been followed for at least 1 year postoperatively. Close review of the author’s series [70] demonstrated that ventral cervical root section and selective spinal accessory nerve rhizotomy were more efficient at relieving some symptoms of torticollis than others (table 7). Spontaneous muscle contractions were noted in all but 1 of the 58 patients preoperatively. These contractions were completely relieved in 72% of patients; another 17% of patients noted only occasional residual spasmodic contractions. Hamby and Schiffer [85] reported 79% overall improvement after anterior cervical rhizotomy in 50 patients followed for more than 1 year. Twenty-five patients (50%) had some residual rotation of the head postoperatively, 38% had residual limitation of voluntary head rotation, 57% suffered from persistent pain in the neck and shoulders, 32% had dysphagia (the majority of which was temporary), and 2 patients died secondary to complications related to surgery. Perot [146] reported that approximately 80% of 50 patients who have undergone upper cervical ventral rhizotomy and selective sectioning of the spinal accessory rootlets for ST been ‘quite pleased with the results obtained’.

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Table 8. Resting head position following selective rhizotomy in 58 patients with ST Duration of disease

=5 years ?5 years 1

Cases, n

34 24

Resting head position 1, % good

fair

poor

74 42

12 17

15 42

See table 5 for a definition of each result.

However, 1 patient in this series suffered from a transient operative myelopathy, and 2 patients developed a cervical subluxation after surgery. Pain has only occasionally been mentioned as a symptom of ST. Sorensen and Hamby [171] reported significant pain in 42 of their 71 patients (59%) suffering from torticollis preoperatively. In the author’s experience [70], 47 of 58 patients (81%) complained of significant preoperative pain. Although initially thought to be primarily related to cervical spondylosis, 64% of these patients were free of their preoperative pain after surgery and an additional 17% noted that their pain was significantly reduced. Nine patients (19%) reported some persistent pain. The head does not always assume a neutral position once the spasmodic contractions abated. Only 34 of 58 patients (59%) had neutral head positions at rest following their operation. An additional 9 patients noted a marked improvement in the resting posture of their heads. The likelihood of the head assuming a neutral position after surgery was inversely related to the duration of the patient’s preoperative condition. Twenty-five of the 34 patients (74%) with a disease duration of less than 5 years preoperatively noted that their heads returned to a neutral position at rest, but only 10 of 24 (42%) patients with ST for more than 5 years reported a neutral head position while at rest (p=0.04) (table 8). This suggests that long-term postural abnormalities may result in permanent contractures. In 1 patient with long-term torticollis and a compensatory thoracic scoliosis, the procedure actually resulted in a worsening of the patient’s resting head position due to a loss of muscle tone. Although the procedure severely denervates the cervical musculature, most patients regained 30–45º of lateral head rotation. Voluntary contraction of the SCM muscle partially returned in most patients during the months following surgery, but the unwanted involuntary contractions of ST did not.

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Complications While dysphagia is generally associated with high intradural spinal accessory nerve section, it is also reported to occur with extradural selective rhizotomy and even with botulinum toxin injections into the cervical muscles [160]. Dandy [44] noted that 2 of his patients had minor dysphagia, most marked in swallowing solid foods following high intradural sectioning of the spinal accessory nerve. In the author’s series [70], minor difficulties with swallowing were common in the immediate postoperative period. No patient reported difficulty with swallowing liquids, but 28 (48%) noted that solid foods would ‘stick in my throat’. This difficulty with swallowing completely resolved at an average of 4 months following surgery. Subjective postoperative swallowing abnormality was noted in 33% of the patients who had intraoperative EMG monitoring and in 46% of those who did not (no significant difference). Thirty-four patients underwent fluoroscopic examination of their swallowing in the week following surgery. Symptomatic patients had a slight delay in pharyngeal swallowing reflexes triggered at the level of the valleculae after the first swallow of solid food. These patients had residual material in their pharynx which cleared during subsequent swallows. This finding indicated a decrease in pharyngeal peristalsis. In the most impaired cases a pulsion diverticulum indicating pharyngeal muscle weakness was demonstrated. Frank aspiration was seen in 3 patients, with 1 developing an aspiration pneumonia. In the small number of patients who underwent a second swallowing study in the months following their surgery, swallowing reflexes and pharyngeal peristalsis were improved. In the author’s series of intradural rhizotomies for torticollis, a total of 22 C4 rhizotomies were performed on 13 patients. Six hemidiaphragms demonstrated paradoxical movement on postoperative fluoroscopy. One patient developed intermittent difficulty with inspiration postoperatively which resolved following correction of a congenital abnormality of the epiglottis. A second patient with severe thoracic scoliosis and chronic bronchitis developed respiratory distress on the day following surgery, which resolved with medical therapy. Sorenson and Hamby [171] reported postoperative dysphagia in 21 of 44 patients (48%) after cervical rhizotomies and spinal acccessory nerve sectioning. Hamby and Schiffer [85] noted that 15 of 47 patients suffered from dysphagia postoperatively. Videofluoroscopic barium swallow examinations were performed by Horner et al. [91] on 41 patients with ST both before and after surgery in order to determine the risk factors for dysphagia after ventral cervical rhizotomies and spinal accessory nerve sectioning. In this group of patients, dysphagia was already present in 68% of patients prior to surgery

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and increased to 95% postoperatively. This increase is probably related to the partial innervation of intrinsic pharyngeal muscles by the cranial (internal) branch of the spinal accessory nerve (CNXI) and the extrinsic pharyngeal muscles by CNXI in addition to the ansa cervicalis (C1–C3) [93]. Increased risk of dysphagia in the postoperative period was related to the preoperative duration of torticollis and seemed unrelated to age, sex, or type of torticollis [93]. Two patients in the author’s series had cerebrospinal fluid leakage through the operative site; both were treated with local wound care and neither required wound revision. Two elderly patients died during the postoperative period, 1 of complications following an intraoperative myocardial infarction and the second of aspiration pneumonia secondary to impaired swallowing. Tasker reported 1 death (2%) and 1 patient each with CSF leakage and meningitis, carbon dioxide narcosis, epileptic seizures, ulnar nerve compression from faulty positioning, transient hemiparesis, and hemihypoesthesia. The latter two complications were postulated to be a result of occlusion of a radicular artery and can potentially be avoided by careful dissection under the operating microscope [2, 164, 165]. Following high cervical rhizotomies, patients may note neck weakness and limited range of neck motion. Abnormal movements may persist due to innervation of the splenius capitus and semispinalis capitus muscles through the C4 and C5 nerve rootlets. Intra- or extradural sectioning of these rootlets can result in shoulder pain and weakness and loss of diaphragm contraction. Most patients note that their cervical range of motion increases with time. The vast majority of patient’s in the author’s experience retained a surprisingly good ability to turn their heads, and neck weakness was a rarity after the completion of postoperative physical therapy. Spinal instability is a potential complication following cervical laminectomy and denervation of the cervical musculature. Sorensen and Hamby [171] reported that 3 of their 70 patients developed cervical spinal subluxation after surgery. Tasker [181] reported a 4% incidence of cervical subluxation or dislocation in 73 patients treated by intradural anterior rhizotomy in various combinations along with either partial intradural section of the eleventh nerve or selective denervation of the sternomastoid muscle in the neck. One patient in Tasker’s series developed cervical spine subluxation severe enough to cause a quadriparesis which resolved after surgical stabilization of the cervical spine. One in 58 patients in the author’s series developed a postoperative worsening of cervical kyphosis associated with a difficulty in maintaining an upright head position. This patient had suffered from torticollis for 23 years and had developed a severe compensatory thoracic scoliosis. This did not require surgical intervention.

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Conclusion Torticollis is an adult-onset focal dystonia characterized by abnormal neck postures with various possible etiologies. Although patients demonstrate characteristic abnormalities on EMG, no neurodiagnostic method exclusively establishes the diagnosis. Botulinum toxin A can be useful for symptomatic relief in most patients with torticollis, but is increasingly associated with the development of antibody formation, unavoidable weakness and a uniform need for repeated administrations. A variety of surgical procedures have been advocated for treatment of torticollis. Although a technically demanding procedure, Bertrand’s selective posterior denervation technique offers certain theoretical advantages. Ventral rhizotomy, when performed in conjunction with spinal accessory neurectomy, offers a more than 80% chance of fair to excellent results. This procedure is more likely to alleviate the patient’s pain and involuntary muscle contractions than restore normal head position. The likelihood of neutral head position postoperatively is inversely related to the duration of the patient’s condition preoperatively. This fact along with an increased risk of dysphagia in patients with a prolonged duration of preoperative torticollis should prompt early referral and evaluation for possible surgical correction after other modalities have failed. References 1 2 3 4

5 6 7 8 9 10

Abrahams VC: The physiology of neck muscles; their role in head movement and maintenance of posture. Can J Physiol Pharmacol 1977;55:332–338. Adams CBT: Vascular catastrophe following the Dandy-McKenzie operation for spasmodic torticollis. J Neurol Neurosurg Psychiatry 1984;47:990–994. Anderson TJ, Rivest J, Stell R, et al: Botulinum toxin treatment of spasmodic torticollis. J R Soc Med 1992;85:524–529. Anderson T, Marsden CD: Botulinum toxin for the treatment of spasmodic torticollis and other movement disorders; in Gildenberg PL, Tasker RR (eds): Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, chapt 109, pp 1059–1069. Ando T, Kayama T, Saito S, et al: The EMG findings of spasmodic torticollis – The character of the EMG findings of neurogenic torticollis. Brain Nerve 1997;49:619–26. Andrew J, Fowler CJ, Harrison MJ: Stereotaxic thalamotomy in 55 cases of dystonia. Brain 1983; 106:981–1000. Andrew J, Rice Edwards JM, Rudolf N de M: The placement of stereotaxic lesions for involuntary movements other than in Parkinson’s disease. Acta Neurochir Suppl (Wien) 1974;21:39–47. Arseni C, Maretsis M: The surgical treatment of spasmodic torticollis. Neurochirurgia (Stuttg) 1971;14:177–180. Ashizawa T, Jankovic J: Cervical dystonia as the initial presentation of Huntington’s disease. Mov Disord 1996;11:457–459. Battista AF: Percutaneous thermolytic fractional destruction of branches of the facial nerve for the relief of blepharospasm; in Bosniak SL (ed): Blepharospasm. Adv Ophthal Plast Reconstr Surg. New York, Pergamon Press, 1985, vol 4, pp 369–377.

Surgery for Spasmodic Torticollis

323

11

12 13 14 15 16 17 18

19

20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 35 36

Becker G, Naumann M, Scheubeck M, et al: Comparison of transcranial sonography, magnetic resonance imaging, and single photon emission computed tomography findings in idiopathic spasmodic torticollis. Mov Disord 1997;12:79–88. Bertrand C, Molina-Negro P, Bouvier G, Benabou R: Surgical treatment of spasmodic torticollis; in Youmans JR (ed): Neurological Surgery, ed 4. Philadelphia, Saunders, 1996, pp 3701–3712. Bertrand C, Molina-Negro P, Bouvier G, Gorczyca W: Observations and analysis of results in 131 cases of spasmodic torticollis after selective denervation. Appl Neurophysiol 1987;50:319–323. Bertrand C, Molina-Negro P, Martinez SN: Combined stereotactic and peripheral surgical approach for spasmodic torticollis after selective denervation. Appl Neurophysiol 1978;50:319–323. Bertrand C, Molina-Negro P, Martinez SN: Stereotactic targets for dystonias and dyskinesias: Relationship to corticobulbar fibers and other adjoining structures. Adv Neurol 1979;24:395–399. Bertrand C, Molina-Negro P: Selective peripheral denervation in 111 cases of spasmodic torticollis: Rationale and results. Adv Neurol 1988;50:637–643. Bertrand CM: Selective peripheral denervation for spasmodic torticollis: Surgical technique, results, and observations in 260 cases. Surg Neurol 1993;40:96–103. Bertrand CM: Surgical management of spasmodic torticollis and adult-onset dystonia; in Schmidek HH, Sweet WH (eds): Operative Neurosurgical Techniques, ed 3. Philadelphia, Saunders, 1995, vol 2, chapt 133, pp 1649–1657. Bertrand CM: Surgical management of spasmodic torticollis and adult-onset dystonia with emphasis on selective denervaton; in Schmidek H, Sweet W (eds): Operative Neurosurgical Techniques. Orlando, Grune & Stratton, 1988, vol 2, pp 1261–1269. Bertrand C, Siegried J: Extrapyramidal Disorders – Session II. Proc 6th Symp Int Soc Res Stereoencephalotomy, Tokyo 1973, Part II. Confin Neurol 1975;37:9. Biary N, Al Deeb SM, Aabed M: Post-traumatic dystonia. Ann Neurol 1991;30:297. Bisdorff AR, Bronstein AM, Wolsley C, Lees AJ: Torticollis due to disinhibition of the vestibulocollic reflex in a patient with Steele-Richardson-Olszewski syndrome. Mov Disord 1997;12:328–336. Blackie JD, Lees AJ: Botulinum toxin treatment in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1990;53:640–643. Bolsen E: Torticollis caused by infratentorial tumors: Three cases. Br J Psychiatry 1979;134:306–307. Boonkongchuen P, Lees A: Case of torticollis occurring following electrical injury. Mov Disord 1996;11:109–110. Braun V, Richter HP: Selective peripheral denervation for the treatment of spasmodic torticollis. Neurosurgery 1994;35:58–63. Bressman SB, Warner TT, Almasy L, et al: Exclusion of the DYT1 locus in familial torticollis. Ann Neurol 1996;40:681–684. Brin MF, Fahn S, Moskowitz CB, et al: Injections of botulinum toxin for the treatment of focal dystonia (abstract). Neurology 1986;36(suppl 1):120. Brin MF, Fahn S, Moskowitz C, et al: Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237–254. Brudny J, Grynbaum BB, Korein J: Spasmodic torticollis: Treatment by feedback display of the EMG. Arch Phys Med Rehabil 1974;55:403–408. Burke RE, Fahn S, Jankovic J, et al: Tardive dystonia: Late-onset and persistent dystonia caused by antipsychotic drugs. Neurology (NY) 1982;32:1335–1346. Burke RE, Fahn S, Marsden CD: Torsion dystonia: A double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986;36:160–164. Callahan A: Neurectomy of the facial nerve plexus and partial removal of orbicularis muscle for blepharospasm; in Bosniak SL (ed): Blepharospasm. Adv Ophthal Plast Reconstr Surg. New York, Pergamon Press, 1985, vol 4, pp 379–384. Cammarota A, Gershankic OS, Garcia S, Lera G: Cervical dystonia due to spinal cord ependymoma: Involvement of cervical cord segments in the pathogenesis of dystonia. Mov Disord 1995;10:500–503. Cardella MA: Botulinum toxoids; in Lewis KH, Cassel K (eds): Botulism: Proceedings of a symposium. Cincinnati, US Department of Health, Education and Welfare, Public Health Service, 1964, pp 113–130. Caress JB, Nohria V, Fuchs H, Boustany RM: Torticollis acquired late in infancy due to a cerebellar gangliocytoma. Int J Pediatr Otorhinolaryngol 1996;36:39–44.

Villavicencio/Friedman

324

37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67

Causey AL, Evans OB, Lewis-Abney K: Intervertebral disk calcification: An unusual cause of acquired torticollis in childhood. Pediatr Emerg Care 1996;12:356–359. Chen XK, Ji SX, Zhu GH, Ma AB: Operative treatment of bilateral retrocollis. Acta Neurochir (Wien) 1991;113:180–183. Claypool DW, Duane DD, Ilstrup DM, Melton LJ 3rd: Epidemiology and outcome of cervical dystonia (spasmodic torticollis) in Rochester, Minnesota. Mov Disord 1995;10:608–6014. Colosimo C, Kocen RS, Powell M, Lees AJ: Torticollis after electrocution. Mov Disord 1993;8: 117–124. Cooper IS: Effect of thalamic lesions upon torticollis. N Engl J Med 1964;270:967–972. Cooper IS: Neurosurgical treatment of the dyskinesias. Clin Neurosurg 1977;24:367–390. Couch JR: Dystonia and tremor in spasmodic torticollis; in Eldridge R, Fahn S (eds): Advances in Neurology, vol 14: Dystonia. New York, Raven Press, 1976, pp 245–258. Dandy WE: An operation for the treatment of spasmodic torticollis. Arch Surg 1930;20:1021–1032. DasGupta BR: The structure of botulinum neurotoxin; in Simpson LL (ed): Botulinum Neurotoxin and Tetanus Toxin. San Diego, Academic Press, 1989, pp 53–66. Dauer WT, Burke RE, Greene P, Fahn S: Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 1998;1121:547–560. Davis DH, Ahlskog JE, Litchy WJ, Root LM: Selective peripheral denervation for torticollis: Preliminary results. Mayo Clin Proc 1991;66:365–371. Davis DH, Duane DD, Swenson MK: Long-term outcome of iontophoresis treatment for torticollis. Stereotact Funct Neurosurg 1996;66:198–201. De Benedittis G: Hypnosis and spasmodic torticollis – Report of four cases: A brief communication. Int J Clin Exp Hyph 1996;44:292–306. Dekel B, Paret G, Vardi A, et al: Torticollis: An unusual presentation of spontaneous pneumomediastinum. Pediatr Emerg Care 1996;12:352–353. Dieckmann G: Stereotaxic treatment of extrapyramidal torticollis. Neurochirurgie 1976;22:568–571. Dieckmann K, Maurage C, Rolland JC, et al: Torticollis as a side effect of cisapride treatment in an infant (letter). J Pediatr Gastroenterol Nutr 1996;22:336. Driollet R, Schvarcz JR, Orlando J: Surgical managment of torticollis. Confin Neurol 1972;37:9. Duane DD, Svien HJ: Preliminary evaluation of labyrinthine suppression in the treatment of spasmodic torticollis. Neurology 1972;22:399. Dutton JJ: Botulinum – A toxin in the treatment of craniocervical muscle spasms: Short- and longterm, local and systemic effects. Surv Ophthalmol 1996;41:51–65. Elston JS, Lee JP, Powell CM, et al: Treatment of strabismus in adults with botulinum toxin A. Br J Ophthalmol 1985;69:718–724. Fabinyi G, Dutton J: The surgical treatment of spasmodic torticollis. Aust NZ J Surg 1980;50: 155–157. Fahn S: High dosage anticholinergic therapy in dystonia. Neurology (Cleveland) 1983;33:1255–1261. Fahn S: Lack of benefit from cervical cord stimulation for dystonia (letter). N Engl J Med 1985; 313:1229. Fahn S, Marsden CD, Calne DB: Clarification and investigation of dystonia; in Marsden CD, Fahn S (eds): Movement Disorders, ed 2. London, Butterworth Int Med Rev, 1987, pp 323–361. Fahn S: The clinical spectrum of motor tics; in Friedhoff AJ, Chase TN (eds): Advances in Neurology, vol 35: Gilles de la Tourette Syndrome. New York, Raven Press, 1982; pp 241–344. Fahn S: The varied clinical expressions of dystonia. Neurol Clin 1984;2:541–554. Fahn S: Torsion dystonia: Clinical spectrum and treatment. Semin Neurol 1982;2:316–323. Finney JMT, Hughson W: Spasmodic torticollis. Ann Surg 1925;81:255–269. Finsterer J, Fuchs I, Mamoli B: Quantitative electromyography-guided botulinum toxin treatment of cervical dystonia. Clin Neuropharmacol 1997;20:42–28. Fletcher NA, Harding AE, Marsden CD: A case control study on idiopathic torsion dystonia. Mov Disord 1991;6:304–309. Freckmann N, Hagenah R, Herrmann HD, Muller D: Bilateral microsurgical lysis of the spinal accessory nerve roots for treatment of spasmodic torticollis – Follow-up of 33 cases. Acta Neurochir (Wien) 1986;83:47–53.

Surgery for Spasmodic Torticollis

325

68

69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

95 96

Freckmann N, Hagenah R, Herrmann HD, Muller D: Bilateral microsurgical lysis of the spinal accessory nerve roots for treatment of spasmodic torticollis – Indication, technique and first results. Acta Neurochir (Wien) 1981;59:167–175. Friedman A, Fahn S: Spontaneous remissions in spasmodic torticollis. Neurology 1986;36:398–400. Friedman A, Nashold BS, Sharp R, et al: Treatment of spasmodic torticollis with intradural selective rhizotomies. J Neurosurg 1993;78:46–53. Galardi G, Perani D, Grassi F, et al: Basal ganglia and thalamo-cortical hypermetabolism in patients with spasmodic torticollis. Acta Neurol Scand 1996;94:172–176. Gelb DJ, Lowenstein DH, Aminoff MJ: Controlled trial of botulinum toxin injections in the treatment of spasmodic torticollis. Neurology 1989;39:80–84. Gilbert JG: Familial spasmodic torticollis. Neurology 1977;27:11–13. Gildenberg PL: Comprehensive management of spasmodic torticollis. Appl Neurophysiol 1981;44: 233–243. Gildenberg PL, Tasker RR: Spasmodic torticollis. Contemp Neurosurg 1982;4:1–7. Greene P, Fahn S, Diamond B: Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord 1994;9:213–217. Greene P, Fahn S: Use of botulinum toxin type F injections to treat torticollis in patients with immunity to botulinum toxin type A. Mov Disord 1993;8:479–483. Greene P, Kang U, Fahn S, et al: Double-blind placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 1990;40:1213–1218. Greene P, Shale H, Fahn S: Analysis of open-label trials in torsion dystonia using high dosages of anticholergics and other drugs. Mov Disord 1988;3:46–60. Grunewald RA, Yoneda Y, Shipman JM, Sagar HJ: Idiopathic focal dystonia: A disorder of muscle spindle afferent processing? Brain 1997;120:2179–2185. Guillain G, Bize R: Sur un cas de scle´rose en plaques avec torticolis spasmodique. Rev Neurol 1933;40:133–138. Gupta AK, Roy DR, Conlan ES, Crawford AH: Torticollis secondary to posterior fossa tumors. J Pediatr Orthop 1996;16:505–507. Haberman E, Dreyer F: Clostridial neurotoxins: Handling and action at the cellular and molecular level. Curr Top Microbiol Immunol 1986;129:93–179. Hambleton P, Cohen HE, Palmer BJ, Melling J: Antitoxins and botulinum toxin treatment. BMJ 1992;304:959–960. Hamby WB, Schiffer S: Spasmodic torticollis: Results after cervical rhizotomy in 50 cases. J Neurosurg 1969;31:323–326. Harries PG: Retropharyngeal abscess and acute torticollis. J Laryngol Otol 1997;111:1183–1185. Hassler R, Dieckmann G: Stereotactic treatment of different kinds of spasmodic torticollis. Confin Neurol 1970;32:135–143. Hassler R, Mundinger F, Riechert T: Stereotaxis in Parkinson Syndrome: Clinical-Anatomical Contributions to Its Pathophysiology. Berlin, Springer, 1979. Hassler R, Hess WR: Experimentelle und anatomische Befunde u¨ber die Drehbewegungen and ihre nervo¨sen Apparate. Arch Psychiatr Nervenkr 1954;192:488–526. Hathaway C, Dang C: Immunogenicity of the neurotoxins of Clostridium botulinum, chapt 8; in Jankovic J, Hallet M (eds): Therapy with Botulinum Toxin. New York, Dekker, 1994. Hernesniemi J, Keranen T: Long-term outcome after surgery for spasmodic torticollis. Acta Neurochir (Wien) 1990;103:128–130. Hertz E, Glaser GH: Spasmodic torticollis: Clinical evaluation. Arch Neurol Psychiatry 1949;61: 227–239. Horner J, Riski JE, Ovelman-Levitt J, Nashold BS Jr: Swallowing in torticollis before and after rhizotomy. Dyshpagia 1992;7:117–125. Houser MK, Sheean GL, Lees AJ: Further studies using higher doses of botulinum toxin type F for torticollis resistant to botulinum toxin type A. J Neurol Neurosurg Psychiatry 1998;64:577– 580. Isaac K, Cohen JA: Post-traumatic torticollis. Neurology 1989;39:1642–1643. Iskandar BJ, Nashold BS Jr: History of functional neurosurgery. Funct Neurosurg 1995;6:1–25.

Villavicencio/Friedman

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Jahanshahi M, Marion MH, Marsden CD: Natural history of adult-onset idiopathic torticollis. Arch Neurol 1990;47:548–552. Jankovic J: Blepharospasm with basal ganglia lesions. Arch Neurol 1986;43:866–868. Jankovic J, Brin MF: Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186–1194. Jankovic J, Fahn S: Dystonic syndromes; in Jankovic J, Tolosa E (eds): Parkinson’s Disease and Movement Disorders. Baltimore, Urban & Schwarzenberg, 1988, pp 283–314. Jankovic J, Nutt JG: The genetics of blepharospasm and orofacial-cervical dystonia (Meige syndrome) (abstract). Neurology 1985;35(suppl 1):271. Jankovic J, Orman J: Botulinum A toxin for cranial-cervical dystonia: A double-blind, placebocontrolled study. Neurology 1987;37:616–623. Jankovic J, Schwartz K: Clinical correlates of response to botulinum toxin injections. Arch Neurol 1991;48:1253–1256. Jankovic J, Schwartz K: Botulin toxin injections for cervical dystonia. Neurology 1990;40:277– 280. Jankovic J, Schwartz K, Donovan DT: Botulinum toxin for treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:663. Jankovic J, Schwartz K: Response and immunoresistance to botulinum toxin injections. Neurology 1995;45:1743–1746. Jho HD, Jannetta PJ: Microvascular decompression for spasmodic torticollis. Acta Neurochir (Wien) 1995;134:21–26. Jho HD, Jannetta PJ: Spasmodic torticollis treated with microvascular decompression of the spinal accessory nerve and the brain stem (abstract). J Neurosurg 1989;70:312A. Kamiji T: Torticollis and traumatic ocular dystopia (letter). Ann Plast Surg 1997;39:554–555. Kandel EI: Spasmodic torticollis; in Kandel EI (ed): Functional and Stereotactic Neurosurgery. New York, Plenum Publishers, 1989, chapt 8, pp 267–288. Keen WW: A new operation for spasmodic wry neck, namely, division or exsection of the nerves supplying the posterior rotator muscles of the head. Ann Surg 1891;13:44–47. Kikuchi K, Kowada M, Kojima H: Hypoplasia of the internal carotid artery associated with spasmodic torticollis: The possible role of altered vertebrobasilar haemodynamics. Neuroradiology 1995;37:362–364. Klostermann W, Vieregge P, Kompf D: Spasmodic torticollis in multiple sclerosis: Significance of an upper cervical spinal cord lesion. Mov Disorders 1993;8:234–236. Korein J, Brudny J: Integrated EMG feedback in the management of spasmodic torticollis and focal dystonia: A prospective study of 80 patients; in Yahr MD (ed): The Basal Ganglia. Research Publications: Associating for Research in Nervous and Mental Diseases. New York, Raven Press, 1976, vol 55, pp 385–424. Krack P, Schneider S, Deuschl G: Geste device in tardive dystonia with retrocollis and opisthotonic posturing. Mov Disord 1998;13:155–157. Krauss JK, Seeger W, Jankovic J: Cervical dystonia associated with tumors of the posterior fossa. Mov Disord 1997;12:443–447. Kutvonen O, Dastidar P, Nurmikko T: Pain in spasmodic torticollis. Pain 1997;69:279–286. Laitinen LV, Vilkki J: Observations on physiologic and psychological function of the ventral oral internal nucleus of the human thalamus. Acta Neurol Scand 1977;55:198–212. Lee MC: Spasmodic torticollis and other idiopathic torsion dystonias. Medical management. Postgrad Med 1984;75:139–141. Leube B, Hendgen T, Kessler KR, et al: Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe. Am J Med Genet 1997;74:529–532. Lew MF, Adornato BT, Duane DD, et al: Botulinum toxin type B: A double-blind, placebocontrolled, safety and efficacy study in cervical dystonia. Neurology 1997;49:701–707. Lobbezoo F, Tanguay R, Thon MT, Lavigne GJ: Pain perception in idiopathic cervical dystonia (spasmodic torticollis). Pain 1996;67:483–491. Lowenstein DH, Aminoff MJ: The clinical course of spasmodic torticollis. Neurology 1988;38: 530–532.

Surgery for Spasmodic Torticollis

327

124 125 126 127 128

129 130 131 132 133 134 135 136 137 138 139 140

141

142 143 144 145 146

147 148 149

Ludlow CL, Naunton RF, et al: Effects of botulinum toxin injections on speech in adductor spasmodic dysphonia. Neurology 1988;38:1220–1225. Magyar-Lehmann S, Antonini A, Roelcke U, et al: Cerebral glucose metabolism in patients with spasmodic torticollis. Mov Disord 1997;12:704–708. Maki Y, Akimoto H, Enomoto T: Injuries of basal ganglia following head trauma in children. Childs Brain 1980;7:113–123. Marsden CD, Marion MH, Quinn N: The treatment of severe dystonia in children and adults. J Neurol Neurosurg Psychiatry 1984;47:1166–1173. Marsden CD: The problem of adult-onset idiopathic torsion dystonia and other isolated dyskinesias in adult life (including blepharospasm, oromandibular dystonia, dystonic writer’s cramp and torticollis, or axial dystonia); in Eldridge R, Fahn S (eds): Advances in Neurology, vol 14: Dystonia. New York, Raven Press, 1976, pp 259–276. Matthews WB, Acheson ED, Batchelor JR, Weller RO: McAlpine’s Multiple Sclerosis. Edinburgh, Churchill Livingstone, 1985, pp 1–118. Matthews WB, Beasley P, Parry-Jones W, et al: Spasmodic torticollis: A combined clinical study. J Neurol Neurosurg Psychiatry 1978;41:485–492. Mazars G, Merienne L, Chodkiewicz JP: La chirurgie des dyskine´sies d’orientation ce´phalique. Neurochirurgie 1968;14:745–752. Mazars G, Merienne L: Surgical treatment of spastic torticollis and associated dyskinesias by interruption of cortico-capsular head-turning pathways. Excerpta Med Int Congr Ser 1974;293:18. McKenzie KG: Intermeningeal division of the spinal accessory and roots of the upper cervical nerves for the treatment of spasmodic torticollis. Surg Gynecol Obstet 1924;39:5–10. McKenzie KG: The surgical treatment of spasmodic torticollis. Clin Neurosurg 1955;2:37–43. Meares R: Natural history of spasmodic torticollis, and effect of surgery. Lancet 1971;ii:149–150. McKnight P, Friedman J: Torticollis due to cervical epidural abscess and osteomyelitis. Neurology 1992;42:696–697. Miller RH, Woodson GE, et al: Botulinum toxin injection of the vocal fold for spasmodic dysphonia: A preliminary report. Arch Otolaryngol Head Neck Surg 1987;113:603–605. Molho ES, Factor SA: Basal ganglia infarction as a possible cause of cervical dystonia. Mov Disord 1993;8:213–216. Mundinger F, Riechert T, Disselhoff J: Long-term results of stereotactic treatment of spasmodic torticollis. Confin Neurol 1972;34:41–50. Naumann M, Perker W, Reiners K, et al: Imaging the pre- and postsynaptic side of striatal dopaminergic synapses in idiopathic cervical dystonia: A SPECT study using [123I]epidepride and [123I]betaCIT. Mov Disord 1998;13:319–323. Nittner K, Petrovici IN: Contribution in the pathogenesis of Parinaud’s syndrome: Vertical gaze paralysis following bilateral stereotaxic lesions in the interstitial nucleus region. Acta Neurochir Suppl (Wein) 1974;21:57–63. Pagni CA, Naddeo M, Faccani G: Spasmodic torticollis due to neurovascular compression of the 11th nerve. Case report. J Neurosurg 1985;63:789–791. Pahor AL, Cole J: The Birmingham mummy: The first torticollis in history. J Laryngol Otol 1995; 109:273–276. Parker AP, Robinson RO, Bullock P: Difficulties in diagnosing intrinsic spinal cord tumours. Arch Dis Child 1996;75:204–207. Patterson RM, Little SC: Spasmodic torticollis. J Nerv Ment Dis 1943;98:571–599. Perot PL: Upper cervical ventral rhizotomy and selective section of spinal accessory rootlets for spasmodic torticollis; in Wilson CB (ed): Neurosurgical Procedures. Baltimore, Williams & Wilkins, 1992, pp 163–168. Perot PL Jr: Selective section of spinal accessory rootlets and upper cervical anterior rhizotomy for spasmodic torticollis (abstract). Acta Neurol Scand 1970;46:619–620. Plant GT, Mermode AG, du Boulay EP, McDonald WI: Spasmodic torticollis due to a midbrain lesion in a case of multiple sclerosis. Mov Disord 1989;4:359–362. Podivinsky F: Torticollis; in Vinken PJ, Bruyn GW (eds): Diseases of the Basal Ganglia. Handbook of Clinical Neurology. Amsterdam, North-Holland/Elsevier, 1969, vol 6, pp 567–603.

Villavicencio/Friedman

328

150

151 152 153 154 155 156 157 158 159 160 161 162 163 164

165 166 167 168 169 170 171 172 173 174 175

Poewe W, Deuschl G, Nebe A, et al: What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double-blind, placebo-controlled, dose-ranging study using Dysport. J Neurol Neurosurg Psychiatry 1998;64:13–17. Poewe W, Schelosky L, Kleedorfer B, et al: Treatment of spasmodic torticollis with local injections of botulinum toxin. J Neurol 1992;239:21–25. Putnam TJ, Herz E, Glaser GH: Spasmodic torticollis: Surgical treatment. Arch Neurol Psychiatry 1949;61:240–247. Riechert T: Stereotactic Brain Operations: Methods, Clinical Aspects, Indications. Bern, Huber, 1980. Sano K, Sekino H, Tsukamoto Y, et al: Stimulation and destruction of the region of the interstitial nucleus in cases of torticollis and see-saw nystagmus. Confin Neurol 1972;34:331–338. Sano K, Yoshioka M, Mayanagi Y, et al: Stimulation and destruction of and around the interstitial nucleus of Cajal in man. Confin Neurol 1970;32:118–125. Sano K, Yoshioka M, Ogashuma M, et al: Central mechanisms of neck movements in the human brain stem. Confin Neurol 1967;29:107–111. Savino PJ, Sergott RC, Bosley TM, Schatz NJ: Hemifacial spasm treated with botulinum A toxin injection. Arch Ophthalmol 1985;103:1305–1306. Schiavo G, Benfenati F, Poulain B, et al: Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 1992;359:832–835. Schroder JM, Huffmann B, Braun V, Richter HP: Spasmodic torticollis: Severe compression neuropathy in rami dorsales of cervical nerves C1–6. Acta Neuropathologica 1992;84:416–424. Schwartz KS, Jankovic J: Predicting the response to botulinum toxin injections for the treatment of cervical dystonia (abstract). Neurology 1990;40(suppl 1):382. Scott AB: Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044–1049. Scott AB: Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc 1981;79:734–770. Scott AB, Kennedy RA, Stubbs HA: Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985;103:347–350. Scoville WB: Surgery for motor tics of the face and neck. Meeting of the British Society of Neurological Surgery and the American Academy of Neurological Surgery, Bermuda, Nov 6–9, 1974. Scoville WB, Bettis DB: Motor tics of the head and neck: Surgical approaches and their complications. Acta Neurochir (Wien) 1979;48:47–66. Shima F, Fukui M, Kitamura K, et al: Diagnosis and surgical treatment of spasmodic torticollis of 11th nerve origin. Neurosurgery 1988;22:358–363. Siegfried J, Hood T: Current status of functional neurosurgery. Adv Tech Stand Neurosurg 1983; 10:19–79. Simpson LL: Peripheral actions of the botulinum toxins; in Simpson LL (ed): Botulinum Neurotoxin and Tetanus Toxin. San Diego, Academic Press, 1989, pp 153–178. Simpson LL: The origin, structure, and pharmacologic activity of botulinum toxin. Pharmacol Rev 1981;33:155–188. Soland V, Evoy F, Rivest J: Cervical dystonia due to a frontal meningioma (letter). Mov Disord 1996;11:336–337. Sorenson BF, Hamby WB: Spasmodic torticollis: Results of 71 surgically treated cases. Neurology 1966;16:867–878. Stejskal L, Vladyka V, Tomanek Z: Surgical possibilities for alleviation of axial dyskinesias – Comparison with forced movements of the head and eyes. Appl Neurophysiol 1981;44:320–329. Stell R, Thompson PD, Marsden CD: Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1988;51:920–923. Svien HJ, Cody DTR: Treatment of spasmodic torticollis by suppression of labyrinthine activity: Report of a case. Mayo Clin Proc 1969;44:825–827. Sweet WH: What should the neurosurgeon do when faced with a malpractice suit? Clin Neurosug 1976;23:112–124.

Surgery for Spasmodic Torticollis

329

176 177 178 179 180

181

182 183

184 185 186 187 188

189 190 191 192 193 194

Taira T, Hitchcock E: Torticollis as an initial symptom of adult-onset dystonia musculorum deformans. No To Shinkei 1990;42:671–867. Taira T, Kawamura H, Tanikawa T, et al: Objective evaluation of selective peripheral denervation for spasmodic torticollis. Neurol Surg 1997;25:927–932. Taira T, Kawashima A, Kawamura H, et al: Lessons from experience of Bertrand’s selective peripheral denervation for splenius type torticollis. Neurol Surg 1996;24:221–226. Tarsy D: Brachial plexus neuropathy after botulinum toxin injection. Neurology 1997;49:1176–1177. Tasker RR: Overview of the surgical treatment of spasmodic torticollis; in Gildenberg PL, Tasker RR (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, chapt 108, pp 1053–1058. Tasker RR: The treatment of spasmodic torticollis by peripheral denervation: The McKenzie operation; in Morley TP (ed): Current Controversies in Neurosurgery. Philadelphia, Saunders, 1976, pp 448–454. Taylor AS: Operation for relief of spasmodic torticollis; in Johnson (ed): Operative Therapeutics. New York, Appleton Centrury-Crofts, 1915, vol 1, pp 525–612. Truong DD, Cullis PA, O’Brien CF, et al: BotB (botulinum toxin type B): Evaluation of safety and tolerability in botulinum toxin type A-resistant cervical dystonia patients (preliminary study). Mov Disord 1997;12:772–775. Tsui JK, Eisen A, Mak E, Carruthers J, et al: A pilot study on the use of botulinum toxin in spasmodic torticollis. Can J Neurol Sci 1985;12:314–316. Tsui JK, Eisen A, et al: Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;ii:245–247. Tsui JK, Wong NLM, Wong E, Calne DB: Production of circulating antibodies to botulinum-A toxin in patients receiving repeated injections for dystonia. Ann Neurol 1988;24:181. Uziel Y, Rathaus V, Pomeranz A, et al: Torticollis as the sole initial presenting sign of systemic onset juvenile rheumatoid arthritis. J Rheumatol 1998;25:166–168. Villavicencio AT, Friedman AH: Intradural rhizotomy for the treatment of torticollis; in Gildenberg PL, Tasker RR (eds): Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1998, chapt 107, pp 1039–1051. Williams CR, O’Flynn E, Clarke NM, Morris RJ: Torticollis secondary to ocular pathology. J Bone Joint SurgB 1996;78:620–624. Wycis HT, Gildenberg PL: Long-range evaluation of the surgical treatment of spasmodic torticollis (abstract). Excerpta Med 1969;193:97. Xinkang C: Selective resection and denervation of cervical muscles in the treatment of spasmodic torticollis: Results in 60 cases. Neurosurgery 1981;8:681–688. von Essen C, Augustinsson LE, Lindqvist G: VOI thalamotomy in spasmodic torticollis. Appl Neurophysiol 1980;43:159–163. Mundinger F, Riechert T, Disselhoff J: Long-term results of stereotaxic operations on extrapyramidal hyperkinesia (excluding parkinsonism). Conf Neurologia 1970;32:71–78. Krauss JK, Pohle T, Weber S, Ozdoba C, Burgunder JM: Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia. Lancet 1999;354:837–838.

Alan T. Villavicencio, MD, Room 4516, Blue Zone, South Hosp., Division of Neurosurgery, Duke University Medical Center, Durham, NC 27710 (USA) Tel. +1 919 681 6421, Fax +1 919 684 3407, E-Mail [email protected]

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Neural Transplantation in Parkinson’s Disease Thomas B. Freeman a, c, Alison E. Willing a, Tanja Zigova a, Paul R. Sanberg a, c, Robert A. Hauser b, c Departments of a Neurosurgery, b Neurology and c Pharmacology and Experimental Therapeutics, University of South Florida, College of Medicine, Tampa, Fla., USA

Background Fetal tissue transplantation was first utilized for the treatment of Parkinson’s disease (PD) for several reasons [1]. PD is characterized by the loss of a limited number of dopamine neurons, and symptoms are improved significantly with dopamine replacement therapies. Dopaminergic neurons function in a modulatory manner, and do not carry highly somatotopically organized information as in other neural systems. The target area for cellular replacement (the striatum) is a reasonably small surgical target. Finally, numerous laboratory studies have demonstrated that grafts can survive, reinnervate the brain, improve behavioral deficits in rodents and nonhuman primates, as well as reproduce many physiologic properties of normal dopaminergic neurons.

Neural Transplantation: Clinical Trials Clinical trials were first initiated in 1987 in Sweden. Since that time, over 350 patients have received neural transplants worldwide [2–25]. It is difficult to compare results from these multiple programs due to methodologic differences [1]. However, recent reports from most programs describe reproducible clinical improvements, as well as increases in fluorodopa uptake on PET scan (FD-PET). Results from most published trials have been reviewed recently [30]. The following will discuss conclusions that can be derived from available studies.

Donor Age The single most important variable that affects graft survival is the donor age [27]. Grafts must be obtained after dopamine neurons first develop, but before axonal extensions reach their target. After this developmental window, axotomy of transplanted neurons leads to poor graft viability. Optimal human fetal donor age in a xenograft model was found to occur between 5.5 and 9 weeks postconception, with a slightly longer age window when solid rather than suspension grafts were used [28]. Using identical techniques in patients [6], equally robust graft survival has been seen in 2 patients that came to autopsy [11, 12, 29]. Transplant programs that used donors older than this have reported poor survival of dopaminergic neurons within grafts [26].

Number of Donors The technical limitations associated with fetal tissue transplantation of multiple donors limits this procedure’s practical applicability if more than 1 or 2 donors are necessary. It is therefore important to define the minimum number of dopamine neurons required to induce clinical benefit before fetal tissue transplantation can be routinely used. It may not be necessary to transplant a full compliment of dopamine neurons, as PD patients only become symptomatic when the majority of nigral neurons and striatal dopamine is lost. When up to 4 donors per side have been transplanted, autopsy studies have demonstrated up to 137,000 surviving dopamine neurons per side, which corresponds to an approximately 5% survival rate of transplanted dopamine neurons [29]. This is similar to what has been observed in animal models [30]. We are currently performing an NIH-funded doseescalation trial to evaluate this parameter in a blinded, placebo-controlled manner.

Site of Transplantation The behavioral improvement that occurs in animals following transplantation correlates with the site of the graft within the brain [1]. Limitations on tissue availability restrict the ability to reinnervate the entire striatum. We initially chose to transplant into the posterior (postcommissural) putamen for several reasons [6]. This is the region that is predominantly depleted of dopaminergic innervation in PD, and that receives input from the precentral

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motor fields. Although there is appealing evidence to suggest that the caudate may be an important target for transplantation [1, 17, 18], no evidence to date suggests that the addition of transplants in the caudate gives improved clinical benefit in comparison to putamen grafts alone [23]. Also, such transplants may increase the risk of psychiatric disturbances [17]. PD is also associated with neuronal changes in other regions [31]. Transplantation into alternative targets, including the nucleus accumbens, substantia nigra or subthalamic nucleus may provide increased efficacy. No clinical trials have been initiated evaluating these alternative sites. Better results appear to be obtained with bilateral grafts [23].

Longevity of Graft Survival Graft survival has been demonstrated at autopsy in 2 patients with PD 18–19 months after transplantation [11, 12, 29, 32]. Longer graft survival can be anticipated for several reasons. Graft rejection was not seen in either of these patients [32]. The disease process does not affect transplants, as no Lewy bodies or abnormal neuromelanin accumulation were seen within any of the grafts [11, 12, 29]. At least 20 patients worldwide have been reported to have progressive improvement in striatal FD-PET at least 6 months after immunosuppression was discontinued [26]. Striatal FD-PET has steadily improved for up to 72 months after transplantation in 1 patient [22]. It is therefore likely that fetal tissue grafts will survive long term.

Immunologic Issues No graft rejection was observed in 13 immunologically unrelated neural grafts in 2 patients from our series [32]. Immunosuppression was not utilized for the last 12 months of the patients’ lives. However, in the same autopsy cases, markers of microglia, macrophages, T cells and B cells were observed in graft sites in the absence of graft rejection [32]. It is unclear if this represented an ineffective or attenuated immune response, a nonspecific reaction to surgical trauma, or a chronic rejection process. As mentioned above, the long-term improvement of FD-PET after discontinuation of cyclosporin further supports the lack of immunologic rejection of unrelated allografts in the absence of immunosuppression. However, definitive autopsy data obtained 5–10 years after transplantation is currently not available. It furthermore remains to be determined if any immunosuppression is required at all.

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Safety Issues The risks of infections related to transplants can be grouped into three categories: donor, nosocomial and opportunistic [33]. Of the greater than 800 estimated donors that have been transplanted using standard techniques, there is only one reported incidence of infection of any type that was treated without complication. Twenty-one of the patients that have received transplants have been reported (at least preliminarily) to have died since surgery. One of the deaths was due to an intraoperative bleed, 2 were due to graft misdissection, and the other 18 deaths were delayed and unrelated to surgery. Of interest, there are no reports of hemiparesis following transplantation, perhaps related to the large size of the striatum and ease of surgical targeting. In spite of this quite favorable safety profile, the Food and Drug Administration has proposed that fetal tissue transplantation be regulated as a cellular therapy [34, 35].

Pathologic Analysis of Fetal Grafts Several conclusions can be drawn from autopsy studies [10, 11, 29, 32]. There is definitive proof that fetal nigral grafts survive within the diseased brain following grafting. Neuritic processes extend into the host brain, and form synaptic connections with the host. Clinical improvement and improved FD-PET correlates with graft survival and host reinnervation. No sprouting occurs in the host. PD does not adversely affect the grafts. Neuritic outgrowth is variable, ranging from 2.5 to 7 mm within the striatum. Confluent reinnervation of up to 78% of the target area can be achieved. Reinnervation occurs in a striasome-matrix fashion reminiscent of the developing nigrostriatal system. Grafts derived from donor ages 6.5–9 weeks postconception, transplanted as solid grafts, survive reliably. Multiple unrelated allografts survive in the absence of chronic immunosuppression. Immune markers are activated following grafting without induction of rejection at 1.5 years. Grafts are metabolically active and take up, synthesize and store dopamine. The blood-brain barrier is intact around grafts. Graft maturation rate is delayed with respect to the normal developmental rate for dopamine neurons. Finally, nearly all of these findings correlate with similar observations in animal models of PD.

Future Directions The future of neural reconstruction for all neurologic diseases most likely rests on the development of new techniques to enhance survival of grafted

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cells, optimize production of specific neuronal phenotypes, reconstruct wider areas of neurodegeneration, and develop new sources of tissue to replace human fetal tissue. There are currently at least 18 different methods to achieve these goals. A clinically useful cell line must be safe, efficacious, and standardized both in vitro and in vivo. Methods to increase cell survival in transplants include the addition of caspase inhibitors to diminish dopaminergic neuronal apoptosis in grafts [36], the addition of antioxidants to increase graft viability [23, 37, 38], and treatment of grafted tissue with trophic factors either before or after transplantation [39–43]. Numerous alternative sources of dopaminergic cells have been proposed, including adrenal chromaffin cells [44], carotid body cells [45], astrocytes [46], genetically modified fibroblasts [47] and cross-species transplants [48]. The most promising techniques, where potential has yet to be fully realized, involve the transplantation of human neural stem cells that are phenotypically appropriate. Such a cell line should have the capability to migrate to appropriate target areas, extend axons, form synapses and integrate appropriately into the host brain without rejection. Human neural stem cells have recently been isolated [49, 50]. It may also be possible to stimulate a patient’s endogenous population of stem cells to proliferate and migrate into a pathologic brain region. The first such cell line to be tested clinically is derived from the hNT neuron [51–54]. Although these cells were initially used for the treatment of stroke, it may be possible to induce these cells to differentiate into dopamine neurons, which would be useful for the treatment of PD [55–56].

Summary In summary, proof of principle exists that neural transplantation provides clinical benefit and improved FD-PET that correlates with graft survival at autopsy. The target area within the striatum is a comparatively simple and safe target in comparison to other surgical therapies for PD. Long-term graft survival is likely. There are numerous ways to improve current techniques. Numerous methods for creating alternative cell sources are under investigation, and may soon reach the clinic.

References 1 2

Olanow CW, Freeman TB, Kordower JH: Fetal nigral transplantation as a therapy for Parkinson’s disease. Trends Neurosci 1996;19:102–109. Deacon T, Schumacher J, Dinsmore J, et al: Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease. Nat Med 1997;3:350–353.

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Defer GI, Geny C, Ricolfi F, et al: Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical approach. Brain 1996;119:41–50. Freed CR, Breeze RE, Rosenberg NL, et al: Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson’s disease. N Engl J Med 1992; 327:1549–1555. Freed CR, Breeze RE, Rosenberg NL, et al: Transplantation of human fetal dopamine cells for Parkinson’s disease. Results at 1 year. Arch Neurol 1990;47:505–512. Freeman TB, Olanow CW, Hauser RA, et al: Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson’s disease. Ann Neurol 1995;38:379–388. Hauser RA, Freeman TB, Snow BJ, et al: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson’s disease. Arch Neurol 1999;56:179–187. Henderson BTH, Clough CG, Hughes RC, et al: Implantation of human fetal ventral mesencephalon to the right caudate nucleus in advanced Parkinson’s disease. Arch Neurol 1991;48:822–827. Iacono RP, Tang ZS, Mazziotta JC, et al: Bilateral fetal grafts for Parkinson’s disease: 22 months’ results. Stereotact Funct Neurosurg 1992;58:84–87. Kopyov OV, Jacques D, Lieberman A, et al: Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson’s disease. Cell Transplant 1996;5:327–337. Kordower JH, Freeman TB, Snow BJ, et al: Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med 1995;332:1118–1124. Kordower JH, Freeman TB, Chen EY, et al: Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease. Mov Disord 1998;13:383–393. Lindvall O, Brundin P, Widner H, et al: Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 1990;247:574–577. Lindvall O, Rehnchrona S, Brundin P, et al: Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol 1989;46:615–631. Lindvall O, Sawle G, Widner H, et al: Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol 1994;35:172–180. Lindvall O, Widner H, Rhencrona S, et al: Transplantation of fetal dopamine neurons in Parkinson’s disease: One-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol 1992;31:155–165. Lopez-Lozano JJ, Bravo G, Brera B, et al: Long-term improvement in patients with severe Parkinson’s disease after implantation of fetal ventral mesencephalic tissue in a cavity of the caudate nucleus: 5-year follow-up in 10 patients. J Neurosurg 1997;86:931–942. Molina H, Quinones R, Alvarez L, et al: Transplantation of human fetal mesencephalic tissue in caudate nucleus as treatment for Parkinson’s disease: The Cuban experience; in Lindvall A, Bjorklund A, Widner H (eds): Intracerebral Transplantation in Movement Disorders. Amsterdam, Elsevier Science, 1991, pp 99–110. Peschanski M, Defer G, N’Guyen JP, et al: Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson’s disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 1994;117:487–499. Saveliev SV, Lebedev VV, Evgeniev MB, Korochkin LI: Chimeric brain: Theoretical and clinical aspects. Int J Dev Biol 1997;41:801–808. Spencer DD, Robbins RJ, Naftolin F, et al: Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease. N Engl J Med 1992;327:1541–1548. Wenning GK, Odin P, Morrish P, et al: Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann Neurol 1997;42:95–107. Widner H: The Lund transplant program for Parkinson’s disease and patients with MPTP-induced parkinsonism; in Freeman TB, Widner H (eds): Cell Transplantation for Neurological Disorders: Toward Reconstruction of the Human Central Nervous System. Totowa/NJ, Human Press, 1998, pp 1–17. Widner H, Tetrud J, Rehhcrona S: Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-2,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992;327:1556–1563.

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Zabek M, Mazurowski W, Dymecki J, et al: A long-term follow-up of fetal dopaminergic neuron transplantation into the brain of three parkinsonian patients. Restor Neurol Neurosci 1994;6:97– 106. Freeman TB, Olanow CW, Hauser RA, et al: Human fetal tissue transplantation; in Germano IM (ed): Neurosurgical Treatment of Movement Disorders. Park Ridge/Ill, AANS Publications, 1998, pp 177–192. Bjorklund A, Stenevi U, Schmidt RH, et al: Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation. Acta Physiol Scand Suppl 1983;522:1–7. Freeman TB, Sanberg PR, Nauert GM, et al: The influence of donor age on the survival of solid and suspension intraparenchymal human embryonic nigral grafts. Cell Transplant 1995;4:141–154. Kordower JH, Rosenstein JM, Collier TJ, et al: Functional fetal nigral grafts in a patient with Parkinson’s disease: Chemoanatomic, ultrastructural, and metabolic studies. J Comp Neurol 1996; 370:203–230. Brundin P, Strecker RE, Widner H, et al: Human fetal dopamine neurons grafted in a rat model of Parkinson’s disease: Immunological aspects, spontaneous and drug-induced behaviour, and dopamine release. Exp Brain Res 1988;70:192–208. Lindvall O: Prospects of transplantation in human neurodegenerative diseases. Trends Neurosci 1991;14:376–384. Kordower JH, Styren S, Clark M, et al: Fetal grafting for Parkinson’s disease: Expression of immune markers in two patients with functional fetal nigral grafts. Cell Transplant 1997;6:213–219. Holt DA, Nauert GM, Othberg AI, et al: Infectious issues in fetal neural transplantation. Cell Transplant 1997;6:553–556. Freeman TB, Hauser RA, Sanberg PR: Fatal transplant cyst. J Neurosurg 1999;90:1148–1150. Food and Drug Administration (FDA): Proposed approach to regulation of cellular and tissuebased products. Docket No 97N-0068. Rockville/Md, FDA, 1997, pp 1–35. Schierle GS, Hansson O, Leist M, et al: Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nat Med 1999;5:97–100. Nakao N, Frodl EM, Duan W-M, et al: Lazaroids improve the survival of grafted rat embryonic dopaminergic neurons. Proc Natl Acad Sci USA 1994;91:12408–12412. Nakao N, Frodl EM, Widner H, et al: Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson’s disease. Nat Med 1995;1:226–231. Willing AE, Othberg AI, Saporta S, et al: Sertoli cells enhance the survival of co-transplanted dopamine neurons. Brain Res 1999;822:246–250. Pierret P, Quenneville N, Vandaele S, et al: Trophic and tropic effects of striatal astrocytes on cografted mesencephalic dopamine neurons and their axons. J Neurosci Res 1998;51:23–40. Albeck DS, Hoffer BJ, Quissell D, et al: A non-invasive transport system for GDNF across the blood-brain barrier. Neuroreport 1997;8:2293–2298. Ling ZD, Potter ED, Lipton JW, Carvey PM: Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 1998;149:411–423. Studer L, Tabar V, McKay RDG: Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1998;1:290–295. Kordower JH, Cochran E, Penn R, Goetz C: Putative chromaffin cell survival and enhanced hostderived TH-fiber innrervation following a functional adrenal medulla autograft for Parkinson’s disease. Ann Neurol 1991;29:565–572. Espejo EF, Montoro RJ, Armengol JA, Lopez-Barneo J: Cellular and functional recovery of parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates. Neuron 1998;20: 197–206. Tornatore C, Baker-Cairns B, Yadid G, et al: Expression of tyrosine hydroxylase in an immortalized human fetal astrocyte cells line: In vitro characterization and engraftment into the rodent striatum. Cell Transplant 1996;5:145–163. Fisher LJ, Jinnah HA, Kale LC, et al: Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-dopa. Neuron 1991;6:371–380. Deacon T, Schumacher J, Dinsmore J, et al: Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease. Nat Med 1997;3:350–353.

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Brustle O, Choudhary K, Karram K, et al: Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats. Nat Biotech 1998;16:1040–1044. Flax JD, Auroara S, Yang C, et al: Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotech 1998;16:1033–1039. Fackelmann K: Stroke rescue: Can cells injected into the brain reverse paralysis? Sci News 1998; 154:120–122. Pleasure SJ, Lee VMY: Ntera 2 cells: A human cell line which displays characteristics expected of a human committed neuronal progenitor cell. J Neurosci Res 1993;35:585–602. Saporta S, Borlongan CV, Sanberg PR: Neural transplantation of human neuroteratocarcinoma (hNT) neurons into ischemic rats. A quantitative dose-response analysis of cell survival and behavioral recovery. Neuroscience 1999;91:519–525. Borlongan CV, Tajima Y, Trojanowski JQ, et al: Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol 1998;149:310–321. Othberg AI, Willing AE, Cameron DF, et al: Trophic effect of porcine Sertoli cells on rat and human ventral mesencephalic cells and hNT neurons in vitro. Cell Transplant 1998;7:157–164. Zigova T, Willing AE, Tedesco EM, et al: Lithium chloride induces the expression of tyrosine hydroxylase in hNT neurons. Exp Neurol 1999;157:251–258.

Thomas B. Freeman, MD, FACS, Professor, Department of Neurosurgery, Department of Pharmacology and Experimental Therapeutics, University of South Florida, College of Medicine, 4 Columbia Dr., Suite 730, Tampa, FL 33606 (USA) Tel. +1 813 259 0889, Fax +1 813 259 0900, E-Mail [email protected]

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Neurosurgical Treatment of Spasticity Marc Sindou, Patrick Mertens Department of Neurosurgery, University of Lyon, France

In patients with upper motor neuron syndromes, spasticity usually develops. In most cases it is useful in compensating for lost motor strength. Nevertheless, in a significant number of patients it may become excessive, leading to further functional losses. When not controllable by physical therapy, medications and/or botulinum toxin, spasticity can benefit from neurosurgical procedures.

Intrathecal Baclofen The effectiveness of the method is linked to the presence of high concentrations of c-aminobutyric acid-B binding sites in the dorsal horn. This allows a decrease in the necessary dosage from an average of 10–90 mg/day orally to an average of 20–800 lg/day intrathecally. The method [1] uses a programmable pump device, implanted subcutaneously, consisting of a reservoir containing the drug that is refilled percutaneously every 3 months on average and a programmable pump that provides the desired flow. The most appropriate pump at the present time is the Synchromed pump from Medtronic Company. Intrathecal baclofen (ITB) is particularly indicated for patients with severe spasticity from spinal cord origin, especially if painful spasms are present, as in advanced multiple sclerosis [1, 2] or after spinal cord injury, when physical therapy and rehabilitation did not succeed in preventing harmful spasticity to appear. Our present experience of ITB to treat hyperspasticity from spinal origin in adults amounts to 45 cases. The results for the first 17 patients studied with an average follow-up of 3 years have been published in detail elsewhere [3, 4]. Hypertonia of the lower limbs was reduced in all patients. The mean Ashworth score (1>no increase in tone, 5>affected part rigid in flexion or extension) dropped from 3.9×0.5 to 1.9×0.9 under ITB (p=0.001) and spasms (0>no

spasm, 4>spasms occurring more than 10 times per hour) were decreased from 2.8×0.7 to 1.2×0.6 (p=0.001). In patients with spastic bladder, ITB produced a decrease of detrusor hyperactivity in half of them, with reduction of urine leakage and increase in bladder capacity. ITB can also be indicated for hyperspasticity due to brainstem lesions, and also in cerebral palsy patients [5]. Due to the big size of the available pump, ITB cannot be performed in children under 4 years of age. Children with associated choreoathetosis, hypotonia of neck and trunk, obesity, poor motivation and/or severe multiple deformities, are poor candidates for ITB. For cerebral palsy patients, it must be emphasized that the adequate doses, i.e. the ones effective on the excess of tone and not producing motor weakness, are often difficult to establish.

Peripheral Neurotomies Selective peripheral neurotomies [6–8] must be as selective as possible by using microsurgical techniques and intraoperative electrical stimulation for better identification of the function of the fascicles constituting the nerve. Selectivity is required to suppress the excess of spasticity without producing excessive weakening of motor strength and amyotrophy. To achieve this goal, preserving at least one-fourth of the motor fibers is necessary. Neurotomies are indicated when spasticity is localized to muscular groups supplied by a single or a few peripheral nerves that are easily accessible. To help the surgeon decide if neurotomy is appropriate, temporary local anesthetic block of the nerve with bupivacaine can be useful. Such a test can determine if articular limitations result from spasticity or musculotendinous contractures and/or articular ankyloses (only spasticity is decreased by the test). In addition, these tests give the patient an idea or what to expect from the operation. Botulinic toxin injections may also act as a (prolonged) test. For spasticity in the lower limbs [8, 9], neurotomies of the tibial nerve at the popliteal region and of the obturator nerve just below the subpubic canal, are the most commonly used, for the so-called spastic foot and for flexionadduction deformity of the hip, respectively. Selective neurotomies of the branches to the knee flexors (hamstrings) can also be performed at the level of the sciatic trunk through a short skin incision in the buttock. Neurotomies are also indicated for spasticity in the upper limb [9], in the musculocutaneous nerve for spastic elbow flexion, in the median (and ulnar) nerve for spastic hyperflexion of the wrist and fingers. Special care must be taken with the sensory fascicles to avoid painful manifestations. Recently neurotomies of brachial plexus branches have been developed for treating the spastic shoulder [10].

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Fig. 1. Movement analysis in a hemiplegic patient with a spastic foot (equino-varus) before and after selective tibial neurotomy. Top: Surface polyelectromyography of the tibialis anterior (LAED) and the triceps surae (LPD) muscles on the spastic leg during walking. Left: Preoperative recordings showing desynchronized activities of the triceps surae, with abnormal cocontractions of antagonist muscles: triceps surae and tibialis anterior. Right: After selective tibial neurotomy, there is a reappearance of muscular activities in the tibialis anterior muscle, a clear decrease in triceps surae activities, and normal alternance of contractions of these muscles (i.e. triceps surae at the end of the stance phase and tibialis anterior during the swing phase). Bottom: Tridimensional movement analysis of the ankle flexion-extension amplitude during the gait with Vicon system. Left: Preoperatively, the amplitude of the spastic ankle is limited to 18 degrees of dorsal flexion. Right: After selective tibial neurotomy, the dorsal flexion increased to 32º. Thus the tonic balance of the ankle has been re-equilibrated by the selective tibial neurotomy; consequently, motor function and gait have been improved.

Selective neurotomies are able not only to reduce excess of spasticity and deformity but also to improve motor function by re-equilibrating the tonic balance between agonist and antagonist muscles (fig. 1). This holds especially true in 82% of patients in our series of 180 tibial peripheral neurotomies (PN) performed in adult patients. Tibial neurotomy was the most frequently used PN in our experience (which amounts to more than 300 PN in adults over the past 20 years). In the spastic hemiplegic child, contrarily to the adult, the effects of tibial PN may be only transient. In our series of 13 pediatric cases

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followed long-term, 8 cases had a recurrence [11]. With regard to the spastic hand which is a very difficult problem to deal with, a functional benefit in prehension can only be achieved if patients retain a residual motor function in the extensor and supinator muscles, together with a sufficient residual sensory function. If these conditions are not present, only better comfort and better cosmetic aspect can be achieved. We recently performed 25 median (and ulnar) neurotomies combined, with tenotomies in the forearm (namely a Page-Scaglietti operation [12]), to treat spastic flexion of the wrist and fingers, with tendinous contractures. All patients in this special group who did not have any voluntary motor function preoperatively had better comfort and a good cosmetic effect, but without any significant functional benefit.

Posterior Rhizotomies To reduce the sensory side effects of the original Foerster method [13], Gros and co-workers [14, 15] introduced a technical modification that consisted of sparing one or several rootlets of each root, from L1 to S1. Later on, in an attempt to reduce the side effects of rhizotomy on postural tone in ambulatory patients, Gros and his pupils [16–18] proposed a topographic selection of the rootlets to be sectioned (sectorial posterior rhizotomy). First, preoperative assessment of spasticity useful for postural tone (abdominal muscles, quadriceps, gluteus medius) and spasticity harmful to the patient (hip flexors, adductors, hamstrings, and triceps surae) is done. Then, mapping the evoked motor activity of the exposed rootlets, from L1 to S2, by direct electrostimulation of each posterior group of rootlets is carried out, and the rootlets to be sectioned are determined according to the preoperative program. Fraioli and Guidetti [19] reported on a procedure of dividing the dorsal half of each rootlet of the selected posterior roots, a few millimeters before its entrance into the posterolateral sulcus (partial posterior rhizotomy). Good results have been reported by the authors, without significant sensory deficit, the latter explained by the fact that partial section leaves intact a large number of fibers of all types. The neurologic search for specially organized circuits responsible for spasticity led Fasano et al. [20] to propose the so-called functional posterior rhizotomy. The method is based on bipolar intraoperative stimulation of the posterior rootlets and analysis of the types of muscle responses by EMG recordings. Responses characterized by a permanent tonic contraction, an afterdischarge pattern or a large spatial diffusion to distant muscle groups, were considered to belong to disinhibited spinal circuits responsible for spasticity. This procedure – which was especially conceived for children with cerebral

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Fig. 2. Lumbosacral posterior rhizotomy for cerebral palsy children. Our personal technique consists of performing a limited osteoplastic laminotomy using a power saw, in one single piece, from T11 to L1 (left). The laminae will be replaced at the end of the procedure and fixed with wires (right). The dorsal (and ventral) L1, L2 and L3 roots are identified by means of the muscular responses evoked by electrical stimulation performed intradurally just before entry into their dural steaths. The dorsal sacral rootlets are recognized at their entrance into the dorsolateral sulcus of the conus medullaris. The landmark between S1 and S2 medullary segments is located at 30 mm approximately from the exit of the tiny coccygeal root from the conus. The dorsal rootlets of S1, L5 and L4 are identified by their evoked motor responses. The sensory roots for bladder (S2–S3) can be identified by monitoring vesical pressure, and those for the anal sphincter (S3–S4) can be identified by rectomanometry (or simply using finger introduced into the patient’s rectum) or EMG recordings. Surface spinal cord SEP recordings from tibial nerve (L5–S1) and pudendal nerve (S1–S3) stimulation may also be helpful. For the surgery to be effective a total amount of 60% of dorsal rootlets must be cut, of course with a different quantity cut according to the level and function of the roots involved. Also, the correspondence of the roots with the muscles having harmful spasticity or useful postural tone must be considered in determining the amount of rootlets to be cut; in most cases, L4 (which predominantly gives innervation to the quadriceps femoris) has to be preserved.

palsy – has also been used by other outstanding surgical teams, each one having brought its own technical modifications to the method [21–24]. Our personal adaptation of these methods is illustrated in figure 2. The results of posterior rhizotomies in children with cerebral palsy – whatever their technical modality may be – have been recently reported in several publications. We have reviewed and quoted them (46 references) on the occasion of the report of our own series [25]. Briefly, these publications show that about 75% of the patients had nearly normal muscle tone at 1 year or more after surgery, that no longer limited the residual voluntary movements of limbs. After a serious and persisting physical therapy and rehabilitation

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program, most children demonstrated improved stability in sitting and/or increased efficiency in walking. But installed deformities were not retrocessive.

Percutaneous Thermorhizotomies Percutaneous radiofrequency rhizotomy [26–30] is appropriate for spastic disturbances limited to a few muscular groups that correspond to a small number of spinal roots (as occurs in spastic hip which can be treated by thermorhizotomy of L2–L3). The effects are most often temporary, but the procedure can be repeated.

Longitudinal Myelotomy Longitudinal myelotomy [31–33] consists of a frontal separation between the posterior and anterior horns of the lumbosacral enlargement from T11 to S2 performed from inside the spinal cord after a posterior commisural incision that reaches the ependymal canal. Longitudinal myelotomy is indicated only for spastic paraplegias with flexion spasms, when the patient has no residual useful motor control and no bladder and sexual function.

Surgery in the Dorsal Root Entry Zone Surgery in the dorsal root entry zone (DREZ) was introduced in 1972 [34] to treat intractable pain. Because of its inhibitory effects on muscular tone, it has been applied to patients with focalized hyperspasticity [35–38]. This method – named microDREZotomy (MDT) – attempts to selectively interrupt the small nociceptive and the large myotatic fibers (situated laterally and centrally, respectively), while sparing the large lemniscal fibers which are regrouped medially. It also destroys the activatory cells of the dorsal horn and aims at preserving the inhibitory mechanisms of Lissauer’s tract and dorsal horn [39] (fig. 3, left). Microsurgical DREZotomy, the technique of which has been detailed elsewhere [40, 41], consists of microsurgical incisions that are 2–3 mm deep and at 35º angle for cervical level and at 45º angle for lumbosacral level followed by bipolar coagulations performed ventrolaterally at the entrance of the rootlets into the dorsolateral sulcus, along all the cord segments selected for operation (fig. 3, right). For patients with paraplegia [40], the L2–S5 segments are approached through a T11–L2 laminectomy, whereas for the

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Fig. 3. MicroDREZotomy. Left: Organization of fibers at the DREZ in humans. The large arrow shows the proposed extent of the microDREZotomy, that is, the lateral and central bundles formed by the nociceptive and myotatic fibers, as well as the excitatory medial part of the TL and the upper layers of the dorsal horn. Right: Principles of the technique of microDREZotomy. Example at the cervical level through a right cervical hemilaminectomy (the procedure for the lumbosacral roots is the same). The right C6 posterior root has been retracted toward the inside to make the ventrolateral region of the DREZ accessible. The incision is performed into the dorsolateral sulcus using a small piece of razor blade (upper operative view). The incision is 2–3 mm deep and is made at 35º angle (at 45º angle for the lumbosacral level). Then microcoagulations are created with a very sharp and graduated bipolar microforceps down to the apex of the dorsal horn (lower operative view).

hemiplegic upper limb [41], a C4–C7 hemilaminectomy with conservation of the spinous processes is sufficient to reach the C5–T1 segments. Identification of the cord levels related to the undesirable spastic mechanisms is achieved by studying the muscle responses to bipolar electrical stimulation of the anterior and/or posterior roots. The motor threshold for stimulation of anterior

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roots is one-third that of the threshold for posterior roots. Then, the lateral aspect of the DREZ is exposed so that the microsurgical lesions can be performed, 2–3 mm in depth and at 35–45º angles in the ventrolateral aspect of the sulcus all along the selected segments of the spinal cord. Intraoperative neurophysiological monitoring may be of some help for identifying cord levels, quantify the extent of MDT, and avoid impairing long fiber tracts. MDT is indicated in paraplegic patients, especially when they are bedridden as a result of disabling flexion spasms, and in hemiplegic patients with irreducible and/or painful hyperspasticity in the upper limb. MDT also can be applied to treat neurogenic bladder with uninhibited detrusor contractions resulting in voiding around a catheter. Our series to date consists of 45 cases of unilateral cervical (C5–T1) MDT for harmful spasticity in the upper limb, 121 cases of bilateral lumbosacral MDT (L2–S1 or S5) for disabling spasticity in the lower limbs, and 12 cases of bilateral sacral S2–S3 (S4) MDT for hyperactive neurogenic bladder only. A ‘useful’ result on spasticity allowing withdrawal of antispasmodic medications, was obtained in 78% of the patients with a spastic upper limb. A similarly useful effect was obtained in 75% of the patients with spasticity in the lower limbs. Improvement in abnormal postures and articular limitations was achieved in about 90% of our patients. For the hemiplegic upper limb, the increase in articular amplitude was most remarkable for the elbow and shoulder (when not ‘frozen’) but much more limited for the wrist and fingers, especially if there was retraction of the flexor muscles and no residual voluntary motor activity in the extensors. For the lower limb(s) with abnormal postures in flexion, the increase in articular amplitude was very much dependent on the degree of the preoperative retractions. When the post-MDT gains were deemed insufficient because of persistent joint limitations, complementary orthopedic surgery was indicated. Bladder capacity was significantly improved in 85% of the 38 patients who had a hyperactive neurogenic bladder with urine leakage around the catheter. These 32 patients who improved, were those in whom the detrusor was not irreversibly fibrotic. Pain when present was in general favorably influenced. MDT constantly produced a marked decrease in sensation. See Sindou [42] for pre- and postoperative assessment of patients (with details on the functional scores used).

Indications In Adults ITB administration is indicated for para- or tetraplegic patients with severe and diffuse spasticity especially when from spinal origin. Because of

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its reversibility, this method has to be considered prior to considering an ablative procedure. But range between excess of hypotonia with loss of strength and an insufficient effect is narrow. An intrathecal test through a temporary access port can be useful before indicating permanent implantation. Neuroablative techniques are indicated for severe focalized spasticity in the limbs of para-, tetra- or hemiplegic patients. Neurotomies are preferred when spasticity is localized to muscle groups innervated by a small number of peripheral nerves. When spasticity affects an entire limb, microDREZotomy is preferred. Several types of neuroablative procedures can be combined in the treatment of one patient, when needed. Whatever the situation and the etiology may be, orthopedic surgery must be considered only after spasticity has been reduced by physical and pharmacological treatments first and, when necessary, by neurosurgical procedures. Guidelines for surgical indications have been detailed elsewhere [43] and are summarized in figure 4. The general rule is to tailor individual treatments as much adapted as possible to the particular problems of the patient. In Children with Cerebral Palsy Surgical indications depend on preoperative abilities and disabilities and the eventual functional goals. For guiding indications we have adopted the classification in six groups as defined by Abbott [44]: independent ambulatory patients, ambulatory patients dependent on assistance devices, quadruped crawlers, commando (or belly) crawlers, totally dependent children, children with no locomotive abilities, and children with asymmetrical spasticity. The main goal in these children is to prevent irreversible orthopedic deformities. Lumbosacral posterior rhizotomies can be indicated for reducing the excessive general level of spasticity in diplegic (or even quadriplegic) patients. ITB is an alternative, but the range between an insufficient effect and an excessive effect responsible for a global decrease in tone impairing the gait and reducing the muscular strength is often very narrow. In case of localized hyperspasticity threatening a joint, peripheral neurotomy(ies) can be the solution. Frequently, complementary orthopedic surgery can be useful for lengthening tendons.

Conclusion When dealing with these patients, the surgeon must know the risks of the available treatments. To minimize those risks, the surgeon needs: a strong anatomic, physiological, and chemical background, rigorous methods to assess and quantify the disorders, and the ability to work within the frame of a multidisciplinary team.

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Fig. 4. Summary of guidelines for surgical indications.

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Penn RD, Kroin JS: Continuous intrathecal baclofen for severe spasticity. Lancet 1985;ii:125–127. Lazorthes Y, Sallerin-Caute B, Verdie JC, Bastide R, Carillo JP: Chronic intrathecal baclofen administration for control of severe spasticity. J Neurosurg 1990;72:393–402. Mertens P, Parise M, Garcia-Larrea L, Beneton C, Millet MF, Sindou M: Long-term clinical electrophysiological and urodynamic effects of chronic intrathecal baclofen infusion for treatment of spinal spasticity. Acta Neurochir 1995;64(suppl):17–25. Parise M, Garcia-Larrea L, Mertens P, Sindou M: Clinical use of polysynaptic flexion reflexes in the management of spasticity with intrathecal baclofen. Electroencephalogr Clin Neurophysiol 1997; 105:141–148. Albricht AL, Cervi A, Singletary J: Intrathecal baclofen for spasticity in cerebral palsy. JAMA 1991;265:1418–1422. Stoffel A: The treatment of spastic contractures. Am J Orthop Surg 1913;10:611–619. Gros C, Frerebeau P, Benezech J, Privat JM: Neurotomie radiculaire selective; in Simon L (ed): Actualite´s en Re´e´ducation Fonctionnelle et Re´adaptation. Paris, Masson, 1977, se´rie 2, pp 230– 235. Sindou M, Mertens P: Selective neurotomy of the tibial nerve for treatment of the spastic foot. Neurosurgery 1988;23:738–744. Mertens P, Sindou M: Selective peripheral neurotomies for the treatment of spasticity; in Sindou M, Abbott R, Keravel Y (eds): Neurosurgery for Spasticity: A Multidisciplinary Approach. Springer, Wien, 1991, pp 119–132. Decq Ph, Filipetti P, Fevet A, Djindjian M, Saraoui A, Keravel Y: Peripheral selective neurotomy of the brachial plexus collateral branches for the treatment of the spastic shoulder: Anatomical study and clinical results on five patients. J Neurosurg 1997;86:648–653. Berard C, Sindou M, Berard J, Carrier H: Selective neurotomy of the tibial nerve in the spastic hemiplegic child: An exploration of the recurrence. J Pediatr Orthop 1998;7:66–70. Brunelli G, Brunelli F: Hyponeurotization in spastic palsies; in Textbook of Microsurgery. Paris, Masson, 1988, pp 861–865. Foerster O: On the indications and results of the excision of posterior spinal nerve roots in men. Surg Gynecol Obstet 1913;16:463–474. Gros C, Ouaknine G, VLahovitch B, Frerebeau P: La radicotomie se´lective poste´rieure dans le traitement neurochirurgical de l’hypertonie pyramidale. Neurochirurgie 1967;13:505–518. Ouaknine G: Le traitement chirurgical de la spasticite´. Union Me´d Can 1980;109:1–11. Gros C: Spasticity: Clinical classification and surgical treatment, in Krayenbu¨hl (ed): Advances and Technical Standards in Neurosurgery. Wien, Springer, 1979, vol 6, pp 55–97. Privat JM, Benezech J, Frerebeau P, Gros C: Sectorial posterior rhizotomy. A new technique of surgical treatment of spasticity. Acta Neurochir 1976;35: 181–195. Frerebeau Ph: Sectorial posterior rhizotomy for the treatment of spasticity in children with cerebral palsy; in Sindou M, Abbott A, Keravel Y (eds): Neurosurgery for Spasticity: A Multidisciplinary Approach. Wien, Springer, 1991, pp 145–147. Fraioli B, Guidetti B: Posterior partial rootlet section in the treatment of spasticity. J. Neurosurg. 1977;46:618–626. Fasano VA, Barolat-Romana G, Ivaldi A, Sguazzi A: La radicotomie poste´rieure fonctionnelle dans le traitement de la spasticite´ ce´re´brale. Neurochirurgie 1976;22:23–34. Peacock WJ, Arens LJ: Selective posterior rhizotomy for the relief of spasticity in cerebral palsy. S Afr Med J 1982;62:119–124. Cahan LD, Kundi MS, McPherson D, Starr A, Peacock WJ: Electrophysiologic studies in selective dorsal rhizotomy for spasticity in children with cerebral palsy. Appl Neurophysiol 1987;50: 459–682. Abbott R, Forem SL, Johann M: Selective posterior rhizotomy for the treatment of spasticity. Childs Nerv Syst 1989;5:337–346. Storrs B: Selective posterior rhizotomy for treatment of progressive spasticity in patients with myelomeningocele. Pediatr Neurosci 1987;13:135–137.

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38 39 40 41

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Hodgkinson I, Berard C, Jindrich ML, Sindou M, Mertens P, Berard J: Radicotomie poste´rieure fonctionnelle chez l’enfant IMC. Re´sultats a` un an post-ope´ratoire sur 18 cas. Ann Re´adapt Me´d Phys 1996;39:103–111. Uematsu S, Udvarhelyi GB, Benson DW, Siebens AA: Percutaneous radiofrequency rhizotomy. Surg Neurol 1974;2:319–325. Young B, Mulcachy JJ: Percutaneous sacral rhizotomy for neurogenic detrusor hyperreflexia. J Neurosurg 1980;53:85–87. Kenmore D: Radiofrequency neurotomy for peripheral pain and spasticity syndromes. Contemp Neurosurg 1983;5:1–6. Herz DA, Parsons KC, Learl L: Percutaneous radiofrequency foraminal rhizotomies. Spine 1983; 8:729–732. Kasdon DL, Lathi ES: A prospective study of radiofrequency rhizotomy in the treatment of posttraumatic spasticity. Neurosurgery 1984;15:526–529. Bischof W: Die longitudinale Myelotomie. Zentralbl Neurochir 1951;2:79–88. Pourpre MH: Traitement neurochirurgical des contractures chez les paraple´giques posttraumatiques. Neurochirurgie 1960;6:229–236. Laitinen LV, Singounas E: Longitudinal myelotomy in the treatment of spasticity of the legs. J Neurosurg 1971;35:536–540. Sindou M: Study of the dorsal root entry zone; thesis, Lyon 1972. Sindou M, Fischer G, Goutelle A, Schott B, Mansuy L: La radicellotomie poste´rieure se´lective dans le traitement des spasticite´s. Rev Neurol 1974;130:201–215. Sindou M, Millet MF, Mortamais J, Eyssette M: Results of selective posterior rhizotomy in the treatment of painful and spastic paraplegia secondary to multiple sclerosis. Appl Neurophysiol 1982;45:335–340. Sindou M, Pregelj R, Boisson D, Eyssette M, Goutelle A: Surgical selective lesions of nerve fibers and myelotomies for the modification of muscle hypertonia; in Eccles J, Dimitrijevic MR (eds): Recent Achievements in Restorative Neurology: Upper Motor Neuron Functions and Dysfunctions. Basel, Karger, 1985, pp 10–26. Sindou M, Abdennebi B, Sharkey P: Microsurgical selective procedures in the peripheral nerves and the posterior root-spinal cord junction for spasticity. Appl Neurophysiol 1985;48:97–104. Eccles J, Eccles R, Magni F: Central inhibitory action attributable to presynaptic depolarization produced by muscle afferent volleys. J Physiol 1961;159:147–166. Sindou M, Jeanmonod D: Microsurgical DREZ-otomy for the treatment of spasticity and pain in the lower limbs. Neurosurgery 1989;2:655–670. Sindou M, Mifsud JJ, Boisson D, Goutelle A: Selective posterior rhizotomy in the dorsal root entry zone for treatment of hyperspasticity and pain in the hemiplegic upper limb. Neurosurgery 1986; 18:587–595. Sindou M: Spinal entry zone interruption for spasticity; in Tasker RR, Gildenberg P (eds): Textbook of Stereotactic and Functional Neurosurgery. New York, McGraw-Hill, 1997, pp 1257–1266. Sindou M, Abbott R, Keravel Y: Neurosurgery for Spasticity: A multidisciplinary Approach. Wien, Springer, 1991, pp 1–320. Abbott R: Indications for surgery to treat children with spasticity due to cerebral palsy; in Sindou M, Abbott R, Keravel Y (eds): Neurosurgery for Spasticity: A Multidisciplinary Approach. Wien, Springer, 1991, pp 215–217.

Marc P. Sindou, MD, DSc, Professor of Neurosurgery, Department of Neurosurgery, University of Lyon, Hoˆpital Neurologique, 59, bd Pinel, F–69003 Lyon (France) Tel. +33 4 72 11 89 01, Fax +33 4 72 35 73 65, E-Mail [email protected]

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Functional Imaging of the Basal Ganglia Toshitaka Nakamura, Christine Edwards, Denise Krch, Marc Mentis, David Eidelberg North Shore University Hospital, Manhasset, N.Y., USA

Functional imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide novel insights into the assessment of normal and pathological functioning of the basal ganglia. Although the precise role of the basal ganglia is unclear, recent neuroimaging studies suggest involvement in motor execution, motor sequence learning [1, 2], and in nonmotor cognitive functions such as attentional allocation, working memory, and implicit learning [3]. In this review, we will examine the role of functional brain imaging in the assessment of: (1) pre- and postsynaptic dopaminergic function in the basal ganglia; (2) abnormal neural circuitry embodied in the metabolic topographies of basal ganglia disorders; (3) disease-related abnormalities in neural function during motor and cognitive brain activation, and (4) surgical interventions including implantation of fetal mesencephalic tissue, pallidotomy, thalamotomy and deep brain stimulation.

Dopaminergic Imaging Dopaminergic activity can be assessed through imaging of presynaptic enzymatic activity (dopa decarboxylase (DDC), dopamine transporter (DAT) and vesicular transporter (VMAT) binding) as well as of postsynaptic D1 and D2 receptor sites. To date, these imaging methods have been utilized in the assessment of disease progression and the efficacy of fetal nigral cell engraftment.

Presynaptic Dopaminergic Function Methods Dopa Decarboxylase Activity [18F]-6-fluorodopa (FDOPA) is a commonly applied radiotracer for the study of striatal dopaminergic nerve terminals in Parkinson’s disease (PD) and related movement disorders. PET studies with this tracer measure the rate of decarboxylation of [18F]fluorodopa to [18F]fluorodopamine by DDC and its subsequent storage in the striatal dopaminergic nerve terminals. FDOPA/PET data can be analyzed using multiple time graphical analysis (MTGA) [4] utilizing plasma or brain input functions [5, 6]. In MTGA, the gradient of the linear regression of the data, described as the net influx constant (Ki), reflects the rate of FDOPA decarboxylation and storage. Compartmental models have also been developed to estimate the specific kinetic rate constant for striatal DDC activity (k3) [7–9]. Simplified quantification of striatal uptake may also be advisable using target-tobackground ratio methods [10]. The assessment of nigrostriatal dopaminergic function using FDOPA/PET yields quantitative parameters that correlate with independent disease severity measures and can discriminate early stage PD patients from normal control subjects [5, 6, 9–11]. Importantly, it has been shown that striatal FDOPA measurements conducted in vivo correlate with dopamine cell counts measured in postmortem specimens [12, 13]. Differential diagnosis is possible using FDOPA/PET. Atypical parkinsonian syndromes (APD) such as striatonigral degeneration (SND), progressive supranuclear palsy (PSP), hemiparkinson-hemiatrophy syndrome (HPHA), and corticobasal ganglionic degeneration (CBGD) are often difficult to distinguish from PD on clinical ground alone. In patients with early stage idiopathic PD, FDOPA uptake is relatively preserved in the caudate and anterior putamen early in the disease. By contrast, in patients with APD such as multiple system atrophy (MSA), equivalent impairment of FDOPA uptake can be observed in the caudate and the putamen [5]. However, this differential dopaminergic topography is often insufficient to discriminate idiopathic PD from MSA at early clinical stages [14]. Striatal FDOPA uptake has been noted to be diminished in other parkinsonian movement disorders such as SND, PSP, Wilson’s disease [15], and Guamanian amyotrophic lateral sclerosis (ALS-PD complex) [16], and X-linked Filipino dystonia parkinsonism [17]. Additionally, asymmetrical parkinsonian syndromes such as HPHA and CBGD show relative reductions in basal ganglia FDOPA uptake contralateral to the affected side [18, 19].

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Fig. 1. PET images obtained with [18F]FP-bCIT in a normal volunteer (left), in a patient with H&Y Stage I PD (middle), and in a patient with H&Y Stage II PD (right).

Dopamine Transporter The development of radiotracers which bind to the striatal DAT has led to another means for directly imaging the nigrostriatal dopaminergic system with PET and SPECT. The most extensively studied agents in this category are the cocaine analogues, such as 2-b-carbomethyl-3b-(4-iodophenyl) tropane (bCIT) and its fluoroalkyl esters. DAT is expressed on dopaminergic nigral terminals, and quantification of striatal DAT appears to be directly related to the extent of nigral cell degeneration [20]. A number of recent SPECT studies have demonstrated the utility of DAT binding ligands as effective markers of nigrostriatal dopaminergic degeneration in parkinsonism [10, 21–23]. SPECT imaging with these tracers reliably differentiates PD subjects from normal volunteers, and the degree of striatal binding correlates with clinical measures of PD severity (fig. 1). In contrast to FDOPA/PET [24, 25] both PET and SPECT measures of DAT binding decline with normal aging [10, 26]. Thus the DAT binding agents may have utility in quantifying the attrition in nigrostriatal dopamine function which occurs in the course of the normal aging process. Nevertheless, this sensitivity may require the introduction of age corrections in longitudinal studies of disease progression in PD. Vesicular Monoamine Transporter The presynaptic VMAT is involved in the packaging and transport of monoamines to storage vesicles located in nerve terminals. Radioactive ligands that bind to VMAT sites such as [11C]dihydrotetrabenazine (DHTBZ) can be

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used as a reliable measure of monoaminergic and nerve terminal density. Frey et al. [27] reported a reduction in VMAT binding in the putamen of 7 PD patients. An age-related decline of 7.7% per year was also observed in normal controls. VMAT binding appears to be unaffected by antiparkinsonian dopaminergic medications such as levodopa giving it potential advantage over FDOPA and DAT. However, this method has comparably low signal to noise, and may not be specific for dopaminergic terminals [28].

Applications Disease Progression Dopaminergic imaging may be valuable in providing objective measurements of the rate of neurodegeneration both natively, and in the presence of a potential neuroprotective agent. Thus, several longitudinal studies with PET and SPECT have been undertaken to determine the natural history of PD progression. In an early study, Bhatt et al. [29] examined disease progression in 9 PD patients and 7 normal controls using FDOPA/PET. All subjects were scanned twice during a 3 to 4 year interval. Results showed a similar 5% annual decline in the striatal/temporoparietal ratio in both groups, which the authors interpreted as a slow progression [33]. In a follow-up study, Vingerhoets et al. [30] found an annual SOR decrement of 7.8% in 16 PD patients compared to 3% in 10 normal controls. This suggests a more rapid rate of progression in the PD group. Indeed, Morrish et al. [31] showed an even faster annual rate of decline (14%) in a study of 17 PD patients when measuring putamenal FDOPA uptake. There was no significant change in FDOPA uptake in a group of normal control subjects. Recent longitudinal SPECT studies with bCIT have also demonstrated a potentially faster rate of progression at early disease stages [32]. Transplantation FDOPA/PET may be used to monitor graft survival following fetal nigral cell implantation. To date only a limited number of patients have been studied with PET. One patient exhibited sustained postoperative increases in local FDOPA uptake in the grafted putamen 33 months after transplantation [33]. Subsequently, Remy et al. [34] reported increases in FDOPA uptake in 5 patients with unilateral implantation in the putamen; changes in FDOPA uptake rate constant were significantly correlated with clinical improvement measures. Sawle et al. [35] reported 2 PD patients who underwent unilateral transplantation into the putamen and had FDOPA/PET imaging before and 12 and 13 months following surgery. These patients had substantial increases

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in FDOPA uptake in the grafted putamen and decreases in the nongrafted striatum. In 1 of these patients, clinical improvement continued 3 years after transplantation and was accompanied by further increase in FDOPA uptake in the grafted putamen. Recently, other investigators have reported increased FDOPA uptake in studies of advanced stage PD patients engrafted with bilateral putamenal implants [36, 37] (fig. 2). Further technological development is required to optimize fetal implantation surgery as a therapeutic option in advanced parkinsonism. The safety and efficacy of these procedures is currently unknown and is a topic of several controlled clinical studies including investigations of porcine nigral cells. Whether or not changes in striatal FDOPA uptake accurately reflect graft survival is also the subject of ongoing investigation. Alternative dopaminergic imaging methods may afford a complementary tool for the assessment of outcome following fetal implantation. Specifically, adjunctive PET imaging of striatal DAT and VMAT activity before and after implantation procedures, as well as the application of functional mapping methods with [15F] fluorodeoxyglucose (FDG) and [15O]H2O/PET, may lead to a broader understanding of the effects of neural transplantation on the nigrostriatal dopaminergic system.

Postsynaptic Function PET studies using ligands that bind selectively to D1 and D2 receptors in the striatum offer a quantitative approach to the measurement of dopamine receptor density in relation to disease progression and pharmacological treatment with antiparkinsonian medication. Moreover, neuroimaging techniques can detect subclinical abnormalities in the basal ganglia of presymptomatic patients. D2 Ligands Radioligands such as [11C]raclopride (RAC) and [11C]N-methylspiperone (CNMSP) can provide sensitive measures of local D2 receptor density. In normal subjects, RAC/PET studies have demonstrated a decrement of dopamine D2 receptor binding of approximately 0.6% per year, suggesting that the striatal projection neurons may also progressively decline with normal aging [38]. By contrast, in PD the postsynaptic response to nigrostriatal deafferentation is likely to differ from that of normal aging. It has been suggested that loss of dopaminergic nerve terminals in association with changes in postsynaptic dopamine receptors may underlie motor complications occurring in the course of treatment of PD [5]. A relative increase of striatal dopamine

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Fig. 2. [18F]fluorodopa (FDOPA)/PET images from a normal volunteer (left) and from 2 patients studied in the course of a blinded sham-controlled study of fetal nigral dopamine cell implantation for advanced PD (right). The upper tier represents baseline and 15-month follow-up FDOPA/PET scans from a PD patient randomized to sham surgery. The lower tier represents baseline and 15-month postoperative scans from another patient who was randomized to bilateral implantation in the putamen. At baseline, both patients demonstrated typical significant reductions in FDOPA uptake involving predominantly the posterior putamen. This decline was comparatively greater in the sham patient at follow-up. By contrast, the patient undergoing implantation demonstrated bilateral increases in putamen FDOPA uptake compatible with engraftment (arrows).

D2 receptor binding has been reported in early untreated parkinsonian patients particularly in the putamen contralateral to the more affected body side [39]. However, the initial dopamine D2 receptor upregulation in the putamen may reverse with increasing disease severity and binding values in the range of control subjects or lower may be encountered in advanced PD patients [40, 41].

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Because RAC and FDOPA changes are associated throughout the disease course, it is likely that dopamine D2 receptor changes result from the decline in presynaptic dopaminergic drive [11]. Relative dopamine D2 receptor upregulation has also been demonstrated in the striatum of patients with doparesponsive dystonia (DRD) and MPTP-induced parkinsonism [42, 43], while binding decrements occur in patients with Huntington’s disease (HD), SND, and PSP [44, 45]. D1 Ligands PET studies using [11C]SCH23390 show no change in striatal D1 receptor binding in Parkinson’s disease. Rinne studied D1 receptor density in untreated early stage PD patients using [11C]SCH23390/PET. Results showed normal striatal binding [46]. Shinotoh et al. [47] found similar results using [11C]SCH23390 in ten patients, half of whom were chronically treated. Both the treated and the untreated PD groups showed normal D1 binding in the caudate and putamen; 5 SND patients displayed a significant reduction in the posterior putamen [47]. In a PET study measuring D1 receptor density in PD patients treated with levodopa, both caudate and putamen uptake was reduced. A greater (although nonsignificant) reduction was seen in patients who had developed dyskinesias [46]. The ultimate utility of D1 neuroreceptor quantification with PET in the study of PD remains unknown. It is likely that a better understanding of the mechanism of the levodopa response, including the potentiation of dyskinesias, will emanate from the quantification of both D1 and D2 striatal neuroreceptors in individual patients.

Regional Cerebral Blood Flow and Metabolism FDG/PET may be useful assessing the consequences of nigrostriatal dopamine loss on the functional organization of the basal ganglia. Functional alterations in basal ganglia activity are accompanied by alterations in regional cerebral glucose metabolism (rCMRGlc) and blood flow (rCBF). FDG/PET has been used in the differential diagnosis of PD and its variants, the assessment of disease severity in parkinsonism, and in the assessment of outcome from stereotaxic surgery in PD.

Differential Diagnosis The differentiation between patients with APD and PD patients is a difficult task. While the presence of resting tremor or levodopa responsiveness

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is commonly considered to be diagnostic of classical PD, these signs have been recognized in parkinsonian patients who are ultimately found to have APD at neuropathological examination. Therefore, an adjunctive diagnostic test such as FDG/PET may be helpful in supporting the clinical suspicion of atypical PD in the presence of minimal atypical features. We recently studied a cohort of 43 patients suspected as having possible APD [48]. We used 56 other patients without atypical features as a reference population with likely idiopathic PD. We found significant reductions in the striatum and the thalamus of the APD suspects relative to the group with likely PD. Indeed, a linear combination of caudate, lentiform, and thalamic metabolic values accurately discriminated typical and atypical patients. This finding was reproduced in two independent APD and PD populations scanned on different PET cameras. These results indicate that FDG/PET can be a helpful adjunct to the clinical examination in differential diagnosis of parkinsonism. This discrimination may be critical in the assessment of patients for possible surgical intervention, especially since patients with atypical parkinsonism show little improvement with medical and surgical therapies intended for classical PD [49].

Network Analysis The measurement of local rates of metabolism may not fully describe the complexities of the neural systems involved in a neurodegenerative process, and therefore may be less sensitive to disease severity and progression than more comprehensive models that quantitatively measure the expression of relevant networks of interacting brain regions. Therefore, the ability to model functional interactions between regions may enhance the usefulness of standard brain maps of regional cerebral blood flow and metabolism. To this end, a comprehensive statistical modeling approach for the detection and quantification of regional functional interactions in disease states has been developed. The approach, known as the Scaled Subprofile Model (SSM) is a general form of the two-way factor analysis of variance model. In SSM modeling, eigenvalue methods are employed to identify regional metabolic covariance patterns from rCMRGlc datasets obtained from combined samples of patients and normals. This form of metabolic analysis is blind to subject class designation and utilizes the variance across the entire population to identify specific patterns associated with the disease state. We have made considerable efforts to validate and implement network imaging methods for the diagnosis and evaluation of patients with parkinsonism and related movement disorders. In initial studies of parkinsonism [6, 50], no significant regional abnormalities in glucose metabolism were found in PD patients. However,

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Fig. 3. Display of the regional metabolic covariance pattern associated with PD identified using the Scaled Subprofile Model (SSM). Region weights for this disease-related pattern have been overlaid on standard Talairach transformed magnetic resonance imaging (MRI) sections. The pattern is characterized by relative lentiform and thalamic hypermetabolism (white) covarying negatively with bilateral metabolic reductions (dark grey) in motor and premotor regions and in the supplementary motor area (SMA).

application of SSM to PET data revealed a significant pattern of regional metabolic covariation characterized by lentiform and thalamic hypermetabolism associated with regional metabolic decreases in lateral frontal and paracentral cortical areas (fig. 3). Subject scores for this pattern were abnormally elevated in PD patients and correlated positively with standardized clinical motor ratings [50, 51]. Subsequently, we have reconfirmed the reproducibility of the previously identified PD-related covariance pattern in two additional independent groups of PD patients, each studied at separate institutions with different tomographs [52]. We also introduced a modification of SSM, referred to as Topographic Profile Rating (TPR), to compute subject scores for a predetermined network from individual PD patient FDG/PET data on a prospective case-by-case basis. TPR is critical to the clinical application of network analysis in disease severity assessment and differential diagnosis [51–53]. We used TPR to compute subject scores for the PD-related pattern in four independent populations of PD patients and normals scanned on different tomographs. We found that subject scores for this pattern accurately discriminated PD patients from normals with high sensitivity [14, 52]. Thus, in addition to being reproducible

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across populations, this unique pattern can be used as an accurate marker for the differential diagnosis of parkinsonism. We have also used network analytical strategies to delineate metabolic covariance patterns associated with other movement disorders such as idiopathic torsion dystonia (ITD), Tourette’s syndrome, and HD [54].

Brain Activation Studies Parkinson’s Disease [15O]H2O/PET activation studies allow us to investigate the role of the basal ganglia and its projections in volitional motor planning and motor execution. Playford et al. [55] studied rCBF in 6 PD and 6 normal controls who were scanned while performing different motor tasks using a joystick. The PD subjects showed reduced rCBF in the contralateral putamen, anterior cingulate cortex, supplementary motor area (SMA) and dorsolateral perfrontal cortex (DLPFC) [55]. Jahanshahi et al. [56] showed similar results while PD subjects performed self-paced extension of the index finger. Hypoperfusion in these areas may play a part in the internal planning of initiation of movement, which is impaired in PD. Recently, Catalan et al. [57] examined motor sequence learning in 13 PD patients and 13 normal control subjects. Subjects performed simple repetitive movements, increased complexity of sequential finger movements, and self-selected movements. The PET experiments showed similar activation patterns in sequential finger movements in both groups, although, the PD group showed increased rCBF in the precuneus, premotor and parietal areas. With increasing complexity of sequential movements, PD patients and normals showed increases in the precuneus, premotor, and parietal areas; the PD group demonstrated additional increases in the rostral SMA and anterior cingulate cortex. Lastly, in self-selected condition, increased rCBF in the anterior SMA and cingulate was demonstrable only in the normal controls. The authors conclude that in PD patients, more cortical areas are recruited to perform sequential finger movements resulting from increasing corticocortical activity to compensate for striatal dysfunction. Other Movement Disorders Temple and Perlmutter [58] measured activation responses during vibrotactile stimulation in patients with writer’s cramp and noted attenuated rCBF responses in contralateral sensorimotor cortex and SMA. Subsequent [15O]H2O/PET studies of ITD patients performing joystick movements demonstrated exaggerated activation of both lentiform nuclei, as well as the contralateral lateral prefrontal cortex, rostral SMA, anterior cingulate, and the

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ipsilateral DLPFC [59]. These abnormally high motor activation responses were associated with concomitant underactivation of the caudal SMA, sensorimotor cortex, posterior cingulate and mesial parietal cortex. Indeed, most of the abnormalities were found to persist in writer’s cramp patients following botulinum toxin treatment [60]. These studies suggested the possibility of underactivity of motor executive areas in ITD occurring concurrently with overactivation of regions associated with motor preparation and sequence learning [61]. Moreover, these findings are compatible with the notion of conjoint overactivity of the indirect and direct pathways in ITD [62]. Based on these results, overactivity of frontal association areas in motor activation studies of ITD can attribute to: (1) a primary abnormality in the brain circuitry subserving complex motor tasks requiring the selection and preparation of movements; (2) a secondary effect of pathological basal ganglia overactivity, or (3) a secondary effect of defective motor executive function with a compensatory volitional suppression of abnormal dystonic movements. The notion of a resting state abnormality in motor networks in ITD, perhaps related to genotype, has been proposed based upon FDG/PET studies conducted specifically in gene carriers [63, 64]. Motor activation data from [15O]H2O/PET studies of patients with hyperkinetic movement disorders are limited, due primarily to the difficulty associated with performing brain activation studies in the presence of involuntary movements. In a preliminary study of 7 HD patients performing joystick movements, Weeks et al. [65] detected bilaterally impaired activation of primary motor cortex, SMA, and DLPFC with enhanced activation of insular areas. However, the interpretation of these findings and their relevance to chorea is complicated by the superimposed presence of bradykinesia in several of the advanced patients. The motor activation paradigms employed in this study were also relatively simple and did not specifically assess more complex functions such as learning. Indeed, it is likely the underlying functional pathology of HD relates to the abnormalities in the expression of the CSPTC circuits other than those mediating simple motor execution.

Stereotaxic Surgery and Deep Brain Stimulation Pallidotomy/Thalamotomy Quantitative functional brain imaging markers may be suitable as outcome measures for the surgical treatment of PD. Indeed, we have found that PET may serve as a useful tool in predicting optimal candidates for certain stereotaxic surgical interventions such as ventral pallidotomy. We originally reported 8 PD patients undergoing pallidotomy who were scanned with FDG/

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Fig. 4. Display of the regional covariance pattern associated with surgical changes in glucose metabolism following pallidotomy identified using the Scaled Subprofile Model (SSM). Region weights for this disease-related pattern have been overlaid on standard Talairach transformed magnetic resonance imaging (MRI) section. This pattern is characterized by surgical changes in lentiform and thalamic metabolism in the surgical hemisphere (S) covarying negatively with bilateral changes in supplementary motor area (SMA) metabolism.

PET preoperatively and 6 months postoperatively [66]. We found that pallidotomy resulted in a metabolic decline in the thalamus which occurred in conjunction with a metabolic increase in primary and associative motor cortical regions. Indeed, the improvement in limb performance at 6 months following surgery was significantly correlated with the operative metabolic decline in the thalamus and with the accompanying increases in lateral premotor cortex. To quantify potential modulations in the expression of motor networks by pallidotomy, we applied SSM to operative differences in regional glucose metabolism. We found that the topography identified in this analysis closely resembled the PD-related profile identified previously [49–51] and was characterized by a postoperative decline in the lentiform and thalamic metabolism ipsilateral to the surgical side associated with bilateral increases in SMA metabolism (fig. 4). The individual expression of this pattern of metabolic operative change correlated significantly with improvements in both contralat-

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Fig. 5. Display of the regional covariance pattern identified by the Scaled Subprofile Model (SSM) in 18 PD patients. Region weights have been mapped on standarized Talairach MRI sections. This pattern was characterized by a network of regional metabolic covariation involving the putamen, pallidum, and thalamus (left) as well as the midbrain and pons (right). Subject scores for this network were highly correlated with intraoperative recordings of spontaneous internal pallidal firing rate.

eral and ipsilateral limb CAPIT scores. These findings indicate that metabolic brain networks comprising functionally and anatomically interconnected brain regions remote from the lesion site may be modulated by pallidotomy, including motor cortical regions of the hemisphere contralateral to the surgery. Spontaneous GPi single unit activity recorded intraoperatively during pallidotomy correlated significantly with preoperative measures of thalamic glucose utilization obtained in the same patients under comparable behavioral conditions [67]. This physiological-metabolic relationship was reproduced in the subgroups of patients scanned on different PET cameras. Moreover, we found that GPi firing rates were also significantly correlated with the expression of an SSM network related to the pallidum and its major efferent projections (fig. 5). It is therefore likely that pallidal ablation may exert its primary metabolic effect in spatially distributed projection fields lying in the ventral tier and intralaminar thalamic nuclei as well as the brainstem.

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PET activation studies using [15O]H2O have also supported the notion of pallidotomy-induced modulation of the CSPTC motor circuit. Grafton et al. [68] reported postpallidotomy increases in rCBF in the ipsilateral premotor and in the supplementary motor area with movement. In another study employing network analysis of motor system connectivity, these authors found significant postoperative reductions in the strength of interactions between the globus pallidus and thalamus, and the thalamus and mesial frontal motor area [69]. These findings are consistent with the notion that pallidal ablation induces alterations in the normal functioning of CSPTC motor networks [70–72]. In addition to adding to our understanding of the network modulations occurring with pallidotomy, FDG/PET may be used to select optimal candidates for this procedure. In our original study of 10 patients undergoing pallidotomy, we found that preoperative FDG/PET measurements of lentiform metabolism in the ‘off’ state correlated with clinical outcome up to 6 months following surgery [66]. We subsequently studied an additional cohort of 22 PD patients and confirmed the usefulness of preoperative FDG/PET as a potential predictor of surgical outcome [48]. Stereotactic thalamotomy has been shown to significantly improve drugresistant tremor in PD. Using [15O]H2O/PET, Boecker et al. [73] observed significant operative declines in sensorimotor, premotor, and parietal rCBF both at rest and during motor activation in 2 PD patients who underwent thalamotomy for tremor. This supports the notion that parkinsonian tremor arises through the overaction of ventral thalamic projections to cortical motor regions as suggested by PET studies of tremulous parkinsonian patients [74, 75]. These findings indicate that in relieving PD tremor, thalamotomy may also alter functional input from the surgical target to sensorimotor cortical regions. Nevertheless, a comprehensive network modeling approach to define the mechanism of surgical improvement using imaging awaits future investigation. Deep Brain Stimulation Deep brain high-frequency stimulation (DBS) has the advantage of avoiding permanent side effects due to the ablative lesion, therefore inducing the possibility of a reversible amelioration of parkinsonian symptoms. Parker et al. [75] observed that rCBF increased in the sensorimotor, premotor, SMA, caudate nucleus and cerebellar vermis and hemisphere during the tremor period compared with the period of tremor arrest. Deiber et al. [76] subsequently observed that suppression of tremor induced by sufficient stimulation specifically associated with the reduction of cerebellar rCBF, whereas the incomplete arrest of tremor induced by insufficient stimulation only reduced rCBF in frontal cortex. They suggest that tremor suppression is mainly associated with a decrease of synaptic activity in the cerebellum.

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Fig. 6. H215O/PET images of changes in regional cerebral blood flow (rCBF) in 6 advanced PD patients undergoing unilateral deep brain stimulation (DBS) of the internal pallidum. The patients were scanned in the DBS ‘on’ and ‘off’ conditions while performing a kinematically controlled motor execution task using the hand opposite the pallidal stimulator. (The rate and amplitude of movement were controlled across DBS conditions.) During task execution, pallidal DBS resulted in a significant increase in rCBF in the putamen and primary motor cortex (BA 4, hand region) ipsilateral to stimulation, bilaterally in the supplementary motor area (SMA), and in the cerebellum contralateral to the stimulator.

Davis et al. [77] examined rCBF and parkinsonian symptoms in patients who had Vim DBS implants. Using [15O]H2O/PET, patients were scanned at rest under three stimulation conditions (‘off’, ‘suboptimal’, and ‘optimal’ stimulation). They found a decrease in rCBF in the SMA, contralateral cerebellum, cingulate motor area and in the ipsilateral sensory association areas during thalamic stimulation; rCBF increases were noted bilaterally in frontal cortex and in the ipsilateral occipital cortex, and in the DLPFC. [15O]H2O/PET has also been used to study the mechanism of pallidal stimulation. In their study, Davis et al. [77] also measured the effects of GPi DBS on cerebral blood flow. They found an increase in rCBF in ipsilateral premotor areas during pallidal stimulation, which clinically improved rigidity and bradykinesia. Comparable rCBF changes with GPi DBS were not evident in the joystick activation study of Limousin et al. [78]. Recently, we studied 6 patients with advanced PD undergoing pallidal stimulation [79]. GPi stimulation during a kinematically controlled motor execution task resulted in significant rCBF increases in contralateral primary motor cortex and in premotor regions as well as in the cerebellar hemisphere ipsilateral to the moving hand (fig. 6). These findings are similar to our previous FDG/PET studies in pallido-

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tomy and suggest that disrupting the excessive inhibitory GPi output to the thalamus reverses the symptoms of parkinsonism by activating areas involved in the initiation of movement. STN is thought to be more effective than GPi stimulation in that it can influence more than one area of basal ganglia inhibitory output, i.e. both the GPi and the substantia nigra reticulata (SNr). Limousin et al. [78] investigated the effect of STN stimulation on rCBF during an activation task. Using [15O]H2O/PET, 6 PD patients with STN DBS implants were scanned while performing self-directed movements with a joystick. Results showed significant rCBF increases in SMA, cingulate cortex, and DLPFC during effective STN stimulation. This suggests that STN DBS may play a role in potentiating auxillary motor cortical regions and the DLPFC which showed greater activation than in GPi during effective stimulation. The effects of GPi and STN stimulation on complex motor functioning, including motor learning and skill acquisition, are a topic of ongoing functional brain imaging research.

Conclusion Functional brain imaging enables us to investigate the role of basal ganglia in normal and pathological states. Patients with movement disorders show changes in receptor binding, regional metabolism, regional blood flow, and motor activation patterns. Neuroimaging techniques such as PET and SPECT are useful in identifying the level of disease severity, aid in the differential diagnosis of parkinsonism, and may, in the future, be used as biological markers for assessing successful medical and surgical therapy. In addition to elucidating the mechanism of stereotaxic surgical interventions for PD and other movement disorders, functional brain imaging is also suitable in selecting candidates for, and evaluating the outcome and efficacy of these new therapeutic approaches.

Acknowledgments Supported by NIH NS RO1 32368, 35069, and 37564, as well as generous grants from the National Parkinson Foundation, Parkinson Disease Foundation and the American Parkinson Disease Association.

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References 1 2 3 4 5

6 7 8 9 10

11 12 13 14 15 16 17 18

19 20 21

22 23

24

Marsden CD: What do the basal ganglia tell premotor cortical areas? CIBA Found Symp 1987; 132:282–295. Hallett M, Khoshbin S: A physiological mechanism of bradykinesia. Brain 1980;103:301–314. Graybiel AM: Building action repertoires: Memory and learning functions of the basal ganglia. Curr Opin Neurobiol 1995;5:733–741. Patlak CS, Blasberg RG: Graphical evaluation of blood-to-brain transfer constants from multipletime uptake data. Generalizations. J Cereb Blood Flow Metab 1985;5:584–590. Brooks DJ, Salmon EP, Mathias CJ, et al: The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with MSA, pure autonomic failure, and PD, studied with PET. Brain 1990;113:1539–1552. Eidelberg D, Moeller JR, Dhawan V, et al: The metabolic anatomy of Parkinson’s disease: Complementary 18F-fluorodopa positron emission tomography studies. Mov Disord 1990;5:203–213. Gjedde A, Reith J, Dyve S, et al: DOPA decarboxylase activity of the living human brain. Proc Natl Acad Sci USA 1991;88:2721–2725. Dhawan V, Ishikawa T, Patlak C, et al: Combined FDOPA and 3-OMFD PET studies in Parkinson’s disease. J Nucl Med 1996;37:209–216. Ishikawa T, Dhawan V, Chaly T, et al: Clinical significance of striatal DOPA decarboxylase activity in Parkinson’s disease. J Nucl Med 1996;37:216–222. Ishikawa T, Dhawan V, Kazumata K, et al: Comparative nigrostriatal dopaminergic imaging with iodine-123-b-CIT-FP/SPECT and fluorine-18-FDOPA/PET. J Nucl Med 1996;37:1760– 1765. Antonini A, Vontobel P, Psylla M, et al: Complementary positron emission tomographic studies of the striatal dopaminergic system in Parkinson’s disease. Arch Neurol 1995;52:1183–1190. Pate BD, Kawamata T, Yamada T, et al: Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices. Ann Neurol 1993;34:331–338. Snow BJ, Tooyama I, McGreer EG, et al: Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels. Ann Neurol 1993;34:324–330. Eidelberg D, Moeller JR, Ishikawa T, et al: Early differential diagnosis of Parkinson’s disease with 18 F-fluorodeoxyglucose and positron emission tomography. Neurology 1995;45:1995–2004. Snow BJ, Bhatt M, Martin WRW, et al: The nigrostriatal dopaminergic pathway in Wilson’s disease studied with positron emission tomography. J Neurol Neurosurg Psychiatry 1991;54:12–17. Guttman M, Steele JC, Stoessl J, et al: 6-[18F]fluorodopa PET scanning in the ALS-PD complex of Guam. Neurology 1987;37(suppl 1):113. Eidelberg D, Takikawa S, Wilhelmsen K, et al: Positron emission tomographic findings in Filipino X-linked dystonia-parkinsonism. Ann Neurol 1993;34:185–191. Eidelberg D, Dhawan V, Moeller JR, et al: The metabolic landscape of cortico-basal ganglionic degeneration: Regional asymmetries studied with positron emission tomography. J Neurol Neurosurg Psychiatry 1991;54:856–862. Przedborski S, Giladi N, Takikawa S, et al: The metabolic tomography of the hemiparkinsonhemiatrophy syndrome. Neurology 1994;44:1622–1628. Wilson JM, Levey AI, Rajput A, et al: Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson’s disease. Neurology 1996;47:718–726. Seibyl JP, Marek KL, Quinlan D, et al: Decreased single-photon emission computed tomographic [123I]b-CIT striatal uptake correlates with symptom severity in Parkinson’s disease. Ann Neurol 1995;38:589–598. Marek KL, Seibyl JP, Zoghbi SS, et al: [123I]b-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology 1996;46:231–237. Tisssingh G, Gergmans P, Booij J, et al: Drug-naive patients with PD in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]b-CIT SPECT. J Neurol 1998;245:14–20. Sawle GV, Colebatch JG, Shah A, et al: Striatal function in normal aging: Implications for Parkinson’s disease. Ann Neurol 1990;28:799–804.

Functional Imaging of the Basal Ganglia

367

25 26 27 28

29 30 31 32 33

34 35

36 37

38 39

40

41 42

43 44 45 46 47

Eidelberg D, Moeller JR, Dhawan V, et al: Striatal 18F-dopa uptake: Absence of an aging effect. J Cereb Blood Flow Metab 1993;13:881–888. Van Dyck CH, Seibyl JP, Malison RT, et al: Age-related decline in striatal dopamine transporter binding with iodine 123-beta-CITSPECT. J Nucl Med 1995;36:1175–1181. Frey KA, Koeppe RA, Kilbourn MR, et al: Presynaptic monoaminergic vesicles in Parkinson’s disease and normal aging. Ann Neurol 1996;40:873–884. Stoessl AJ, Ruth TJ: Neuroreceptor imaging: New developments in PET and SPECT imaging of neuroreceptor binding (including DATs, vesicle transporters and post-synaptic receptor sites). Curr Opin Neurol 1998;11:327–333. Bhatt MH, Snow BJ, Martin WRW, et al: Positron emission tomography suggests that the rate of progression of idiopathic parkinsonism is slow. Ann Neurol 1991;29:673–677. Vingerhoets FJG, Snow BJ, Lee CS, et al: Longitudinal fluorodopa positron emission tomographic studies of the evolution of idiopathic parkinsonism. Ann Neurol 1994;36:759–764. Morrish PK, Sawle GV, Brooks DJ: An [18F]dopa-PET and clinical study of the rate of progression in Parkinson’s disease. Brain 1996;119:585–591. Marek K, Innis R, Seibyl J: bCIT/SPECT assessment of determinants of variability in progression of Parkinson’s disease. Neurology 1999;52:A91. Freed CR, Breeze RE, Rosenberg NL, et al: Survival of implanted fetal dopamine cells and neurologic improvement 12 and 24 months after transplantation for Parkinson’s disease N Engl J Med 1992; 327:1549–1555. Remy P, Samson Y, Hantraye P, et al: Clinical correlates of [18F]fluorodopa uptake in five grafted parkinsonian patients. Ann Neurol 1995;38:580–588. Sawle GV, Bloomfield PM, Bjorklund A, et al: Transplantation of fetal dopamine neurons in Parkinson’s disease: PET[18F]6-L-fluorodopa studies in two patients with putaminal implants. Ann Neurol 1992;31:166–173. Hauser RA, Freeman TB, Snow BJ, et al: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson’s disease. Arch Neurol 1999;56:179–187. Dhawan V, Nakamura T, Margouleff C, et al: Double-blind controlled trial of human embryonic dopaminergic tissue transplants in advanced Parkinson’s disease: Fluorodopa PET imaging. Neurology 1999;6(suppl 2):P05.028. Antonini A, Leenders KL, Reist H, et al: Effect of age on D2 dopamine receptors in normal human brain measured by positron emission tomography and [11C]raclopride. Arch Neurol 1993;50:474–480. Antoninini A, Schwarz J, Oertel WH, et al: [11C]raclopride and PET in previously untreated patients with PD: Influence of L-dopa and lisuride therapy on striatal dopamine D2 receptors. Neurology 1994;44:1325–1329. Antonini A, Schwarz J, Oertel WH, et al: Long-term changes of striatal dopamine D2 receptors in patients with Parkinson’s disease: A study with positron emission tomography and [11C]raclopride. Mov Disord 1997;12:33–38. Brooks DJ, Ibanez V, Sawle GV, et al: Striatal D2 receptor status in patients with PD, SND, and PSP, measured with [11C]raclopride and positron emission tomography. Ann Neurol 1992;31:184–192. Kishore A, Nygaard TG, de la Fuente-Fernandez R, et al: Striatal D2 receptors in symptomatic and asymptomatic carriers of DRD measured with [11C]-raclopride and positron emission tomography. Neurology 1998;50:1028–1032. Perlmutter JS, Kilbourn MR, Raichle ME, Welch MJ: MPTP-induced up-regulation of in vivo dopaminergic radioligand-receptor binding in humans. Neurology 1987;37:1575–1579. Turjanski N, Weeks R, Dolan R, et al: Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas: A PET study. Brain 1995;118:689–696. Weeks RA, Harding AE, Brooks DJ: PET demonstrates a parallel loss of D1 and D2 receptors in asymptomatic mutation carriers of Huntington’s disease. Ann Neurol 1996;40:49–54. Rinne JO, Laihinen A, Nagren K, et al: PET demonstrates different behaviour of striatal D1 and D2 receptors in early Parkinson’s disease. J Neurosci Res 1990;27:494–499. Shinotoh H, Inoue O, Hirayama K, et al: Dopamine D1 receptors in Parkinson’s disease and striatonigral degeneration: A positron emission tomography study. J Neurol Neurosurg Psychiatry 1993;56:467–472.

Nakamura/Edwards/Krch/Mentis/Eidelberg

368

48 49 50 51 52 53 54 55 56

57 58 59 60 61 62 63 64 65 66 67 68 69

70 71 72 73 74

Antonini A, Kazumata K, Feigin A, et al: Differential diagnosis of parkinsonism with [18F]fluorodeoxyglucose and PET. Mov Disord 1998;13:268–274. Kazumata K, Antonini A, Dhawan V, et al: Preoperative indicators of clinical outcome following stereotaxic pallidotomy. Neurology 1997;49:1083–1090. Eidelberg D, Moeller JR, Dhawan V, et al: The metabolic topography of parkinsonism. J Cereb Blood Flow Metab 1994;14:783–801. Eidelberg D, Moeller JR, Ishikawa T, et al: Early differential diagnosis of Parkinson’s disease with [18F]-fluorodeoxyglucose and positron emission tomography. Neurology 1995;45:1995–2004. Moeller JR, Nakamura T, Mentis M, et al: Reproducibility of regional metabolic covariance patterns: Comparison of four populations. J Nucl Med 1999;40;1264–1269. Eidelberg D, Moeller JR, Ishikawa T, et al: The assessment of disease severity in parkinsonism with 18F-fluorodeoxyglucose and positron emission tomography. J Nucl Med 1995;36:378–383. Eidelberg D: Functional brain networks in movement disorders. Curr Opin Neurol 1998;11:319–326. Playford ED, Jenkins IH, Passingham RE, et al: Impaired mesial frontal and putamen activation in Parkinson’s disease: A positron emission tomography study. Ann Neurol 1992;32:151–161. Jahanshahi M, Jenkins IH, Brown RG, et al: Self-initiated vs. externally treated movements. I. Measurements of regional blood flow and movement-related potentials in normals and Parkinson’s disease. Brain 1995;118:913–934. Catalan MJ, Ishii K, Honda M, et al: A PET study of sequential finger movements of varying length in patients with Parkinson’s disease. Brain 1999;122:101–112. Temple LW, Perlmutter JS: Abnormal cortical responses in patients with writer’s cramp. Neurology 1993;43:2252–2257. Ceballos-Baumann AO, Passingham RE, Warner T, et al: Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia. Ann Neurol 1995;37:363–372. Ceballos-Baumann AO, Sheean G, Passingham RE, et al: Botulinum toxin does not reverse the cortical dysfunction association with writer’s cramp: A PET study. Brain 1997;120:571–582. Jenkins IH, Brooks DJ, Nixon PD, et al: Motor sequence learning: A study with positron emission tomography. J Neurosci 1994;14:3775–3790. Hallet M: Physiology of basal ganglia disorders: An overview. Can J Neurol Sci 1993;20:177–183. Eidelberg D, Moeller JR, Ishikawa T, et al: The metabolic topography of idiopathic torsion dystonia. Brain 1995;118:1473–1484. Eidelberg D, Moeller JR, Kazumata K, et al: Functional brain networks in DYTl dystonia. Ann Neurol 1998;44:303–312. Weeks RA, Ceballos-Baumann A, Piccini P, et al: Cortical control of movement in Huntington’s disease: A PET activation study. Brain 1997;120:1569–1578. Eidelberg D, Moeller JR, Ishikawa T, et al: Regional metabolic correlates of surgical outcome following unilateral pallidotomy for Parkinson’s disease. Ann Neurol 1996;39:450–459. Eidelberg D, Moeller JR, Kazumata K, et al: Metabolic correlates of pallidal neuronal activity in PD. Brain 1997;120:1315–1324. Grafton ST, Waters C, Sutton J: Pallidotomy increases activity of motor association cortex in Parkinson’s disease: A positron emission tomographic study. Ann Neurol 1995;37:776–783. Grafton ST, Sutton J, Couldwell W, et al: Network analysis of motor system connectivity in Parkinson’s disease: Modulation of thalamocortical interactions after pallidotomy. Hum Brain Mapp 1994;2:45–55. Bathia KP, Marsden CD: The behavioral and motor consequences of focal lesions of the basal ganglia in man. Brain 1994;117:859–876. DeLong M: Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990; 13:281. Marsden CD, Obeso JA: The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson’s disease. Brain 1994;117:877–897. Boecker H, Wills AJ, Ceballos-Baumann A, et al: Stereotactic thalamotomy in tremor-dominant Parkinson’s disease: An H215O/PET motor activation study. Ann Neurol 1997;41:108–111. Antonini A, Moeller JR, Nakaura T, et al: The metabolic anatomy of tremor in Parkinson’s disease. Neurology 1998;51:803–810.

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Parker F, Tzourio N, Blond S, et al: Evidence for a common network of brain structures involved in parkinsonian tremor and voluntary repetitive movement. Brain Res 1992;584:11–17. Deiber MP, Pollak P, Passingham R, et al: Thalamic stimulation and suppression of parkinsonian tremor. Brain 1993;116:267–279. Davis KD, Taub E, Houle S, et al: Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms. Nat Med 1997;3:671–674. Limousin P, Greene J, Pollak P, et al: Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997;42:283–291. Eidelberg D, Nakamura T, Mentis M, et al: Brain activation responses with internal pallidal stimulation in Parkinson’s disease. Neurology 1999;52:A176.

David Eidelberg, MD, North Shore University Hospital, Functional Brain Imaging Laboratory, 350 Community Drive, Manhasset, NY 11030 (USA) Tel. +1 516 562 2498, Fax +1 516 562 1008, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 371–380

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CNS Drug Delivery for Movement Disorders Richard D. Penn, Jeffrey S. Kroin Rush Medical College, Chicago, Ill., USA

The primary treatment of most movement disorders is medical. Surgical approaches are employed only after medicines have failed. The prototypical example is Parkinson’s disease, with L-dopa therapy offered long before pallidotomy or electrical stimulation. In the parkinsonian patient, this is a reasonable policy because the initial response to L-dopa is excellent in most cases and the risks of surgical intervention, although relatively low, are certainly more than the side effects of the medicines. However, for many other movement disorders, the usefulness of medical approaches is not so clear. Severe spasticity, in our experience, is rarely well managed by oral antispastic medications. Many forms of dystonia do not respond, and only mild to moderate tremor will sometimes be adequately controlled. The resistance to early surgical intervention in these medically, relatively nonresponsive conditions is due to an antisurgical bias on the part of many physicians and the lack of understanding of the true risks and potential benefits of new surgical approaches. Direct delivery of medications to the CNS using implant technology should drastically change the situation. The concepts and approaches are readily understandable to clinicians who manage these movement disorders, and the surgical risks are minimized because the procedures involved are nondestructive. The use of intrathecal baclofen to control spasticity is the best example of a combined medical surgical therapy. Even with this very successful treatment it has taken over 15 years from its first application for it to now be accepted as the first choice for severe spasticity. In this chapter we will review the reasons for intrathecal baclofen’s success for spasticity and its relative failure in generalized dystonia, and then discuss areas in which regional or local delivery of medications may prove in the future to be of major benefit.

Intrathecal Baclofen Since its introduction in the 1970s, baclofen has been the primary, most effective oral medication for treating spasticity [1]. Early double-blind studies demonstrated conclusively that it was effective, significantly lowering the average score of spasticity several points on a 5-point scale (Ashworth) [2]. Its wide acceptance is due not only to the amount of reduction in the symptoms of spasticity, but to its safety and ease of use. The problem with controlling severe spasticity with oral baclofen is not that it will not work, but that the central side effect of drowsiness becomes limiting in most patients. High enough doses of oral baclofen will completely control the worst spasticity but the patient is likely to be comatose. The solution to this is regional delivery of baclofen to the CNS in a way that reduces the brainstem and supratentorial effects and maximizes its effects on the spinal cord where the relevant GABAB receptors are found. The early clinical observations that oral baclofen works in patients with a complete anatomical transection of the cord proved that the spinal cord is the primary site of action for its reducing spasticity. The anatomical demonstration of the high concentration of the GABAB receptors in Rexed II of the spinal cord confirmed its specific site of action [3]. The introduction of a programmable implanted drug pump to infuse continuous intrathecal baclofen has made possible regional delivery [4]. If a patient has spasticity due to spinal cord injury or multiple sclerosis, intrathecal baclofen will work more than 95% of the time and will achieve normal tone [5, 6]. The rare exception is due to lack of adequate CSF perfusion of the spinal cord due to an anatomical obstruction. The limitations of intrathecal baclofen therapy should be mentioned. They relate to the imperfect nature of using the CSF for regional delivery of medication. Our studies have shown that the steady infusion of water-soluble medications like baclofen into the lumbar subarachnoid space results in a ratio of 4:1 in concentration between the lumbar-to-cervical region [7, 8]. This means that lower extremity spasticity is more effected than upper. Investigators have mentioned this problem and tried to compensate for it by moving the catheter tip cephalad to have a higher concentration near the cervical cord. This may work for some patients, but the usual result is more sedation because of brainstem effects. The same sedation occurs with increasing the dose given into the lumbar region to raise the baclofen levels at the upper cord. Thus use of the CSF for delivery can only achieve a stereotyped distribution of drug along the cord which may not meet the patient’s needs [9]. If baclofen were more lipid-soluble and were absorbed rapidly by the cord and dura, then the distribution would be more limited (fig. 1). This approach is often used for pain control with lipid-soluble medications such as fentanyl [10]. In that

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Fig. 1. Differential distribution of lipophilic vs. hydrophilic drugs along the spinal cord with continuous intrathecal infusion.

case the catheter tip is placed closer to the dermatomal level of the pain, and neighboring spinal regions are exposed to lower levels of drug. Another limitation of intrathecal delivery is that CSF flow (e.g. clearance) and anatomical spaces vary considerable from patient to patient [7]. The ratio of lumbarto-cervical of 4:1 is an average and the variability is considerable. Thus the concentration and distribution of baclofen will not be fully predictable; empirical adjustment of dose is a rule, and patients with the same amount of spasticity may require doses that vary as much as several fold. Baclofen is not as useful in the generalized dystonias as in spasticity. The reason is that these diseases are due to basal ganglia malfunctions [11] so that the delivery of a GABAB agonist to the normal spinal cord has little effect. GABAA receptors may be the more relevant targets for dystonia and they are plentiful in the basal ganglia. While we and others have found a mild decrease in dystonic symptoms, the required dose is high and the small effect that is seen may be due to supratentorial distribution [12]. This would account for the dose-limiting sedation in patients, just as with oral baclofen. Intraparenchymal delivery of a GABA agonist into the basal ganglia to produce local inhibition might be a more effective approach.

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In contrast to the generalized dystonias, some focal limb dystonias can be effectively treated by intrathecal baclofen [13]. We have reported success in controlling dystonic foot cramping in a patient who had a nerve injury secondary to lumbar disease. In this case local spinal circuitry is responsible for the movement disorder, so regional application makes sense. Such limb dystonias are now treated with botulism toxin injections, which weaken the dystonic muscle group. Baclofen, by working on spinal cord inhibitory pathways, does not effect strength. This point needs to be emphasized because it is one of the major advantages of using medications that do not directly change motoneuron output to muscles. As has been shown in spasticity patients, voluntary movements are not harmed by intrathecal baclofen [14, 15]. In fact, in some patients voluntary movements improve because hyperreflexia is reduced and ‘overflow’ activation of inappropriate muscle groups is eliminated (fig. 2). Confirming this clinical observation is a finding that in normal subjects given intrathecal baclofen, voluntary motor function remains intact [H. Muller, pers. commun.]. In dystonia, inhibition of basal ganglia output by local injection of a GABA agonist might similarly leave major direct motor pathways intact, and have minimal effects on voluntary movements. However motor learning and coordination of movement with posture, the presumed activity of the basal ganglia, might be effected. As more dystonics are implanted with neurostimulators in GPi or STN, these questions may be answered. If major improvements are seen with stimulation, then chronic infusion with a GABAA agonist could be attempted.

Local Drug Infusion for Parkinson’s Disease The availability of realistic animal models (e.g. the neurotoxin MPTP in primates) has made it possible to test new agents within the brain on their ability to alleviate parkinsonian symptoms. This has been done within the framework of neurochemical models of basal ganglia function [16]. Some corroboration of this has also come from the clinical outcomes following lesioning or electrical stimulation within the basal ganglia [17–21]. Globus pallidus interna (GPi) Inhibition It has been known for some time now that the main inhibitory input to the GPi is GABAergic [22]. In particular, the GABAA receptor has been identified at synapses in this region. This has been confirmed in primate studies in which muscimol, the most widely used agonist at the GABAA receptor, inhibits the output from the GPi. In a particularly relevant experiment, Baron et al. [23] injected 1 lg muscimol into the GPi of a monkey with MPTP-induced

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Fig. 2. Attempts at voluntary dorsiflexion before (A) and 120 min (B) after intrathecal baclofen administration. Note disappearance of SOL and HAM coactivation. (From Latash et al. [14].)

parkinsonian symptoms. After 15–20 min, there was marked improvement in akinesia, bradykinesia, and posture on the contralateral side and this effect lasted several hours. Mink and Thach [24] injected 1–2 lg muscimol into the GPi of normal monkeys and found that within a short time there was a change in movements that lasted 7–8 h. Kato and Kimura [25] injected 0.5–2 lg muscimol into the GPi of normal monkeys and found changes in movement lasting a few hours. In all of these experiments, the behavioral changes caused by a bolus injection of muscimol into the GPi were reversible. We have recently injected muscimol into the GPi of 2 patients with Parkinson’s disease prior to creating a GPi lesion and seen improvements in motor

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Fig. 3. Movement speed and amplitude before and 20 min after muscimol injection, and then after a pallidotomy lesion. A shows an increase in velocity after muscimol injection and pallidotomy during a 40 s trial. B depicts amplitude changes that parallel the velocity changes. (From Penn et al. [26].)

performance. In particular, 20 min after 2.5 lg of muscimol was injected into the GPi, patient arm movement increased in amplitude and velocity, and rigidity decreased (fig. 3) [26]. Microinjection of 1–2 microliters of muscimol into the ventral intermediate nucleus of thalamus has recently been shown to arrest tremor in patients with essential tremor [48]. There is also an excitatory, glutamatergic input to GPi [27, 28]. Injection of the glutamate antagonist kynurenic acid, into the primate GPi alleviated parkinsonian symptoms in a MPTP monkey [29]. Therefore, drug delivery to GPi may be an alternative to lesioning or high-frequency electrical stimulation. Subthalamic Nucleus (STN ) Inhibition Although the output of the STN is excitatory, the primary input is GABAergic [28]. Injection of muscimol into the STN of rats produced complete inhibition of cell firing [30]. In monkeys with MPTP-induced parkinsonian signs, injection of 1 lg muscimol into the STN reduced neuronal activity near the injection site, which was followed by reduced akinesia, tremor, and rigidity [31]. The effect lasted from 10 to 60 min. Similar behavioral improvement had been produced by lesioning the STN [16], or electrical stimulation in the STN [32]. Although both GPi and STN can be transiently inhibited by drugs, it is not known if these effects could be maintained for years with chronic infusion. Neurotrophic Factors It is possible that some of the symptoms of Parkinson’s disease could be reduced or even eliminated by direct administration of neurotrophic factors in the brain. In vitro studies have shown that BDNF promotes the survival of dopaminergic neurons in the substantia nigra [33]. In rats with axotomized

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nigral neurons, continuous supranigral infusion of BDNF prevented the loss of nigral neurons in the vicinity of the cannula [34]. When BDNF is slowly infused into the striatum of rats or primates it is retrogradely transported back to the dopaminergic neurons in the substantia nigra [35–37]. This may be a convenient route by which BDNF can be delivered to the cytoplasm of neurons that are degenerating in Parkinson’s disease, although the relatively limited spread of BDNF means that a more complex catheter infusion system must be employed [37]. When delivered systemically, only a negligible amount of BDNF reaches brain tissue. This can be increased by suitably complexing the protein [38], however, there is still the potential problem that increasing BDNF levels in areas outside the nigrostriatal pathway may cause side effects. In vitro studies also demonstrated that GDNF is a survival factor for substantia nigra dopaminergic neurons [39]. When GDNF is injected into the nigrostriatal pathway in rodents it rescues nigral cells from axotomy or MPTP [40, 41]. Intraventricular GDNF moderates parkinsonian signs in MPTP monkeys [42], and some of this protein has been shown to reach the substantia nigra region [43]. A clinical trial is now underway in which GDNF is being delivered to Parkinson’s disease patients as an intraventricular bolus. With systemic administration GDNF does not significantly cross the blood-brain barrier. While there are strategies for increasing blood-brain barrier penetration [44], there again may be risks in delivering this trophic factor to all regions of the brain and spinal cord.

Huntington’s Disease Huntington’s disease is a neurodegenerative disorder characterized by the loss of cells in the striatum. In the animal model of striatal neuron loss produced by focal injection of quinolinic acid, the neurotrophic factor CNTF protected GABAergic and cholinergic neurons [45]. In this case CNTF was delivered from encapsulated cells placed in the monkey striatum a week before the quinolinic acid injection. Other neurotrophic factors which protect striatal neurons from damage due to quinolinic acid are NGF [46] and GDNF [47].

Conclusion Intrathecal baclofen is well established for treating severe spasticity, and appears to be effective in some focal limb dystonias. Whether or not CSF infusion of neurotrophic factors can help in Parkinson’s disease remains to be seen, although the primate MPTP model certainly responds to intraventricular GDNF.

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In the future, direct intraparenchymal delivery may play an important role in modifying basal ganglia circuitry, as our operative experiments with muscimol suggest. The advantage of using local medications instead of ablative procedures is that it is reversible and adjustable. Stimulation has these advantages also. These two techniques are likely to have different physiological outcomes. Stimulation most likely blocks by depolarizing cells and axons in a global way in the areas of highest current density. Drug infusion is selective, activating receptor sites at synapses. It will have more specific effects because it will not block axons of passage. As the equipment for chronic intraparenchymal infusion becomes simpler and less bulky, drug infusion could potentially be the preferable means of local inhibition of abnormal CNS circuits for a variety of movement disorders. References 1 2 3

4 5 6 7

8 9 10 11 12 13 14 15 16

Jones RF, Burke D, Marosszeky JE, Gillies JD: A new agent for the control of spasticity. J Neurol Neurosurg Psychiatry 1970;33:464–468. Hattab JR: Review of European clinical trials with baclofen; in Feldman RG, Young RR, Koella WP (eds): Spasticity: Disordered Motor Control. Chicago, Yearbook, 1980, pp 71–85. Waldvogel HJ, Faull RLM, Jansen KLR, Dragunow M, Richards JG, Mohlers H, Streit P: GABA, GABA receptors and benzodiazepine receptors in the human spinal cord: An autoradiographic and immunohistochemical study at the light and electron microscopic levels. Neuroscience 1990; 39:361–385. Penn RD, Kroin JS: Continuous intrathecal baclofen for severe spasticity. Lancet 1985;ii:125–127. Penn RD, Savoy SM, Corcos D, Latash M, Gottlieb G, Parke B, Kroin JS: Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517–1521. Penn RD: Intrathecal baclofen for spasticity of spinal origin: Seven years of experience. J Neurosurg 1992;77:236–240. Kroin JS, Penn RD: Cerebrospinal fluid pharmacokinetics of lumbar intrathecal baclofen; in Lakke JPWF, Delhaas EM, Rutgers AWF (eds): Parenteral Drug Therapy in Spasticity and Parkinson’s Disease. Carnforth/UK, Parthenon Publishing, 1991, pp 73–83. Kroin JS: Intrathecal drug administration: Present use and future trends. Clin Pharmacokinet 1992; 22–319–326. Kroin JS, Ali A, York M, Penn RD: The distribution of medication along the spinal canal after chronic intrathecal administration. Neurosurgery 1993;33:226–229. Payne R: CSF distribution of opioids in animals and man. Acta Anaesthesiol Scand 1987; 31(suppl 85):38–46. Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD: The pathophysiology of primary dystonia. Brain 1998;121:1195–1212. Albright AL, Barry MJ, Painter MJ, Shultz B: Infusion of intrathecal baclofen for generalized dystonia in cerebral palsy. J Neurosurg 1998;88:73–76. Penn RD, Gianino JM, York MM: Intrathecal baclofen for motor disorders. Mov Disord 1995;10: 675–677. Latash ML, Penn RD, Corcos DM, Gottlieb GL: Short-term effects of intrathecal baclofen in spasticity. Exp Neurol 1989;103:165–172. Latash ML, Penn RD: Changes in voluntary motor control induced by intrathecal baclofen in patients with spasticity of different etiology. Physiother Res Int 1996;1:229–246. Bergman H, Wichmann T, DeLong M: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1348.

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17

18

19 20

21

22 23 24 25 26 27

28 29

30 31

32

33 34 35

36

37

Iacono RO, Shima F, Lonser RR, Kuniyoshi S, Maeda S, Yamada S: The results, indications, and physiology of posteroventral pallidotomy with Parkinson’s disease. Neurosurgery 1995;36: 1118–1127. Limousin P, Pollak P, Benazzouz A, Hoffmann D, LeBas JF, Broussole E, Perret JE, Benabid AL: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995;345:91–95. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO: Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–1387. Baron MS, Vitek JL, Bakay RAE, Green J, Kaneoke Y, Hashimoto T, Turner RS, Woodward JL, Cole SA, McDonald WM, DeLong MR: Treatment of Parkinson’s disease by posterior GPi pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355–366. Shannon KM, Penn RD, Kroin JS, Adler CH, Janko KA, York M, Cox SJ: Stereotactic pallidotomy for the treatment of Parkinson’s disease: Efficacy and adverse effects at six months in 26 patients. Neurology 1998;50:434–438. McGeer EF, Staines WA, McGeer PL: Neurotransmitters in the basal ganglia. Can J Neurol Sci 1984;11:889–899. Baron MS, Wichmann T, DeLong ML: Inactivation of the sensorimotor territory in the internal palladium reverses parkinsonian signs in MPTP-treated monkeys. Soc Neurosci Abstr 1992;22:693. Mink JW, Thach WT: Basal ganglia motor control. III. Pallidal ablation: Normal reaction time, muscle coordination, and slow movement. J Neurophysiol 1991;65:330–351. Kato M, Kimura K: Effects of reversible blockage of basal ganglia on a voluntary arm movement. J Neurophysiol 1992;71:1151–1164. Penn RD, Kroin JS, Reinkensmeyer A, Corcos DM: Injection of GABA-agonist into globus pallidus in patient with Parkinson’s disease. Lancet 1998;351:340–341. Kitai ST, Kita H: Anatomy and physiology of the subthalamic nucleus: A driving force of the basal ganglia; in Carpenter MB, Jayaraman A (eds): The Basal Ganglia. II. Structure and Function: Current Concepts. New York, Plenum, 1987, pp 357–373. Smith Y, Parent A: Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity. Brain Res 1988;453:353–356. Graham WC, Robertson RG, Sambrook MA, Crossman AR: Injection of excitatory amino acid antagonists into the medial pallidal segment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primate reverses motor symptoms of parkinsonism. Life Sci 1990;47:91–97. Robledo P, Feger J: Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: Electrophysiological data. Brain Res 1990;518:47–54. Wichmann T, Bergman H, DeLong M: The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophysiol 1994;72:521–530. Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B: Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 1993;5:382–389. Hyman C, Hoeffer M, Barde YA, Juhasz M, Squinto S, Lindsay RM: BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991;350:230–232. Hagg T: Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo. Exp Neurol 1998;149:183–192. Mufson EJ, Kroin JS, Sobreviela T, Burke MA, Kordower JH, Penn RD, Miller JA: Intrastriatal infusions of brain-derived neurotrophic factor: Retrograde transport and colocalization with dopamine containing substantia nigra neurons in the rat. Exp Neurol 1994;129:15–26. Anderson KD, Alderson RF, Alter CA, DiStefano PS, Corcoran TL, Lindsay RM, Wiegeland SJ: The differential distribution of exogenous BDNF and NGF in the brain corresponds to the distribution of high-affinity low-affinity neurotrophin receptors. J Comp Neurol 1995;357:296–317. Mufson EJ, Kroin JS, Liu YT, Sobreviela T, Penn RD, Miller JA, Kordower JH: Intrastriatal and intraventricular infusion of brain-derived neurotrophic factor in the cynomolgus monkey: Distribution, retrograde transport and colocalization with substantia nigra dopamine containing neurons. Neuroscience 1996;71:179–191.

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Pardridge WM, Wu D, Sakane T: Combined use of carboxyl-directed protein pegylation and vector-mediated blood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenous administration. Pharm Res 1998;15:576–582. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F: GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993;260:1130–1132. Beck KD, Valverde J, Alexi T, Poulsen KT, Moffat B, Vandlen R, Rosenthal A, Hefti F: Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature 1995;373:339–341. Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoeffer B, Olson L: Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 1995;373:335–339. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA: Functional recovery in parkinsonian monkeys treated with GDNF. Nature 1996;380:252–255. Lapchak PA, Araujo DM, Hilt DC, Jiao S, Collins F, Miyoshi Y, Yi A, Zhang Z, Gash DM: Topographical distribution of [125I]-glial cell line-derived neurotrophic factor in unlesioned and MPTP-lesioned rhesus monkey brain following a bolus intraventricular injection. Brain Res 1998; 789:9–22. Albeck DS, Hoffer BJ, Quissell D, Sanders LA, Zerbe G, Granholm AD: A non-invasive transport system for GDNF across the blood-brain barrier. Neuroreport 1997;8:2293–2298. Emerich DF, Winn SR, Hantraye PM, Peschanski M, Chen ER, Chu Y, McDermott P, Baetge EE, Kordower JH: Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 1997;386:395–399. Martinez-Serrano A, Bjorklund A: Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J Neurosci 1996;16:4604–4616. Perez-Navarro E, Arenas E, Reiriz J, Calvo N, Alberch J: Glial cell line-derived neurotrophic factor protects striatal calbindin-immunoreactive neurons from excitotoxic damage. Neuroscience 1996; 75:345–52. Pahapill PA, Levy R, Dostrovsky JO, Davis KD, Rezai AR, Tasker RR, Lozano AM: Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor. Ann Neurol 1999;46: 249–252.

Richard D. Penn, MD, Department of Neurosurgery, Mount Sinai Center, One Gustave L. Levy Place, Box 1136, New York, NY 10029 (USA) Tel. +1 212 241 3457, Fax +1 212 410 0603, E-Mail [email protected]

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Lozano AM (ed): Movement Disorder Surgery. Prog Neurol Surg. Basel, Karger, 2000, vol 15, pp 381–394

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Gene Therapy Approaches to Parkinson’s Disease Andrew Freese Department of Neurosurgery, Thomas Jefferson University, Philadelphia, Pa., USA

Over the past decade a number of improvements in gene therapy approaches to neurological diseases have made it possible that clinical trials for genetic intervention in patients with Parkinson’s disease and other movement disorders will occur within the next several years, although significant obstacles persist that may restrain immediate application to patients. Approaches to neurological gene therapy can be divided into two broad categories: (i) ex vivo systems which are based on altering the genetic framework of cells or tissues and in turn these are grafted into the host brain and (ii) in vivo systems which are predicated on directly introducing therapeutic genetic information into desired locations within the brain, altering the host brain’s physiology directly. Each of these systems has seen enormous advances, resulting in encouraging results in animal models of Parkinson’s disease. These approaches will likely supplant tissue transplantation techniques that do not have the same scientific sophistication and have proven to be suboptimal and impractical in most clinical trials.

Ex vivo Approaches to Parkinson’s Disease Many studies have focused on the development of cell lines that express neuroprotective or neurorestorative genes, and these cell lines are then grafted directly into the brain, usually adjacent to or within the corpus striatum. The primary goal of these studies has been to introduce cells that function as a genetically engineered transplant that can secrete desirable substances that would ameliorate the symptoms associated with Parkinson’s disease. Most published studies have focused on introducing genes encoding the enzymes responsible for dopamine biosynthesis, including tyrosine hydroxylase

(TH) and aromatic amino acid decarboxylase (AADC or dopa decarboxylase), which respectively convert tyrosine into L-dopa, and in turn L-dopa into dopamine. More recently, studies have examined introducing cells transfected with alternative genes, including the gene encoding the enzyme (GTP cyclohydrolase) responsible for production of the cofactor for TH (tetrahydrobiopterin) and the gene encoding vesicular monoamine transporter, responsible for reuptake and storage of dopamine in the presynaptic terminal, augmenting its storage and neurotransmission. The hypothesis is that by introducing cells that secrete and increase levels of dopamine in the extracellular milieu, dopaminergic tone increases, and since dopamine appears to function more as a paracrine, slow-acting transmitter, an increase in dopamine tone is likely to have a beneficial effect on behavior. More recent studies have focused on genes that offer neuroprotective or even neuroregenerative functions, such as certain classes of growth factors, including glial cell line-derived neurotrophic factor. Background of ex vivo Approaches A number of groups, led by Gage et al. [45], first initiated studies in the mid-1980s focused on developing techniques to transfer genes into fibroblast cell lines. Early studies resulted in significant variability of transgene expression, which was largely due to the specific technique used for gene transfer, but the choice of promoter and other cellular factors also played a role in controlling gene expression. An early study by Palmer et al. [44], found that fibroblasts that had been transfected using retrovirus vectors had strong transgene expression, but this expression downregulated by over 1,000-fold within 1 month of transplantation into a host animal. Immunological rejection was not the cause of this downregulation, but rather instability of the regulatory elements was determined to be the cause [44]. In another report, Scharfmann et al. [48] found that long term gene expression could be achieved with an endogenous promoter, such as the housekeeping dihydrofolate reductase promoter, in place of viral promoters, and current studies have expanded the armamentarium of endogenous promoters used [24, 25], largely focusing on endogenous cellular promoters. Immortalized Cell Lines Immortalized cell cultures provided an initial focus for the development of an appropriate cell type for grafting into the recipient brain. At first, immortalized fibroblast cell lines [55] were used because they were easy to grow and could readily be genetically manipulated in tissue culture. A rat fibroblast cell line (208F) was transfected with the TH cDNA, and in vitro in the presence of the TH cofactor, tetrahydrobiopterin, L-dopa was synthesized and secreted extracellularly. In turn, these modified cells were grafted

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into the brains of rats previously treated with 6-hydroxydopamine (6-OHDA), a neurotoxin that is used to create the rat rotational model of Parkinson’s disease. Two weeks after grafting, a small reduction in the abnormal rotational behavior of the rats was observed, but immunohistochemical staining failed to show any TH staining, and a significant immunological response was identified, presumably due to a mismatch between host and graft. Thus, some of the behavioral effect may have been due to the induction of a lesion. Based on these and other studies, it has become quite clear that the brain is not ‘immuneprivileged’ and therefore the immune system is an important constraint in any tissue grafting paradigm. Therefore, another study used immortalized, syngeneic Fischer fibroblast cell lines which were transfected with the TH gene and grafted into 6-OHDA-treated rats. Unfortunately these cells were found to form rapidly expanding tumors that ultimately killed the test animals. From this it became clear that cells that divide and form tumors cannot be the basis for ex vivo genetic manipulation. Primary Culture Approaches Over the past decade, numerous additional studies have developed improved approaches towards defining the appropriate tissue source for grafting. Initially much attention focused on immortalized cell lines, but more recent attention has focused on primary cell cultures since they are likely to be dormant within the postmitotic host brain and not form expanding tumor masses. In addition, much attention is now focused on the use of ‘stem’ cells or neural precursor cells derived from the subependymal zone, and other immortalized human stem cellderived platforms for gene transfer and implantation. Kawaja and Gage [32] studied striatal implantation of cultured primary skin fibroblasts in Fischer 344 rats. These fibroblasts lasted at least several months when transplanted into the host brain. In culture, these cells grow robustly, but once they form a confluent monolayer, growth arrest occurs. Similarly, in situ in the brain, these cells form a capillary network, a rudimentary blood-brain barrier, and a dormant tissue mass which can secrete substances into the adjacent host tissue. When such fibroblasts were transfected with the TH gene and grafted into the 6-OHDA rat rotational model, the grafts expressed the transgene and survived for more than 10 months. In tissue culture and in situ in the brain, L-dopa secretion was observed, and the 6-OHDA rats demonstrated significant behavioral recovery. Other related studies have expanded the potential role of such isogeneic cells that do not form expanding tumors to express the TH gene and amplify L-dopa, and presumably dopamine, formation in situ. An alternative gene target has been the focus of more recent studies [30, 52]. The gene encoding the enzyme responsible for biosynthesis of the

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TH cofactor, tetrahydrobiopterin, GTP cyclohydrolase (GTPCH1), in combination with the TH gene were transfected into primary fibroblasts, and these cells were grafted into the 6-OHDA rat model, with evidence of amplified L-dopa and dopamine biosynthesis and behavioral recovery. In addition, by combining the gene encoding the vesicular monoamine transporter [2] and aromatic amino acid decarboxylase in a construct introduced into primary skin fibroblasts, a significant increase in dopamine storage and behavioral recovery in parkinsonian rats were observed. Numerous alternative cell types have been applied as well towards developing ex vivo approaches to genetic intervention. Included among these are autologous muscle grafts [27–29], Schwann cells [42], certain tumor cells lines [40], pig xenograft tissue, and biohybrid implants [38], as well as human stem cells. Similarly, alternative genetic targets have been identified, including glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Studies using cell lines that secrete these substances have suggested a neuroprotective and potentially neuroregenerative effect on the nigrostriatal system [16, 23]. Disadvantages of the ex vivo Approaches There are a number of advantages of ex vivo approaches to genetic intervention in neurological disorders, such as Parkinson’s disease. These include a clear identification of the genetic elements that drive gene expression, unlike some of the in vivo approaches based on viruses that have less well characterized genetic elements. The concept of using grafted cells that act as ‘factories’ that secrete desirable products appears to be particularly appealing. Current technology permits long-term survival of the grafted cell lines, without producing tumors that kill the host. There are, nonetheless, significant problems with ex vivo approaches. A tissue mass is grafted into the host brain which disrupts normal host circuitry and which does not integrate into the host circuitry. Cells that can divide or migrate may form masses or disrupt appropriate anatomy and/or physiology of the host brain. Endogenous control elements that regulate homeostasis are therefore bypassed, and regulation of the secreted substance becomes a problem. Because of the focal location of the tissue graft, diffusion of the secreted substance is essential, and for most substances, this diffusion is suboptimal and may not reach the desired target tissue. The long-term outcome from application of the most recent cellular grafts, such as the porcine cells and human stem cells, in humans for the former and in animal models for the latter, are still uncertain. Furthermore, in many studies using cellular-based grafts, scale-up from the rat 6-OHDA model to primates and eventually to humans has proven problematic.

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In vivo Systems In part because of the disadvantages of ex vivo approaches, particularly early on when grafted tissues formed expanding tumors, and because of the advent of new technology that permits direct gene transfer into target tissues, an alternative approach from ex vivo gene therapy has emerged, and has progressed in parallel, often intersecting the ex vivo systems whenever transgene delivery is desired. Because of the inherent elegance of in vivo approaches, and the increased sophistication of gene transfer technology, it is possible that in vivo approaches will prevail in clinical application of gene therapy for Parkinson’s disease and other movement disorders, although such predictions are often proven incorrect as technology progresses Gene Transfer Techniques: Background A myriad of techniques has been used to transfer genes into mammalian cells, including use of liposomes, plasmids, viruses, and direct DNA transfer [10, 15]. Although the technology is advancing rapidly for nonviral systems, in general gene transfer vectors based on DNA viruses appear to hold the greatest promise for direct genetic intervention in Parkinson’s disease. These viruses can transfect the postmitotic CNS, typically have large enough genomes to accommodate most therapeutic genes, and have been sufficiently attenuated to prevent a toxic infection in the host brain. At this point, three virus vector systems have been successfully applied to animal models of Parkinson’s disease, resulting in a number of publications, although studies applying novel lentivirus vectors and nonviral liposome systems are ongoing. The three viruses that have been used are (i) herpes simplex virus-1 (HSV-1); (ii) adenovirus, and (iii) adeno-associated virus (AAV). Each of these has advantages and disadvantages, although it appears that AAV vectors are likely to reach clinical application first. HSV-1 Vectors There are a number of features of HSV-1 that make it an attractive vector for gene delivery into the brain. These include its wide host range in numerous neuronal and glial cell types, its regulated expression of genes, its ability to infect postmitotic cells, its large genome that can accommodate most therapeutic genes, its ability to remain quiescent in a latent state, and its absence of toxicity in the latent state [3, 4, 10–15, 17–20, 39, 43, 49]. There are two categories of HSV-1 vectors that have been developed for CNS gene transfer [10, 15]: (i) defective viral vectors and (ii) recombinant vectors. Defective viral vectors are based on defective interfering HSV-1 particles, which occur when HSV-1 is grown at high multiplicities of infection (moi, or

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the ratio of the number of viral particles to the number of cells). Defective interfering particles possess only a portion of the entire 150 kb HSV-1 genome, but this portion is repeated until approximately 150 kb of DNA is generated and this is then packaged into an HSV-1 virion. Defective interfering particles need help from wild-type HSV-1 since they cannot replicate and package their own DNA, but they do contain an HSV-1 origin of replication and the packaging signals needed for packaging the DNA into a virion [49, 53, 54]. Spaete and Frenkel [49] developed a prototype plasmid, termed an amplicon, which eliminated most of the native HSV-1 DNA and replaced it with a foreign transgene, but allowed packaging of the DNA into virus particles. This amplicon packaged multiple copies of the gene of interest in one particle, allowing these multiple copies of the transgene to gain access to the desired target cell. The resulting packaged viral vector was termed a defective viral vector, which contains a gene of interest packaged into an HSV-1 coat which cannot replicate on its own and which elicits minimal immune responses since it contains no or only a few HSV-1 proteins. A disadvantage is that a helper virus is required to provide the missing proteins required for gene therapy applications, and this helper virus can induce an immune response or prove to be toxic or even cause a lytic herpes infection. The other type of HSV-1 vector is the recombinant vector, or replicon, in which one or more essential genes are eliminated from the HSV-1 genome. This, in turn, reduces the ability of the virus to replicate and cause toxicity in host cells or tissues. A new transgene, or gene of interest, can replace the gene(s) which has been eliminated, and now the transgene is expressed in host cells. Although most of these replicons have been developed with a solitary gene deletion, such that most of the other approximately 70 HSV-1 proteins are still made, newer systems are being developed which have numerous deletions, which further debilitate the virus’ ability to damage tissue and reduce its immunogenicity. Unfortunately, because the majority of people have latent HSV-1 infections residing within their trigeminal ganglia, the potential for recombination between the vector and the endogenous wild-type virus is problematic, since it could result in a fatal encephalitis. Early Studies with HSV-1 Vectors A number of studies in the late 1980s used defective HSV-1 vectors [11, 12, 14, 17, 18, 20, 33] to demonstrate that they could transfect dividing cells and postmitotic neurons in tissue culture, resulting in transgene expression. Once the principle was established, a novel HSV-1 amplicon vector system was devised by Geller et al. [8, 10], which contained the cDNA expressing human TH (type II). This vector directed expression of human TH RNA and protein in neonatal rat striatal cells in culture [8, 10]. After

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several days of transfection, cellular RNA was extracted and the presence of human TH mRNA was determined using reverse transcriptase polymerase chain reaction. This vector was also shown to direct expression of human TH protein in these cultures, as assayed by immunohistochemical techniques; most of the transfected cells were neurons. Both L-dopa and dopamine release were shown to increase in cells transfected with the experimental vector, compared to controls, and the release of these catecholamines was stimulated by physiologically depolarizing conditions. It is of note that the amount of TH enzyme produced was similar to that endogenously found in native catecholaminergic neurons [8, 10], and L-dopa production was comparable to that found in genetically engineered cells (for ex vivo gene therapy studies) transfected with TH. In vivo Studies After establishing that an HSV-1 vector could direct TH expression and L-dopa production in cultured neostriatal neurons, attention was focused on applying this vector to the 6-OHDA rat rotational model [8]. In those rats which received the TH vector directly introduced stereotactically into the striatum, compared to controls, there was an approximately 65% reduction in aberrant rotational behavior, sustained for 1 year. Microdialysis studies directly measuring levels of dopamine in situ in these rats revealed significant increases in extracellular dopamine levels, which responded to physiological depolarizing conditions. Furthermore, immunocytochemical evaluation for TH expression in sacrificed rats showed numerous cells, mostly neurons, expressing human TH in those animals transfected with the TH vector, and not seen in controls. These results indicated that the experimental vector directed human TH gene transfer into the rat brain, which resulted in transcription, translation, and expression of a functional TH protein that increased L-dopa and dopamine production. This resulted in a sustained and significant behavioral improvement in 6-OHDA-treated rats. Unfortunately, in this study, some rats succumbed to HSV-1 encephalitis, presumably mediated by reversion of the vector system to wild-type virus. These results were the first demonstration of efficacy of an in vivo gene therapy approach to Parkinson’s Disease, but also highlighted the significant problems with HSV-1 vectors, and viral gene transfer in general. Newer HSV-1 Vectors More recently approaches have been developed to reduce the cytopathic effects of HSV-1 vectors. Cell type-specific factors, such as Oct-2 [26], have been used to interfere with HSV lytic infections. Novel recombinants with multiple deletions have been developed that appear to reduce neurovirulence

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[22]. Newer, helper-free amplicon vector stocks have been developed which appear to reduce cytotoxicity as well [21]. However, there remains significant reluctance to use HSV-based vectors for restorative molecular gene therapy because of the concerns of immunogenicity and cytoxicity, largely related to the risk of recombination and production of endogenous, immunogenic viral proteins. Adenovirus Vectors Because of the established cyototoxicity of HSV-1 vectors, other virus vector systems have been explored for potential application to Parkinson’s disease. In 1993, a number of publications suggested the potential of adenovirus vectors to direct gene transfer into the mammalian brain [1, 2, 5, 34]. In most of the studies, it appeared that glial cells were predominantly targeted, but neurons appeared to express the transgene as well. At low titers, minimal toxicity was seen, whereas at higher titers, significant evidence of neurotoxicity was observed. Although in the short term (up to 1 month), a large number of cells were transduced and showed transgene expression, at 2 months most of the gene expression had disappeared. Based on these encouraging preliminary studies, a number of groups have used adenovirus vectors to direct TH transfer and expression in striatal cells, both in tissue culture and in the 6-OHDA rat rotational model. In one study, a significant reduction in rotational behavior was observed for just 2 weeks; in another study, longer term efficacy was demonstrated [24, 25]. In a recent study, Leone and co-workers [unpubl. results] have recently found that there is a direct linear correspondence between the number of cells which express TH following adenovirus vector-mediated gene transfer and behavioral recovery in rats. Additional studies have focused on gene transfer of neuroprotective substances using adenovirus vectors. Human GDNF cDNA was introduced into substantia nigra cells, resulting in increased sprouting and survival of these cells. Further definition of the role of such neuroprotective strategies using adenovirus-mediated gene transfer is ongoing. A significant obstacle in the application of adenovirus vectors to CNS gene therapy is their inherent immunogenicity. Although newer generation adenovirus vectors appear to have reduced induction of an immune response, in most studies this has proven to limit long-term expression and induce inflammatory responses in target tissues, including the brain. Human trials using adenovirus vectors for application to CNS malignancy has revealed that the immune response in the human brain is quite significant, and more effective strategies need to be developed to obviate this issue before application to human patients with Parkinson’s disease may be considered.

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Adeno-Associated Virus Vectors Based on the limitations of HSV-1 and adenovirus vectors, a number of investigators have focused their attention on an alternative viral vector, based on AAV [13, 31]. AAV is a nonpathogenic DNA virus which is incapable of autonomous replication and spread, and which can, under certain circumstances, integrate into the host chromosome, increasing transgene stability [31, 41, 47]. Vectors based on AAV can be produced to be entirely free of helper viruses and do not express any endogenous viral proteins. This reduces the likelihood of toxicity or immunogenicity, and offers a significant advantage over other DNA viruses which retain the ability to produce endogenous viral proteins. In all published reports using AAV vectors, there is no evidence of cytopathic effects, in sharp contrast to studies using adenovirus and HSV-1. There are some disadvantages for AAV, however. These include observations that viral titers are lower than those obtained with adenovirus and HSV-1. The AAV genome can only accommodate 5 kb or smaller transgene sequences, in contrast to HSV-1 which has a much larger genome and can therefore incorporate larger transgene sequences [10, 15]. A number of investigators have performed studies over the past several years examining the potential application of AAV vectors for therapy in Parkinson’s disease. During and co-workers [31] developed an AAV vector expressing human TH (form II) cDNA, which caused significant expression of TH in cultured striatal neurons. The majority of transfected cells were neurons, although glial cells also expressed human TH. Elevation of L-dopa synthesis was observed, leading to application of this vector to the 6-OHDA rat rotational model of Parkinson’s disease. Injection of the AAV vector expressing TH resulted in a sustained and significant recovery of apomorphine-induced asymmetrical rotation for several months, whereas control vector or buffer injections had no effect. A more recent study [9] used an AAV vector which not only expressed human TH, but also AADC cDNA. By expressing both of the enzymes responsible for dopamine biosynthesis, the hypothesis was that there would be even further amplification of dopamine production, since this strategy would not have to rely on endogenous decarboxylase activity. This vector was then applied to the MPTP primate model of Parkinson’s disease. In the experimental animals which received the TH/AADC vector, a number of molecular biological techniques demonstrated the presence of human TH and AADC, which were not found in control animals. Although the number of primates was small, in some animals a significant and sustained behavioral recovery was noted, which in some cases was quite dramatic. Expansion of this study to a larger animal cohort is planned.

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Another study [6, 7] evaluated an AAV vector expressing glial cell line-derived neuronotrophic factor (GDNF). GDNF has been shown to be a neurotrophic factor that promotes midbrain dopaminergic survival [35, 37, 51]. In embryonic mesencephalic rat cells in culture, the AAV vector expressing GDNF resulted in increased survival of dopaminergic neurons. Similarly, when applied to animal models, there was evidence of neuroprotection. Two animal models of nigral degeneration were used. In the first, rats had prelabeling of nigrostriatal neurons performed with fluorogold; subsequently bilateral 6-OHDA lesioning was induced. The AAV vector expressing GDNF was introduced unilaterally prior to introduction of 6-OHDA, and significant neuroprotection was observed on this side, with increased striatal dialysate levels of dopamine and rotational effects. Similarly, in two primates treated with MPTP, stereotactic introduction of AAV-expressing GDNF unilaterally resulted in increases in single-photon emission-computed tomography (SPECT)-based imaging of the dopamine transporter on the treated side, which was not seen on the control side. Ideally, a combination of neuroprotective and neurorestorative genetic intervention would be available. Therefore, studies are currently focused on developing novel vectors that express both enzymes involved in dopamine biosynthesis, as well as proteins that are neuroprotective. Included among the target-restorative genes currently being evaluated are TH, AADC, GTP cyclohydrolase, and antisense to the dopamine transporter. Included among target neuroprotective/neuroregenerative genes being studied are GDNF, BDNF, Nurrl, and other members of different neurotrophin families. Problems with Gene Therapy for Parkinson’s Disease Although significant advances have been made in the development of gene therapy approaches to Parkinson’s disease, and other neurological diseases, there still remain significant obstacles that preclude immediate application to human patients of these approaches. Among these obstacles are (i) the need to define the most appropriate transgene and promoter; (ii) identification of which vector or cell line should be applied; (iii) optimization of the delivery system; (iv) definition of the target tissue, and (v) assurance of no toxicity or immune response. It is incumbent upon investigators to avoid the mistakes of the tissue transplant field, which rushed prematurely into clinical trials, at first leading to a debacle with autologous adrenal transplants that had no efficacy and evidence of toxicity, and more recently the significant evidence that fetal transplants also may cause significant morbidity, worsen parkinsonian symptoms, and have no meaningful long-term efficacy. The ideal choice of transgene in gene therapy for Parkinson’s disease has not yet been decided. Even if one favors a dopaminergic restorative approach, should one use TH, AADC, GTP cyclohydrolase, vesicular monoamine trans-

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porter, or a combination thereof ? No study has directly compared these transgenes in animal models, and clearly such a study must be done prior to moving into human clinical trials. The choice of promoter is also uncertain. A plethora of promoters has been used in a number of studies, and it does appear that endogenous cellular promoters are the optimal choice, but these even vary, in part dependent on the cell types that are transfected, the brain location that is chosen, and the amount and longevity of expression that is achieved. Ultimately, comparative analysis of different promoters in must be undertaken before moving into clinical trials. The ideal choice of viral (or nonviral) vector or cell line used for gene transfer remains unclear, and is largely driven by the selected experience of individual research laboratory groups rather than an objective understanding of what the best system may be. Furthermore, as more biotechnology companies are focusing on the significant economic potential of genetic intervention in neurological diseases, they will tend to promote their own proprietary technology, rather than identifying the most appropriate system for human application. Ultimately, to avert a potential disaster, the scientific and medical community must develop its own consensus about which approach to first use in human patients, unfettered by economic considerations. The delivery system used to introduce into the brain cell lines or genetic vectors is still an area that needs much investigation. Simple stereotactic delivery appears to be the most appropriate, but questions of volume of injection, rate of injection, number of injections, use of drugs to alter the extracellular fluid compartment and blood-brain barrier (such as mannitol), and other issues remain unsolved. Alternatively, endovascular approaches using newer generations of catheters that could target select brain regions may provide an elegant alternative to invasive surgery. The optimal choice of target tissue is still uncertain. Is the corpus striatum the right choice? Should attention be focused on the substantia nigra, or even the subthalamic nucleus? Comparative studies have not yet been performed, and these must be done prior to rushing into human trials. Finally, the issue of cytoxicity and immune responses, particularly to viral vectors, is paramount. Because of the sequestered nature of the target tissues, and the limited flexibility of the nigrostriatal system, particularly in a fragile Parkinson’s disease patient, it must be clearly established that whatever system is used cannot lead to problems, even in the long term. Since there are attractive pharmacological and surgical options for patients with Parkinson’s disease, before clinical trials are undertaken, it is an ethical responsibility of investigators to ensure the safety of any gene transfer approach to these patients. Longterm studies in animal models must therefore be done, and focusing on safety and efficacy in patients should be paramount.

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References 1

2 3 4 5

6

7 8 9

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19 20 21

Akli S, Caillaud C, Vigne E, Stratford-Perricaudet LD, Ponnaru L, Perricaudet M, Kahn A, Peschanski MR: Transfer of a foreign gene into the brain using adenovirus vectors. Nat Genet 1993;3:224–228. Bajocchi G, Feldman SH, Crystal RG, Mastrangeli A: Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors. Nat Genet 1993;3:229–234. Baringer JR, Sworeland P: Recovery of herpes-simplex virus from human trigeminal ganglions. N Engl J Med 1973;228:9593–9596. Cook ML, Bastone UB, Stevens JG: Evidence that neurons harbor latent herpes simplex virus. Infect Immun 1974;9:946–951. Davidson BL, Allen ED, Kozarsky KF, Wilson JM, Roessler BJ: A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nat Genet 1993;3:219– 223. During MJ, Choi-Lundberg D, Leone P, Lin Q, Kaplitt MG, Xiao X, Samulski RJ, Freese A, Hoffner P, Roth RH, Elsworth JD, Sladek JR Jr, O’Malley KL, Federoff HJ, Redmond DE Jr, Bohn MC: Neuroprotection and neuroregeneration in rodent and primate parkinsonian models using an AAV vector expressing GDNF. Abstr Soc Neurosci 1995;21:225.9. During MJ, Leone P: Targets for gene therapy of Parkinson’s disease: Growth factors, signal transduction, and promoters. Exp Neurol 1997;144:74–81. During MJ, Naegele JR, O’Malley KL, Geller AI: Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. Science 1994;266:1399–1403. During MJ, Samulski RJ, Elsworth JD, Kaplitt MG, Leone P, Xiao X, Li J, Freese A, Taylor JR, Roth RH, Sladek JR, O’Malley KL, Redmond DE: In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. Gene Ther 1998;5:820–827. Freese A (ed): Gene therapy for Parkinson’s disease: Rationale, prospects and limitations. Exp Neurol 1997;144 (the entire issue is devoted to gene therapy of Parkinson’s disease). Freese A, During MJ, O’Malley K, Geller AI: Expression of tyrosine hydroxylase in striatal cells with a HSV-1 vector causes stable production and regulated release of dopa and dopamine: Potential gene therapy for Parkinson’s disease. Abstr Soc Neurosci 1991;17:424.15. Freese A, Geller AI: Infection of cultured striatal neurons with a defective HSV-1 vector: Implications for gene therapy. Nucl Acids Res 1991;19:7219–7223. Freese A, Kaplitt MG, O’Connor WM, Langer D, O’Connor MJ, Kaplitt MG: Direct gene transfer into human epileptogenic hippocampal tissue with an adeno-associated virus vector: Implications for a gene therapy approach to epilepsy. Epilepsia 1997;38:759–766. Freese A, Neve R, Geller AI: HSV-1 vector-mediated neuronal gene delivery: Strategies for neuroscience and neurology. Biochem Pharmacol 1990;40:2189–2199. Freese A, Stern M, Kaplitt MG, O’Connor WM, Abbey MV, O’Connor MJ, During MJ: Prospects for gene therapy in Parkinson’s disease. Mov Disord 1996;11:469–488. Frim DM, Uhler TA, Galpern WR, Beal MF, Breakefield XO, Isacson O: Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridium toxicity to dopamine neurons in the rat. Proc Natl Acad Sci USA 1994;91:5104–5108. Geller AI, Breakefield XO: A defective HSV-1 vector expresses Escherichia coli b-galactosidase in cultured peripheral neurons. Science 1988;241:1667–1669. Geller AI, During MJ, Haycock JW, Freese A, Neve R: Long-term increases in neurotransmitter release from neuronal cells expressing a constitutively active adenylate cyclase from a herpes simplex virus type 1 vector. Proc Natl Acad Sci USA 1993;90:7603–7607. Geller AI, During MJ, Neve RL: Molecular analysis of neuronal physiology by gene transfer into neurons with herpes simplex virus vectors. Trends Neurosci 1991;14:428–432. Geller AI, Freese A: Transfection of cultured central nervous system neurons with a defective HSV1 vector which expresses b-galactosidase. Proc Natl Acad Sci USA 1990;87:1149–1153. Geller A, Song S, Lim F: A helper virus-free packaging system for HSV-1 plasmid vectors that supports efficient gene transfer in the rat brain. Abstr Soc Neurosci 1995;21:330.1.

Freese

392

22 23 24 25

26

27 28 29 30

31

32 33 34

35 36

37 38 39 40

41 42

43

44

Glorioso JC, Goins WF, Meaney CA, Fink DJ, DeLuca NA: Gene transfer to brain using herpes simplex virus vectors. Ann Neurol 1994;35:28–34. Hofer MM, Barde YA: Brain-derived neurotrophic factor prevents neuronal death in vivo. Nature 1988;331:261–262. Horellou P, Sabate O, Buc-Caron MH: In vivo and ex vivo gene therapy in a rat model of Parkinson’s disease. Proc Int Conf on Gene Therapy for CNS Disorders, 1996, 3.15. Horellou P, Vigne E, Castel MN, Barneoud P, Colin P, Perricaudet M, Delaere P, Mallet J: Direct intracerebral gene transfer of an adenoviral vector expressing tyrosine hydroxylase in a rat model of Parkinson’s disease. Neuroreport 1994;6:49–53. Jacoby DR, Breakefield XO, Latchman DS: Construction of an HSV-1 amplicon with an inducible Oct-2 operon to modulate cytopathic effect. Proc Int Conf on Gene Therapy for CNS Disorders, 1996, 1.31. Jiao S, Gurevich V, Wolff JA: Long-term correction of a rat model of Parkinson’s disease by gene therapy. Nature 1993;362:450–453. Jiao S, Schultz E, Wolff JA: Intracerebral transplants of primary muscle cells: A potential ‘platform’ for transgene expression in the brain. Brain Res 1992;575:143–147. Jiao S, Wolff JA: Long-term survival of autologous muscle grafts in rat brain. Neurosci Lett 1992; 137:207–210. Kang UJ, Benecsics C, Cahill AL, Hatakeyama K, Milstein S: Regulation of L-dopa production by 5,6,7,8-tetrahydro-L-biopterin in genetically modified cells. Proc Int Conf on Gene Therapy for CNS Disorders, 1996, 3.11. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfatt DW, O’Malley KL, During MJ: Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 1994;8:148–154. Kawaja MD, Gage FH: Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. J Comp Neurol 1992;317:102–116. Kwong D, Frenkel N: The herpes simplex virus virion host shutoff function. J Virol 1989;63:487–496. Le Gal La Salle G, Robert JJ, Berrard S, Ridoux V, Stratford-Perricaudet LD, Perricaudet M, Mallet J: An adenovirus vector for gene transfer into neurons and glia in the brain. Science 1993; 259:988–990. Lin LFH, Doherty DH, Lile JD, Bektesh S, Collins F: GDNF: A glial cell-line derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993;260:1130–1132. Lin O, Choi-Lundberg DL, Ravenell J: Adenoviral (Ad)-mediated gene transfer of GDNF and bgalactosidase (lac Z) to the rat nigrostriatal system in vitro and in vivo. Abstr Soc Neurosci 1995; 21:224.12. Lindsay RM: Neuron-saving schemes. Nature 1995;273:289–290. Lysaght MJ, Frydel B, Gentile F, Emerich D, Winn S: Recent progress in immunoisolated cell therapy. J Cell Biochem 1994;56:196–203. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM: Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991;252:854–856. Morassutti DJ, Atasoy E, Staines WA, McBurney MW: Characterization of murine P19 EC-derived neurons expressing foreign rat TH cDNA in vitro and in vivo. Proc Int Conf on Gene Therapy for CNS Disorders, 1995, 3.12. Muzyczka N: Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 1992;158:97–129. O’Malley K, Geller AI: Gene therapy in neurology: Potential application to Parkinson’s disease; in Vecsei L, Freese E, Swartz KJ, Beal MF (eds): Neurological Disorders: Novel Experimental and Therapeutic Strategies. Chichester/UK, Horwood, 1992, pp 223–248. Palella TD, Hidaka Y, Silverman LJ, Levine M, Glorioso J, Kelley WN: Expression of human HPRT mRNA in brains of mice infected with a recombinant herpes simplex virus-1 vector. Gene 1989;80:137–144. Palmer TD, Rosman GJ, Osborne WRA, Miller AD: Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes. Proc Natl Acad Sci USA 1991; 88:1330–1334.

Gene Therapy Approaches to Parkinson’s Disease

393

45 46 47 48 49 50 51 52

53 54

55

Ray J, Gage FH: Gene transfer into established and primary fibroblast cell lines: Comparison of transfection methods and promoters. Biotechniques 1992;13:598–603. Raymon HK, Thode S, Gage FH: Application of ex vivo gene therapy in the treatment of Parkinson’s disease. Exp Neurol 1997;144:82–91. Samulski RJ, Chang LS, Shenk T: Helper-free stocks of adeno-associated viruses: Normal integration does not require viral gene expression. J Virol 1989;63:3822–3828. Scharfmann R, Axelrod JH, Verma IM: Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc Natl Acad Sci USA 1991;88:4626–4630. Spaete RR, Frenkel N: The herpes simplex virus amplicon: A new eucaryotic defective virus cloningamplifying vector. Cell 1982;30:295–304. Stern MB, Freese A: Parkinson’s disease: The case for novel treatment strategies. Exp Neurol 1997; 144:2–3. Tomac A, Lindqvist E, Lin LFH, Ogren SO, Young D, Hoffer BJ, Olson L: Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 1995;373:335–339. Uchida K, Ishii A, Kaneda N, Toya S, Nagatsu T, Kohsaka S: Tetrahydrobiopterin-dependent production of L-dopa in NRK fibroblasts transfected with tyrosine hydroxylase cDNA: Future use for intracerebral grafting. Neurosci Lett 1990;109:282–286. Vlazny DA, Frenkel N: Replication of herpes simplex virus DNA: Localization of replication recognition signals within defective virus genomes. Proc Natl Acad Sci USA 1981;78:742–746. Vlazny DA, Kwong A, Frenkel N: Site-specific cleavage/packaging of herpes simplex virus DNA and the selective maturation of nucleocapsids containing full-length viral DNA. Proc Natl Acad Sci USA 1979;79:1423–1427. Wolff JA, Fisher LJ, Xu L, Jinnah HA, Langlais PJ, Luvone PM, O’Malley KL, Rosenberg RB, Shimohama S, Friedman T, et al: Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease. Proc Natl Acad Sci USA 1989;86:9011–9014.

Dr. Andrew Freese, Department of Neurosurgery, Thomas Jefferson University, Suite 1400, 1015 Chestnut Street, Philadelphia, PA 19107 (USA) Tel. +1 215 955 0951, Fax +1 215 955 0957

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Author Index

Alvarez, L. 58 Ashby, P. 236 Aziz, T. 132 Bain, P. 132 Bakay, R.A.E. 118 Benabid, A.L. 196 Benazzouz, A. 196 Bowen, J. 132 Burchiel, K.J. 172 Clatterbuck, R.E. 227 Cossette, M. 21 DeLong, M.R. 31 Desaloms, J.M. 279 Edwards, C. 351 Eidelberg, D. 351 Fraix, V. 196 Freeman, T.B. 331 Freese, A. 381 Friedman, A.H. 296 Gildenberg, P.L. 1 Gill, S.S. 188 Gregory, R. 132 Gross, C.E. 148 Grossman, R.G. 279 Guridi, J. 58 Hall, B. 132

Hamilton, W.J. 279 Hariz, M.I. 246 Hauser, R.A. 331 Heywood, P. 188 Hutchison, W.D. 103 Jankovic J. 78, 279 Joint, C. 132

Parent, A. 21 Penn, R.D. 371 Piallat, B. 196 Pollak, P. 196 Rodriguez, M. 58 Rodriguez-Oroz, M.C. 58

Koller, W.C. 181 Kondziolka, D. 91 Koudsie, A. 196 Krch, D. 351 Kroin, J.S. 371

Saint-Cyr, J.A. 266 Sanberg, P.R. 331 Scott, R.B. 132 Silburn, P. 132 Sindou, M. 339 Slavin, K.V. 172 Stein, J. 132

Le´vesque, M. 21 Lee, J.-I. 227 Lenz, F.A. 227 Linhares, M.N. 156 Lopez, G. 58 Lozano, A.M. 103 Lunsford, L.D. 91

Tan, E.-K. 78 Tasker, R.R. 156 Thompson, T.P. 91 Tre´panier, L.L. 266

Macias, R. 58 Mentis, M. 351 Mertens, P. 339 Munro-Davies, L.E. 132 Nakamura, T. 351 Obeso, J.A. 58 Ondo, W. 279

Van Blerkom, N. 196 Villavicencio, A.T. 296 Vitek, J.L. 31, 118 Wichmann, T. 31 Wilkinson, S.B. 181 Willing, A.E. 331 Yoshor, D. 279 Young, R.F. 272 Zigova, T. 331

395

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Subject Index

Adeno-associated virus, gene therapy vectors for Parkinson’s disease 388, 389 Adenovirus vectors, gene therapy for Parkinson’s disease 388 Ansa lenticularis, anatomy 22 peduncularis, anatomy 24, 25 Atlas, development 3–5, 8 Baclofen, intrathecal dystonia treatment 373, 374 limitations 372 rationale 372 spasticity treatment outcomes 339, 340, 372, 373 spinal cord distribution 372, 373 Ballismus definition 42 pathophysiology 60, 61 Barona Index 267 Basal ganglia cortical circuits 31, 32, 119–122 dopaminergic pathways 26, 27, 29, 33 external ganglia projections 48 forebrain bundles ansa lenticularis 22 ansa peduncularis 24, 25 lenticular fasciculus 22–24 medial forebrain bundle 25, 26 subthalamic fasciculus pallidosubthalamic fibers 24 subthalamopallidal fibers 24

thalamic fasciculus 24 functions 33, 34 lesion studies of motor functions 34 motor circuit in monkeys 58, 59 Brain atlases, development 3–5, 8 Botulinum toxin type A, spasmodic torticollis type A treatment 303, 304 Brain-derived neurotrophic factor, Parkinson’s disease treatment 376, 377 Cerebral palsy, spasticity treatment in children 347 Chorea definition 42 pathophysiology 60, 61 Ciliary neurotrophic factor, Huntington’s disease therapy 377 Computed tomography accuracy in brain nuclei identification 132 evaluation of movement disorder surgery patients 83, 92, 249 non-microelectrode recording-guided pallidotomy with magnetic resonance imaging 132, 133, 135 Core Assessment Program for Intracerebral Transplantation 79, 85 Deep brain stimulation, see also Globus pallidus, Subthalamic nucleus stimulation, Thalamic deep brain stimulation advantages and limitations 233, 234

396

complication avoidance 252, 253 lesioning comparison 227–232 mechanism of action high-frequency stimulation 237, 243 single stimuli 236, 237, 243 positron emission tomography applications 364–366 targets and indications 253 Dopamine biosynthetic genes for gene therapy 381–384, 390, 391 receptor, antagonism and dystonia induction 45 Dorsal root entry zone, spasticity treatment with surgery 344–346 Drug-induced dyskinesia pathophysiology 43, 44 problems with models 70–73 Dyskinesia models, see 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine pathophysiology 60–63 subthalamic nucleus stimulation induction 217 Dystonia cervical dystonia, see Torticollis classification and genetics dystonia-plus syndromes 281 heredodegenerative 281 primary 280 secondary 281 definition 42 drug therapy 279, 291 intrathecal baclofen therapy 373, 374 pathophysiology 44–47, 121, 281, 282 prevalence 279 surgical management overview 282, 283, 292 pallidotomy 287–291 thalamotomy 283–287, 291, 292 Electromyography, spasmodic torticollis 300, 301, 303 Essential tremor thalamic deep brain stimulation electrode placement 184–186

Subject Index

frame placement 183 macroelectrode stimulation 183 outcomes 186 patient selection 182 preoperative preparation 182, 183 target localization 183, 184 Vim thalamotomy 173 Fetal tissue transplantation, see Neural transplantation, Parkinson’s disease Frame application and alignment 93, 94, 183 complications 248 Gamma knife surgery complications 276 limitations in movement disorder surgery 252 outcomes Parkinson’s disease 275, 276 stroke-related tremor 275, 276 patient selection 277, 278 radiosurgical technique 274, 275, 277 target localization 273, 274, 278 selection 272, 273, 278 Gene therapy, Parkinson’s disease ex vivo approaches advantages and limitations 384 immortalized cell lines 382, 383 overview 381, 382 primary cultures 383, 384 gene targets 381–384, 390, 391 in vivo systems adeno-associated virus vectors 388, 389 adenovirus vectors 388 advantages 385 herpes simplex virus-1 vectors cell culture studies 386, 387 rat model studies 387 types 385–388 overview 385 limitations 390, 391 Glial-derived neurotrophic factor Parkinson’s disease treatment 377

397

Globus pallidus, see also Pallidotomy bicuculline inhibition 65 deep brain stimulation of internal segment clinical assessment 149 complications 258, 259 high-frequency stimulation effects 242 implants 41, 42 indications 154 mechanism of action 240, 241 outcomes 151–153 pallidotomy comparison 228–230 patient selection 149 positron emission tomography applications 365, 366 rationale 148, 149 single stimulus effects 242 surgical technique 149, 151 dopaminergic pathways 26, 27, 29 dystonia role 281, 282 fiber systems 22–27, 29 inactivation and movement disorder improvement 34, 38, 40 internal segment hyperactivity in Parkinson’s disease 21, 34, 59, 119, 149 lesioning 40, 91, 120 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine model findings 59–65, 67–74 muscimol inhibition 374–376 pathophysiology drug-induced dyskinesia 43, 44 dystonia 44–47 hemiballism 43 Huntington’s disease 43 tremor role 38, 39 Hemiballism, pathophysiology 43, 121 Herpes simplex virus-1, gene therapy vectors for Parkinson’s disease cell culture studies 386, 387 rat model studies 387 types 385–388 High-frequency stimulation, see Deep brain stimulation Hoehn & Yahr staging 82, 85, 124, 141 Horsley-Clarke apparatus, development 2, 3

Subject Index

Huntington’s disease neurotrophic factor therapy 377 pathophysiology 43 Hypophonia, subthalamic nucleus stimulation induction 217, 218 Idiopathic torsion dystonia, positron emission tomography activation studies 360, 361 Intradural rhizotomy, spasmodic torticollis treatment anatomy 315, 316 complications 321, 322 historical perspective 313, 314 outcomes 316–320, 323 technique 315, 316 Intraoperative monitoring, see also Microelectrode recording history of recording 6, 10, 12 somatosensory evoked potentials 99 visual evoked potentials 99, 101 Intrathecal therapy baclofen, see Baclofen, intrathecal muscimol 374–376 neurotrophic factors 377 prospects 377, 378 Iontophoresis of middle ear, spasmodic torticollis treatment 309, 310 Kaufman Brief Intelligence Test 267 Lenticular fasciculus, anatomy 22–24 Levodopa dyskinesia induction 43, 44, 70–73, 148 history of use 10, 11, 78, 120 response and surgical outcome prognosis 79 Macroelectrode, complication avoidance 250 Magnetic resonance imaging evaluation of movement disorder surgery patients 83, 87, 92, 124 gamma knife surgery planning 273, 275 non-microelectrode recording-guided pallidotomy with computed tomography 132, 133, 135

398

stereotactic surgery 94, 249 subthalamic nucleus stimulation 203, 205, 215 Medial forebrain bundle, anatomy 25, 26 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine brain distribution of effects 29 dyskinesia model overview 60, 61 predictions from model 62, 63 monkey model of Parkinson’s disease pathophysiology 35, 58–60 predictions from model 61, 62 problems with model clinical observations 67–70 experimental findings 63–65, 67 subthalamic nucleus stimulation of models 214 Microelectrode recording assembly of microelectrode 103, 104 complication avoidance 250, 251 instrumentation 104 overview 103 pallidotomy landmarks 105 globus pallidus external segment border cells 107 firing rates 105, 106 globus pallidus internal segment measurements 107, 108 subthalamic nucleus deep brain stimulation firing rates 109–111 landmarks 108, 109 substantia nigra 112 zona incerta 110–112 subthalamic nucleus stimulation 206 surgical technique 105 thalamotomy Vc 113, 115 Vcpc 113, 115 Vim 112, 113, 115 Voa 113 Vop 113 Microvascular decompression, spasmodic torticollis treatment 310 Mini-Mental State Test 84

Subject Index

Minnesota Asberg Depression Rating Scale 87 Minnesota Multiphasic Personality Inventory 87 Muscimol globus pallidus interna inhibition 374–376 subthalamic nucleus inhibition 376 Myelotomy, spasticity treatment 344 Myotomy, spasmodic torticollis treatment 304, 305 Neural transplantation, Parkinson’s disease clinical trials 331 donor age effects 332 donor number effects 332 immunological rejection 333 longevity of graft survival 333 pathologic analysis of fetal grafts 334 positron emission tomography imaging applications 354, 355 prospects 334, 335 rationale 331 safety 334 site of transplantation 332, 333 Neuropsychological testing 87, 266–270 New Adult Reading Test – Revised 267 Pallidotomy, see also Stereotactic surgery age and outcome 125, 126 bilateral surgery 259, 260 cognition effects 268, 269 comparison with medical therapy outcomes 126 complications 127, 128, 256–260 dystonia treatment comparison to thalamotomy 291 complications 290 outcomes 287–290 technique 289, 290 evaluation of patients blinded assessment of motor function 86, 87 computed tomography 83, 92 contemporary data importance 123, 124

399

Pallidotomy, evaluation of patients (continued) magnetic resonance imaging 83, 87, 92, 124 neuropsychological testing 87, 127 positron emission tomography 87, 88, 92, 93 preoperative evaluation 83 rating scales 82–85, 124 self-reporting 85, 86 timed tests 86 external segment lesion avoidance 125 gamma knife surgery 276 globus pallidus internal segment stimulation comparison 228–230 indications 121 lesion location and outcome 124, 125 microelectrode recording globus pallidus external segment border cells 107 firing rates 105, 106 globus pallidus internal segment measurements 107, 108 landmarks 105 non-microelectrode recording-guided pallidotomy approach 136 combination of imaging modalities 132, 133, 135 complications 145 electrode placement and operation 136–138 neurological outcome bilateral pallidotomy 141 statistical analysis 139, 141 unilateral pallidotomy 141 neuropsychological and functional outcome bilateral pallidotomy 144 cognition 145 patient characteristics 141, 143 unilateral pallidotomy 144 outcome assessment, overview 134, 135 patient selection 133, 134 planning 135, 136 outcomes at the University of Pittsburgh 101, 102

Subject Index

patient selection, see Patient selection, movement disorder surgery positron emission tomography applications 361–364 rationale for Parkinson’s disease 118–122 target localization 95, 96, 98 unilateral vs bilateral surgery 146 Panic attack, prevention in surgery 267 Parkinson’s disease akinesia/bradykinesia pathophysiology 36, 37, 59, 60 approaches for symptom treatment bradykinesia 80 dyskinesia 79, 80 tremor 80 clinical features 35 gene therapy, see Gene therapy, Parkinson’s disease genetics 35 monkey model, see 1-Methyl-4-phenyl1,2,3,6-tetrahydropyridine muscimol therapy globus pallidus interna 374–376 subthalamic nucleus 376 neuropsychological testing 87, 266–270 neurotrophic factor therapy 376, 377 nonmotor phenomena pathophysiology 39 positron emission tomography activation studies 61, 62, 67, 360 preoperative evaluation 83 prevalence 91 rigidity pathophysiology 37, 38, 68, 69 surgery, see also Pallidotomy, Subthalamic nucleotomy, Subthalamic nucleus stimulation, Thalamic deep brain stimulation, Thalamotomy history of stereotactic surgery graft injections 11, 12 lesion targets 8–10, 12 levodopa effects on popularity 10, 11 neural transplantation, see Neural transplantation, Parkinson’s disease patient selection, see Patient selection, movement disorder surgery targets, overview 196 tremor pathophysiology 38, 39, 68, 69

400

Parkinson’s Disease Quality-of-Life Questionnaire 86 Patient selection, movement disorder surgery evaluation of patients blinded assessment of motor function 86, 87 computed tomography 83, 92 magnetic resonance imaging 83, 87, 92, 124 neuropsychological testing 87, 266–270 positron emission tomography 87, 88, 92, 93 preoperative evaluation 83 rating scales 82–85 self-reporting 85, 86 timed tests 86 exclusion criteria advanced age 81, 82, 248 alcohol abuse 81 cardiovascular conditions 93, 248 dementia 81, 248 overview 122, 123 psychiatric illness 81 severe brain atrophy or ischemia 81 terminal illness 81 typical Parkinsonism 80, 81 inclusion criteria 79, 122, 123 Pedunculopontine nucleus/midbrain extrapyramidal area akinesia role 37 lesioning 41 Peripheral neurotomy, see Selective peripheral denervation Positron emission tomography dystonia studies 282 evaluation of movement disorder surgery patients 87, 88, 92, 93 postsynaptic dopaminergic function studies D1 ligands 357 D2 ligands 355–357 presynaptic dopaminergic function studies applications disease progression 354 graft survival 354, 355 dopa decarboxylase 352 dopamine transporter 353

Subject Index

radiotracers 352–354 vesicular monoamine transporter 353, 354 regional cerebral blood flow and glucose metabolism applications activation studies hyperkinetic disorders 361 idiopathic torsion dystonia 360, 361 Parkinson’s disease 61, 62, 67, 360 differential diagnosis of Parkinson’s disease variants 357, 358 network analysis Scaled Subprofile Model 358, 359 Topographic Profile Rating 359, 360 stereotactic surgery applications deep brain stimulation 364–366 pallidotomy 361–364 thalamotomy 364 Radiofrequency lesioning, complication avoidance 252 Rhizotomy intradural rhizotomy for spasmodic torticollis treatment anatomy 315, 316 complications 321, 322 historical perspective 313, 314 outcomes 316–320, 323 technique 315, 316 spasticity treatment percutaneous thermorhizotomy 344 posterior rhizotomy 342–344 Selective peripheral denervation spasmodic torticollis treatment 310–313 spasticity treatment 340–342 Somatosensory evoked potentials, intraoperative monitoring 99 Spasmodic torticollis clinical features 296 etiology 296, 297, 300 evaluation of patients electromyography 300, 301 imaging 301 nerve blocks 301 physical examination 299, 300 incidence 296

401

Spasmodic torticollis (continued) natural history 299 nonsurgical therapy botulinum toxin type A 303, 304 pharmacotherapy 302, 303 surgery indications 304 intradural rhizotomy anatomy 315, 316 complications 321, 322 historical perspective 313, 314 outcomes 316–320, 323 technique 315, 316 iontophoresis of middle ear 309, 310 microvascular decompression 310 myotomy 304, 305 selective peripheral denervation 310–313 stereotactic targets 309 thalamotomy 305, 306, 308, 309 Spasticity nonsurgical therapy 339, 371 surgical treatment dorsal root entry zone surgery 344–346 indications adults 346, 347 children with cerebral palsy 347 intrathecal baclofen 339, 340, 371–374 myelotomy 344 rhizotomies posterior rhizotomy 342–344 percutaneous thermorhizotomy 344 selective peripheral neurotomy 340–342 Spiegel-Wycis apparatus, development 4, 93 Stereotactic surgery, see also Deep brain stimulation, Gamma knife surgery, Pallidotomy, Subthalamic nucleotomy, Thalamotomy ablation techniques 100, 101 computed tomography 249 definition 1, 2 electrode placement 99, 100 expectations of patient 200, 262, 266 frame application and alignment 93, 94 complications 248

Subject Index

history arc-centered devices 7, 8 atlases 3–5, 8 extrapyramidal system interruption 3, 5 Horsley-Clarke apparatus 2, 3 implanted stimulators 12–14 intraoperative recording 6, 10, 12 lesion-inducing methods 5–7, 14 nineteenth century 1 Parkinson’s disease treatment campotomy 188 graft injections 11, 12 lesion targets 8–10, 12, 91, 92, 120, 227 levodopa effects on popularity 10, 11 thalamotomy 156, 157 Spiegel-Wycis apparatus 4, 93 intraoperative exploration 250–252 magnetic resonance imaging 94, 249 mortality 247 patient cooperation in complication avoidance 246 target localization 95, 96, 98 trephination 249, 250 Substantia nigra, microelectrode recording 112 Substantia nigra pars reticulata hyperactivity in Parkinson’s disease 59 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine model findings 59, 61, 64, 69 Subthalamic fasciculus, anatomy pallidosubthalamic fibers 24 subthalamopallidal fibers 24 Subthalamic nucleotomy clinical assessment 191 complications 192, 194, 260 lesioning, overview 40, 43, 122, 148, 188, 189 outcomes 192 patient selection 190, 191 surgical technique 191, 192 Subthalamic nucleus deep brain stimulation, see Subthalamic nucleus stimulation dopaminergic pathways 26, 27, 29

402

fiber systems 22–27, 29 inactivation and movement disorder improvement 38, 188, 189 lesioning, see Subthalamic nucleotomy 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine model findings 59–62, 65, 67–74, 188, 189 muscimol inhibition 376 projections 48 Subthalamic nucleus stimulation comparison with other techniques advantages 220 neural grafts 217 pallidotomy 216, 217 implants 41, 42, 189 indications for deep brain stimulation 154, 189, 197 microelectrode recording during deep brain stimulation firing rates 109–111 landmarks 108, 109 substantia nigra 112 zona incerta 110–112 motor control studies 218, 220 Parkinson’s disease treatment approach to target 214, 215 bilateral stimulation outcomes 232, 233 chronic electrode insertion 207–209 clinical evaluation 201, 202 complications 210, 211, 220, 260–262, 269 costs 216 electrical parameter setting 201, 202, 213 high-frequency stimulation effects 243 imaging and target localization 202, 203, 205, 215 long-term stability 219, 220 microelectrode insertion 206 microrecording 206, 215, 216 microstimulation 207 mortality 208, 209 patient selection factors degree of disability 198, 199 expectations of patient 200 general health 199 magnetic resonance imaging 199

Subject Index

type of Parkinson’s disease 197, 198 rationale of targeting 196, 197, 213, 214 single stimulus effects 242, 243 surgical technique 203, 206 unilateral vs bilateral stimulation 200 Unified Parkinson’s Disease Rating Scale score outcomes 211–213 positron emission tomography applications 366 symptoms of stimulation cognitive function effects 218 dyskinesia 217 hypophonia 217, 218 Thalamic deep brain stimulation complications 255, 256 electrode placement 184–186 frame placement 183 high-frequency stimulation effects 239, 240 indications 181, 182 macroelectrode stimulation 183 outcomes 186 patient selection 182 preoperative preparation 182, 183 safety 181, 182 single stimuli effects 237, 239 target localization 183, 184 Vim stimulation comparison with ventral thalamotomy 230–232 Thalamic fasciculus, anatomy 24 Thalamic premotor neurons, GABAergic inhibition in movement disorders 21 Thalamotomy, see also Stereotactic surgery balancing disturbances 248 bilateral surgery 173 comparison to pallidotomy 291 complications bilateral surgery 256 overview 254, 255 dystonia treatment complications 286, 287 outcomes 283–285 targets 283 technique 285 gait freezing 248 gamma knife surgery 275–277

403

Thalamotomy (continued) historical perspective 156, 157 indications 173 meta-analysis of studies 177, 178 microelectrode recording Vc 113, 115 Vcpc 113, 115 Vim 112, 113, 115 Voa 113 Vop 113, 167 positron emission tomography applications 364 radiothalamotomy 169, 170 rationale for Parkinson’s disease 157 spasmodic torticollis treatment 305, 306, 308, 309 Toronto Hospital experience with microelectrode recording clinical evaluation 159, 160 complications 163, 164, 168 deep brain stimulation following failure 165, 169 failure and repeat surgery outcomes 164–167 learning curve 169 operative technique 157, 158 outcomes comparison with other studies 168 dexterity 162, 163, 168 gait 163 speech 162, 163 technical factors affecting 160 tremor 160, 167 patient selection 157 target localization 158, 159, 169 Vim stimulation comparison 230–232 Vim thalamotomy without microelectrode recording electrode insertion 175, 176 imaging 174 intraoperative macrostimulation 176 outcomes 177, 178 patient selection 173

Subject Index

radiofrequency lesion 176, 177 rationale 178, 179 target calculation 174, 175 Torticollis, see also Spasmodic torticollis classification by etiology 298, 299 surgical management, overview 282, 283 Trail Making Test 267 Trephination, complication avoidance 249, 250 Unified Parkinson’s Disease Rating Scale 82, 84–86, 124, 126, 128, 141, 144, 146, 160, 202 Vc anatomy 173 microelectrode recording 113, 115 Vcpc, microelectrode recording 113, 115 Ventralis intermedius nucleus, see Vim Ventral oral anterior nucleus, see Voa Ventral oral posterior nucleus, see Vop Ventriculography accuracy in brain nuclei identification 132 subthalamic nucleus stimulation 215 Ventrolateral thalamus lesioning 41, 47, 91 stimulation, see Thalamic deep brain stimulation Vim anatomy 172, 173 lesioning, see Thalamotomy microelectrode recording 112, 113, 115 stimulation for tremor treatment 148, 237 stimulation with implants 41 stimulation, see Thalamic deep brain stimulation Visual evoked potentials, intraoperative monitoring 99, 101 Voa, microelectrode recording 113 Vop, microelectrode recording 113, 167 Wechsler Adult Intelligence Scale 267

404