Stereotactic and Functional Neurosurgery: Movement Disorders and Pain: Medical Management and Functional Neurosurgery

Movement Disorders and Pain: Medical Management and Functional Neurosurgery Proceedings of the International Conference...

Author: T. Z. Aziz | P. L. Gildenberg

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Movement Disorders and Pain: Medical Management and Functional Neurosurgery Proceedings of the International Conference, Oxford, UK, April 26–28, 2002

Editors

T.Z. Aziz, Oxford P.L. Gildenberg, Houston, Tex.

14 figures and 8 tables, 1999

Basel . Freiburg . Paris . London . New York . Bangalore . Bangkok . Singapore . Tokyo . Sydney

S. Karger Medical and Scientific Publishers Basel . Freiburg . Paris . London New York . Bangalore . Bangkok Singapore . Tokyo . Sydney

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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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2002 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7573–4

Vol. 78, No. 3–4, 2002

Contents

119 Deep Brain Stimulation for Parkinson’s Disease. A Critical

Re-Evaluation of STN versus GPi DBS Vitek, J.L. (Atlanta, Ga.) 132 MRI-Directed Subthalamic Nucleus Surgery for Parkinson’s

Disease Patel, N.K.; Heywood, P.; O’Sullivan, K.; Love, S.; Gill, S.S. (Bristol) 146 Safety and Risk of Microelectrode Recording in Surgery for

Movement Disorders Hariz, M.I. (Umeå) 158 Exploration of the Role of the Upper Brainstem in Motor

Control Nandi, D.; Stein, J.F.; Aziz, T.Z. (Oxford) 168 Deep Brain Stimulation for Dystonia in Adults. Overview

and Developments Krauss, J.K. (Mannheim) 183 Deep Brain Stimulation for Dystonia. Surgical Technique Coubes, P.; Vayssiere, N.; El Fertit, H.; Hemm, S.; Cif, L.; Kienlen, J.; Bonafe, A.; Frerebeau, P. (Montpellier) 192 Transcranial Magnetic Cortical Stimulation Relieves Central

Pain Canavero, S.; Bonicalzi, V.; Dotta, M.; Vighetti, S.; Asteggiano, G.; Cocito, D. (Turin/Alba) 197 Author Index Vol. 78, 2002 198 Subject Index Vol. 78, 2002 after 198 Contents Vol. 78, 2002

© 2002 S. Karger AG, Basel Fax+ 41 61 306 12 34 E-Mail [email protected] www.karger.com

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Stereotact Funct Neurosurg 2002;78:119–131 DOI: 10.1159/000068959

Deep Brain Stimulation for Parkinson’s Disease A Critical Re-Evaluation of STN versus GPi DBS

Jerrold L. Vitek Department of Neurology, Emory University School of Medicine, Atlanta, Ga., USA

Key Words Deep brain stimulation W Parkinson’s disease W Subthalamic nucleus W Globus pallidus

Abstract Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) is increasingly being used for the treatment of advanced Parkinson’s disease (PD). Although both targets have demonstrated clinical efficacy in the treatment of the cardinal motor signs of PD, the STN has gained greater popularity and is now considered the site of choice by most centers performing these procedures. This preference stems predominately from the belief that STN DBS provides greater improvement in reducing the motor manifestations of PD and allows a reduction in dopaminergic medication not permitted with GPi DBS. There are, however, a number of issues that must be considered before abandoning GPi in favor of STN as the surgical target of choice for DBS. The maximal benefit reported for GPi stimulation is not significantly different than that reported for the STN, 67 versus 71%, and while reductions in medication are required with STN stimulation to avoid inducing dyskinesia, GPi stimulation may directly suppress dyskinesia obviating any need to reduce medication. As such, many centers may not attempt to reduce antiparkinsonian medication with GPi DBS. In addition, there are significantly more reports of changes in mood, behavior and a higher incidence of adverse events reported for STN stimulation. Most studies of DBS are nonrandomized,

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Jerrold L. Vitek, MD, PhD, Department of Neurology Emory University School of Medicine Suite 6000, WMRB, 1639 Pierce Drive Atlanta, GA 30322 (USA), Tel. +1 404 727 7177 Fax +1 404 727 3157, E-Mail [email protected]

assessment protocols are not standardized, and lead locations are not reported. Thus, before drawing conclusions regarding the optimal site for DBS for advanced PD we must take a critical eye to the present data and address the outstanding questions that remain with well-designed clinical trials that evaluate motor, nonmotor and adverse events and address the above clinical variables by randomizing patients, using standardized methods of assessment and defining the lead location. Copyright © 2002 S. Karger AG, Basel

Introduction

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) is increasingly being used for the treatment of advanced Parkinson’s disease (PD). Although both targets have demonstrated clinical efficacy in the treatment of all the cardinal motor signs of PD, the STN has gained greater popularity and is now considered the site of choice by most centers performing these procedures. This preference stems predominately from the belief that STN DBS provides greater improvement in reducing the motor manifestations of PD and allows a reduction in dopaminergic medication not permitted with GPi DBS. Although the only randomized clinical trial comparing these two sites showed no difference in clinical efficacy [1], there are few centers at this time that would choose GPi over STN as the preferred stimulation site for patients with advanced PD. In this paper we shall review the available clinical data and discuss some of the problems with current studies of DBS for PD, explore the variables that may play a role in determining clinical efficacy and critically examine the outstanding questions regarding the application of DBS in each of these sites.

What Do We Know?

What we know and what we think we know are two different things. The error is to accept as fact dogma that is not supported by scientific data. What is supported by clinical data is that both STN and GPi DBS are effective in improving the cardinal motor signs of PD (bradykinesia, rigidity and tremor), both improve midline symptoms (gait, balance and ‘off’ freezing), increase the percent of ‘on’ time and decrease the amount and severity of drug-induced dyskinesia (table 1). It is generally accepted that STN DBS requires a reduction of antiparkinsonian medication to improve dyskinesia, while GPi DBS may do so directly without a reduction in medication [2–6].

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Table 1. Effect of DBS on UPDRS motor scores

Author

U/B-STN

% change DBS Study Group, 2001 Volkmann, 2001 Alegret, 2001 Lopiano, 2001 Romito, 2002 Figueiras-Mendez, 2002a Burchiel, 1999 Moro, 1999 Limousin, 1998 Krack, 1998 Kumar, 1998 Figueiras-Mendez, 2002b Simuni, 2002 Marks, 2002 Marks, 2002 Houteo, 2000 Bejjani, 2000 Fraix, 2000 Molinuevo, 2000 Yokoyana, 1999 Brown, 1999 Pinter, 1999 Mean a b

0/96 0/16 0/15 0/16 0/22 0/22 0/5 0/7 0/20 0/8 1/5 0/9 0/12 11/0 0/5 0/23 0/12 0/24 0/5 0/5 0/6 0/9

U/B–GPi Author

UPDRS motor score

–51 –60 –57 –57 –50 –63 –44 –41 –60 –71 –41 –49 –47 –22 –35 –67 –64 –67 –66 –44 –57 –46 –52

% change –33 –67 –36 –50

0/38 0/11 1/5 1/5

DBS Study Group, 2001 Volkmann, 2001 Duriff, 1999 Ghika, 1998

–39 –50 –31 –39 –27

0/4 0/6 7/0 0/5 4/4

Burchiel, 1999 Ghina, 1998 Gross, 1997 Krack, 1998 Kumar, 1998

–27 –53 –21 +6 –56 –29

12/0 0/5 2/3 0/6 0/9 6/0

–42

0/6

Marks, 2002 Marks, 2002 Pahwa, 1999 Tronnier, 1997 Volkmann, 1998 Merello, 1999 Brown, 1999

–37

1-year follow-up. 2-year follow-up.

What Do We Think We Know?

What we think we know (what is not solidly supported by clinical research) is that STN is more effective than GPi DBS, that STN DBS provides greater improvement in midline symptoms, i.e. gait, balance and freezing, and that one can reduce antiparkinsonian medications with STN but not with GPi DBS. This was the impression of most groups attending a workshop of deep brain stimulation in Miami in 1996 and has become the prevalent view throughout the world to this day. Are these statements of fact or do they require further investigation? Based on available data, I would argue that they require further investigation.

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Results of DBS Studies

The available data from studies reporting the effect of DBS in STN and GPi on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscore (part III) shows a wide range of benefit for each site (table 1). The range of change in UPDRS III motor scores is much greater for GPi than for STN, ranging from 6% worsening to 67% improvement (table 1), while that for STN DBS has ranged from 35 to 71% improvement (table 1). Although the average improvement in UPDRS III motor scores across studies is greater for STN than GPi, the maximal benefit reported for each is not significantly different. The greatest reduction in UPDRS III motor scores for GPi was reported by Volkmann et al. [7] at 67%, while the greatest reduction for STN was reported by Krack et al. [8] at 71%.

Questions to Be Addressed

In examining the results of these studies several questions should be asked. Why are the results across studies implanting the same site so different? What factors contribute to these differences? To what degree can we account for differences in studies and across sites by controlling for these factors?

Problems with Current Studies of DBS for PD

All but one of the above studies comparing STN to GPi were nonrandomized. Patients were selected for a particular site based either on symptomatology, on the particular expertise of the center or on the belief by the implanting center that one target was better than the other. Without randomization, however, one cannot perform a fair comparison of sites. Indeed, in the only study to randomize patients, although only a small number of patients were enrolled (n = 10), the results were not significantly different for GPi versus STN DBS (39 vs. a 44% reduction in UPDRS III, respectively) [1]. Thus, although nonrandomized studies are important and can provide valuable information concerning the effect of DBS on parkinsonian signs, they are not designed to provide the type of information necessary to compare the effect of two different target sites and should not be used to do so. The lack of a standardized assessment procedure for DBS patients should also be taken into account when evaluating the clinical efficacy of DBS or when comparing data across studies. The time at which motor assessments are performed relative to the time the stimulator is turned on or off varies from study to

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study. Since neither the washout period nor the time to maximal benefit from the onset of stimulation has been determined, the time at which the motor assessment is performed relative to turning the stimulator off or on becomes an important variable in determining the degree of clinical benefit. Although not well documented, it is generally accepted that there is a greater delay for maximal improvement in parkinsonian motor signs to occur following onset of GPi stimulation. Therefore, if patients are assessed before enough time is allowed for the maximal benefit to be reached with GPi stimulation, it is likely that greater benefit will have occurred with STN than GPi DBS. There is, however, great variability in the temporal response of PD motor signs to GPi DBS. The delay from onset of stimulation to improvement in bradykinesia and rigidity may occur as quickly with GPi DBS as with STN. Last, the time to maximal improvement may be different for different motor symptoms. It is this variability that must be accounted for by allowing enough time for maximal motor benefit to occur before the clinical evaluation is performed. The length of follow-up for most clinical efficacy studies of DBS is less than 12 months, with most studies reporting the effect of DBS on patients followed for less than 1 year. Only a small number of studies have reported the effect of DBS in the STN or GPi in patients followed for longer than 1 year. Given our experience with pallidotomy where loss of benefit with a poorly placed lesion may not occur until 6–12 or more months following pallidotomy [9, 10], follow-up periods for less than a year may not be long enough to assess critically the efficacy of a single procedure, let alone comparing the efficacy of one site to another. Equally important as the time of assessment is the issue of lead location. Very few studies report the location of their leads and those that do generally report the location in terms of absolute coordinates relative to the AC-PC line rather than relative to the target structure. In addition to the location of the lead within the target, it is also critically important to report which contact was the most effective in improving parkinsonian signs, since it has been suggested by some that the most effective contact may lie outside the target structure [11, 12]. If we have learned nothing else from lesion surgery it should be that location is a critical factor in determining clinical outcome [9, 13, 14]. Lessons from the past concerning the importance of where lesions are placed or leads are located must not be forgotten. We must remember ‘Those who are ignorant of history are destined to repeat it’. Last, we should note that results from studies where all patients have bilateral implantations of the STN are often compared to studies of GPi DBS where some or all of the patients had unilateral implantations. There are significantly more studies with unilateral implantation in GPi than STN. Seven studies of GPi DBS had unilaterally implanted patients (table 1), while only two studies in the table reported the effect of unilateral stimulation in the STN [15, 16]. Although

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not comparable, the results of these studies are often discussed as though they were equivalent; such comparisons bear little merit and should not be done.

Nonmotor Symptoms and Adverse Events

The effect of stimulation on nonmotor symptoms and the incidence of adverse events should also be taken into account when evaluating the relative efficacy of DBS in the STN versus GPi. Although nonmotor symptoms have a great impact on the patients’ quality of life, few studies have addressed the effect of stimulation on behavior, mood or cognitive function. In a brief review of the literature there were significantly more studies reporting a change in mood with STN stimulation than with GPi (table 2). Similarly, for neuropsychological studies there are many more reports of neuropsychological changes occurring with STN DBS compared to GPi (table 3). In addition to the increased incidence of mood and neuropsychological side effects, significantly more adverse events have been reported to occur with STN than with GPi stimulation [7]. Lest I bear the brunt of my own critical observations, however, it should be noted that these studies carry the same burden of problems as previously discussed. In addition, there have been many more studies of STN stimulation. Thus, by virtue of numbers, one may expect to see more problems reported with STN. What then are we to conclude? Perhaps we should not conclude anything, but merely summarize our clinical observations in the following way: Is the motor improvement better with STN than GPi DBS? Maybe Are their more nonmotor side effects with STN than GPi DBS? Probably Is the incidence of adverse events higher with STN than GPi DBS? Likely As such, if we consider the clinical picture as a whole and view clinical outcome as the sum of motor + nonmotor + adverse events, stimulation of which site do we conclude is more effective? Is STN DBS more effective than GPi? Can GPi DBS be as effective as STN? Could GPi be more effective than STN? Would the answer to these questions vary based on the patient profile, their cognitive status, behavioral state, medication requirement or MRI changes? Should these factors be taken into consideration when choosing a site for implantation? If so, how? Last, do we have enough information at this time to answer these questions?

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Table 2. Effects of DBS on mood

Author

Year

Uni/Bil

Effect

STN Bejjani Dujardin

1999 2001

Bil (0/1) Bil (0/9)

Saint-Cyr

2000

Bil (0/11)

Diedrich Krack Volkmann

2000 2001 2001

Bil (0/1) Bil (0/2) Bil (0/6)

Limousin

1998

Bil (0/20)

depression depression apathy/anxiety irritability executive probs apathy disinhibition visual hallucinations mirthful laughter depression anhedonia abulia/apathy abulia

Gpi Dujardin

2000

Bil (0/1)

apathy/abulia

Anatomical/Physiological Factors to Be Taken into Account when Comparing STN to GPi DBS

There are several anatomical/physiological characteristics of the STN and GPi that should be taken into consideration when comparing studies of DBS in these sites. The first relates to the relative size of these respective structures and how this may relate to clinical outcome. GPi is considerably larger than STN, 458 versus 158 mm3 [17]. This has several implications; first, the motor area in GPi is larger than STN. Thus, if one subscribes to the theory that clinical efficacy is related to the relative amount of the motor area affected by stimulation, there is a larger area to affect with GPi than with STN stimulation. Given the standard lead sizes currently employed, for a comparable voltage more of the motor area is likely to be affected with STN than with GPi stimulation. Thus, there is a greater likelihood that STN DBS will provide a greater clinical efficacy at lower voltages than GPi DBS. Can similar benefits to STN be obtained with GPi if higher voltages are used or other stimulation parameters are changed? Based on comparable maximal benefits reported in the UPDRS III motor subscore, I believe the answer is yes, provided the lead is optimally placed. In this regard it should be noted that surrounding

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Table 3. Neuropsychologic effects of DBS

Author

Year

Uni/Bil

Effect

STN Lopiano Limousin Alegret

2001 1998 2001

Bil (0/16) Bil (0/24) Bil (0/15)

Pillon

2000

Bil (0/48)

Trepanier

2000

Bil (0/9)

Pillon

2000

Bil (0/15)

Perozzo Dujardin

2001 2001

Bil (0/20) Bil (0/9)

Saint-Cyr

2000

Bil (0/11)

Tagaris Johanshahi

2001 2000

Bil (0/16) Bil (0/7)

no change no change frontal (+) fluency (–) trails A, B (+) lexial fluency (–) stroopa color/word (–) trails (–) fluency (–) cond learn (–) spatial work (–) memory (–) no change free recall (–) work mem (–) attention (–) stroop int (+) work mem (–) executive (–) no change trails B (+) WCS (+) VCLT (–) assoc. learning (–)

Gpi Vingerhoets Troster

1999 1997

Uni (20/0) Uni (9/0)

Trepanier Dujardin

2000 2000

Bil (0/4) Bil (0/1)

Johanshahi

2000

Bil (0/6)

a

126

Secondary to increased psychomotor speed.

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no change frontal (+/–) attention (+/–) memory (+/–) digit span (–) DRS (–) work mem (–) trails (–) fluency (–) No change

white matter pathways (anterior-internal capsule; lateral-internal capsule; posterior-lemniscal pathway; medial-oculomotor nerve) limit the location of lead placement within the STN. The development of side effects during stimulation due to activation of adjacent white matter pathways (if the location of the lead varies by more than a millimeter or two), together with the smaller size of the STN, may promote more consistent placement of the lead in or near the motor area of STN. GPi, on the other hand, is large enough that placement can occur far enough from the motor area without incurring limiting side effects during stimulation that would necessitate moving the lead to a more optimal area within GPi. In addition to anatomical differences, the response of parkinsonian motor signs to stimulation in GPi can be delayed (minutes to hours). The delay in benefit following onset of stimulation in GPi leaves the examiner without the immediate feedback of the effect of stimulation on parkinsonian motor signs that generally occurs during acute stimulation in STN (seconds). This is particularly true if one relies on macrostimulation as the sole means for determining the particular site within the target structure to place the lead. Thus, the temporal response to stimulation and the physical characteristics of these two structures, i.e. the relative size of each and the location of adjacent fiber pathways may promote more consistent placement of STN stimulators in or near the ‘optimal’ site for improvement in parkinsonian motor signs and may provide an explanation for the consistently greater benefit reported across studies of STN stimulation, i.e. consistently better lead placement. While the smaller size of STN may provide an advantage in lead placement and contribute to the consistently greater motor benefit reported with STN stimulation, it, together with the location of surrounding fiber pathways, may also explain the apparently greater incidence of nonmotor and other adverse effects reported with STN stimulation. The medial forebrain bundle, hypothalamus, zona incerta and lemniscal pathways are all near the STN and may be affected by stimulation. Similarly, given its smaller size, nonmotor regions of the STN are more likely to be affected during stimulation in the STN than in GPi. The larger size of GPi and lack of structures lateral and anterior to GPi that would necessitate relocation of the lead during screening stimulation in the operating room, together with a delayed effect of stimulation on parkinsonian motor signs, makes GPi a target that is in some ways more forgiving of developing side effects but more difficult to place accurately to obtain maximal benefit for motor symptoms.

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Medication Reduction – Effect on Dyskinesia

It is generally accepted that one can reduce antiparkinsonian medications with STN but not with GPi stimulation. In this regard, however, we should ask whether adequate attempts to reduce antiparkinsonian medications were made at centers implanting GPi stimulators? Because STN stimulation worsens dyskinesia if antiparkinsonian medications are not reduced, most centers automatically reduce antiparkinsonian medications to avoid this worsening. Since GPi DBS does not exacerbate dyskinesia, but may in fact suppress dyskinesia, centers implanting GPi stimulators are not forced to reduce antiparkinsonian medications to improve dyskinesia. As such, many centers may not attempt to do so. Thus, the question must be asked whether adequate attempts to reduce antiparkinsonian medication in patients with GPi stimulators have been made? If such reductions are not attempted, how do we know whether or not such reductions are possible? My own observations are that one can substantially reduce antiparkinsonian medication in patients with GPi stimulators. Whether the amount of reduction will be comparable to that observed and reported with STN stimulation remains to be determined. Although STN is generally considered to exacerbate dyskinesia, while GPi DBS improves it, there are some exceptions. There is some evidence that STN DBS can, in some patients, reduce dyskinesia without an associated reduction in medication [Vitek, unpubl. obs.; St. Cyr, pers. commun.]. There is also evidence that dyskinesia can be induced with stimulation in the pallidum [4, 5, 12, 18]. Although it is unclear whether this occurs as the result of stimulation in dorsal GPi or ventral GPe, there is increasing evidence that stimulation in the pallidum can induce dyskinesia similar to that observed with STN DBS. In order to more fully understand the underlying basis for the above exceptions, details of the patient’s history, location of the effective contact, whether dyskinesias were present before surgery, their severity, distribution and relationship to antiparkinsonian medication should be characterized. Given the potential for STN DBS to suppress dyskinesia in some patients we are left to search for a physiological explanation for this observation. Given recent suggestions that stimulation may activate fibers tonically, STN DBS could suppress the development of dyskinesia by tonically activating pallidothalamic fibers coursing near the STN. Thus, whether STN stimulation induces or suppresses dyskinesia could well be determined by the precise location of the stimulating contact. Similarly, induction of dyskinesia during pallidal stimulation may also depend on the location of the effective contact relative to striato-pallidal or GPe to GPi fiber pathways. These exceptional effects of STN and GPi DBS should be investigated further, as they may provide clues to the pathophysiological basis underlying the development of dyskinesia and lead, in turn, to improved methods of treatment.

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What Is the Mechanism and Why Is That Important to the Question of Efficacy?

The mechanism of DBS has been extensively debated with some arguing for inhibition [19], while others support excitation as the mechanism underlying the effects of stimulation [18, 20, 21, 22]. Evidence is accumulating that stimulation does indeed suppress neuronal activity at the site of stimulation [19, 23, 24], but at the same time activates incoming and outgoing axons leading to a net effect of increased output from the stimulated site [25]. Axonal activation during stimulation has both theoretical and experimental support. Modeling studies [26], microdialysis studies [21] and electrophysiological recording studies [20, 22, 27] all support activation of the stimulated site as the mechanism underlying the beneficial effects of stimulation. If one accepts the hypothesis that DBS works by activation of fibers, then we must pose the question of whether the net effect of STN and GPi stimulation on basal ganglia-thalamocortical circuitry is really different, i.e. do we have equivalent circuits during stimulation? Given the extensive collateralization of projection pathways with GPe projecting to STN and GPi and STN projecting to GPe and GPi, by virtue of the fact that fibers will be both orthodromically and antidromically activated, it would seem that the net physiological effect of stimulation in STN, GPe and GPi could be equivalent. Of course the fact that they are not as attested by the aforementioned clinical studies listed above may say more about lead placement and patient profiles than whether STN, GPe and GPi DBS may represent equivalent physiological changes in the network controlling the manifestation of parkinsonian symptomatology. What is not equivalent and what may be the deciding factors in choosing a target site are the anatomical features of each site, i.e. size of the nucleus, segregation of motor and nonmotor regions within the nucleus, location and projection sites of adjacent fiber pathways.

Summary of Clinical Variables to Consider when Comparing STN to GPi DBS

E E E E E E

These include but are not exclusive to Randomization of patients Assessment methods (washout period; time to maximal benefit) Duration of follow-up Comparison of comparable procedures (bilateral to bilateral; unilateral to unilateral) Patient symptomatology Incidence and severity of nonmotor effects

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Incidence and severity of adverse events Lead location Anatomical physiological characteristics of STN and GPi Mechanism underlying the effects of stimulation There are a number of clinical, anatomic and physiological variables that must be considered when weighing the relative efficacy of STN versus GPi DBS. We must be careful not to exclude potential stimulation sites based on previous and present biases without consideration of all the issues that may contribute to these observations. Future considerations should include better characterization of the role of each of these variables in influencing clinical outcome and how they vary based on the site of stimulation. We should incorporate new engineering designs for stimulation leads that take into account the anatomical site of implantation and underlying pathophysiological changes in neuronal activity that occur at each potential target. Three-dimensional leads that would allow one to affect a greater volume or that allow one to sculpt the area of stimulation should be developed. We must clarify the mechanism of action of DBS. If stimulation preferentially activates fibers we may choose to place leads in fiber bundles rather than nuclei. As such, avoiding other fiber bundles will be equally important. Last, trials with self adjusting ‘smart’ patterns of stimulation based on the desired clinical effect should be developed. Given the broad potential of this tool and its early development, one should be cautious before dismissing a stimulation site based on present studies, particularly given the multitude of issues that have not been adequately addressed. Thus, before drawing conclusions based on what we think we know, we should always ask what do we know, i.e. ‘Show Me the Data’! E E E E

Acknowledgements Thanks to Ms. Rachael Miller and Mr. John Peoples for their assistance in manuscript preparation and Dr. Michael Okun for providing statistical data.

References 1

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Burchiel KJ, et al: Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson’s disease: Results of a randomized, blinded pilot study. Neurosurgery 1999;45: 1375–1382; discussion 1382–1384. The Deep-Brain Stimulation for Parkinson’s Disease Study Group: Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001;345:956–963. Limousin P, et al: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339:1105–1111. Bejjani B, et al: Pallidal stimulation for Parkinson’s disease – Two targets? Neurology 1997;49: 1564–1569.

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Krack P, et al: Opposite motor effects of pallidal stimulation in Parkinson’s disease. Ann Neurol 1998;43:180–192. Krack P, et al: Treatment of tremor in Parkinson’s disease by subthalamic nucleus stimulation. Mov Disord 1998;13:907–914. Volkmann J, et al: Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced Parkinson’s disease. Neurology 2001;56:548–551. Krack P, et al: Inhibition of levodopa effects by internal pallidal stimulation. Move Dis 1998;13: 648–652. Vitek JL, Bakay RA, DeLong MR: Microelectrode-guided pallidotomy for medically intractable Parkinson’s disease. Adv Neurol 1997;74:183–198. Fine J, et al: Long-term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. N Engl J Med 2000;342:1708–1714. Alterman RL, et al: Microelectrode recording during posteroventral pallidotomy: Impact on target selection and complications. Neurosurgery 1999;44:315–321; discussion 321–323. Yelnik J, et al: Functional mapping of the human globus pallidus: Contrasting effect of stimulation in the internal and external pallidum in Parkinson’s disease. Neuroscience 2000;101:77–87. Eskandar EN, et al: The importance of accurate lesion placement in posteroventral pallidotomy: Report of two cases. J Neurosurg 1998;89:630–634. Bronte-Stewart H, et al: Lesion location predicts clinical outcome of pallidotomy. Move Dis 1998; 13:300. Marks W, et al: Unilateral chronic deep brain stimulation of the globus pallidus or subthalamic nucleus in patients with medically refractory Parkinson’s disease: Short-term results from a randomized trial. Move Dis 2000;15(suppl 3):53. Kumar R, et al: Pallidotomy and deep brain stimulation of the pallidum and subthalamic nucleus in advanced Parkinson’s disease. Move Dis 1998;13(suppl 1):73–82. Yelnik J: Functional anatomy of the basal ganglia. Move Dis 2002;17(suppl 3):S15–S21. Vitek J: Mechanisms of deep brain stimulation: Excitation or inhibition. Move Dis 2002;17 (suppl 3):S69–S72. Dostrovsky JO, et al: Microstimulation-induced inhibition of neuronal firing in human globus pallidus. J Neurophysiol 2000;84:570–574. Hashimoto T, et al: Responses of pallidal neurons to electrical stimulation of the subthalamic nucleus in experimental primates. Sixth Int Congr Parkinson’s Disease and Movement Disorders, 2000. Barcelona, Lippincott, Williams & Wilkins, 2000. Windels F, et al: Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur J Neurosci 2000;12: 4141–4146. Postupna N, Ruffo M, Anderson M: The activity of most thalamic neurons is reduced, not increased, during trains of high frequency pallidal stimulation. Soc Neurosci 2001. Wu YR, et al: Does stimulation of the GPi control dyskinesia by activating inhibitory axons? Move Dis 2001;16:208–216. Beurrier C, et al: High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 2001;85:1351–1356. McIntyre C, Grill W: Excitation of central nervous system neurons by nonuniform electric fields. Biophys J 1999;76:878–888. Grill W: Mechanisms of deep brain stimulation; in: Neuromodulation: Defining the Future. Cleveland, The Cleveland Clinic Foundation, 2001. Montgomery EB, Baker KB, Rezai AR: Effects of GPi stimulation on human thalamic neuronal activity; in: Neuromodulation: Defining the Future. Cleveland, The Cleveland Clinic Foundation, 2001.

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Stereotact Funct Neurosurg 2002;78:132–145 DOI: 10.1159/000068964

MRI-Directed Subthalamic Nucleus Surgery for Parkinson’s Disease Nikunj K. Patel Peter Heywood Karen O’Sullivan Seth Love Steven S. Gill Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK

Key Words Subthalamic nucleus W Magnetic resonance imaging W Deep brain stimulation W Subthalamotomy W Guide tubes W Direct targeting

Abstract The subthalamic nucleus (STN) is now regarded as the optimal surgical target for the treatment of medically refractory idiopathic Parkinson’s disease. In our center, a predominantly MRI-directed method has been developed for targeting the STN. The STN is localized on T2-weighted images from a 1.5-T MRI scanner. Long acquisition, high-resolution images are acquired in both the axial and coronal planes under strict stereotactic conditions with the patient under general anesthesia. The boundary of STN is co-registered in both planes to give optimal 3-dimensional target definition. Stereotactic coordinates of the dorsolateral STN are recorded and the trajectory is planned down the axis of the nucleus in the coronal plane. Initially, per-operative macrostimulation was used for adjustment at the target prior to unilateral subthalamotomy in 26 patients. Five patients were lost to follow-up. Assessments of the lesions in post-operative images confirmed successful localisation of the lesions within the dorsolateral STN in all of the remaining 21 cases. In a subsequent series of 19 patients treated by deep brain stimulation (DBS), unilateral in 1 patient and bilateral in 18, the STN was targeted using the same MRI-directed method, guide tubes and radioopaque stylettes were implanted, and target verification was entirely MRIbased. Following implantation of the guide tubes and stylettes, assess-

ABC

© 2002 S. Karger AG, Basel 1011–6125/02/0784–0132$18.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] Accessible online at: www.karger.com/sfn www.karger.com

Mr. Steven Gill, Department of Neurosurgery Institute of Clinical Neurosciences, Frenchay Hospital Frenchay Park Road, Bristol BS16 1LE (UK) Tel. +44 117 970 1212, Fax +44 117 970 1161 E-Mail [email protected]

ments of the per-operative MRI images for the 37 STN targetings confirmed a mean target error, between the stylette and the desired target in the axial plane, of 0.3 mm mediolaterally (SD = 0.4) and 0.4 mm anteroposteriorly (SD = 0.4), with median errors of 0.5 mm. This study demonstrates that MRIdirected targeting of the STN through guide tubes is accurate, and allows direct verification and corrections as necessary. Cumulative frequencies predict that the majority of DBS electrodes placed in this manner will be within 0.5 mm of the planned target. Because physiological methods are not required, the whole procedure can be performed under general anesthesia. We feel that planning with reference to a standard atlas is unreliable and not significantly helped by the addition of microelectrode recording, the accuracy of which in the axial plane is dependent upon the distance between the recording trajectories, which is typically 2 mm. Copyright © 2002 S. Karger AG, Basel

Introduction

Chronic high frequency deep brain stimulation (DBS) [1–3] and lesioning [4–6] of the subthalamic nucleus (STN) appear to be safe and effective methods for treating medically refractory idiopathic Parkinson’s disease (PD), and many are persuaded that STN is the optimal target for patients requiring surgery for PD. DBS is being used as a preferred approach to ablation due to the reversibility of DBS and concerns that subthalamotomy may cause intractable unilateral or bilateral hemiballism [1–3]. Reports of surgery of the subthalamic region extend to the 1960s [7–10], when a procedure known as campotomy was used as an alternative procedure to pallidotomy and thalamotomy, in an attempt to improve results with smaller lesions targeted at pallidofugal fibers. These fibers pass through the H field of Forel, the zona incerta, and prerubral field, all of which lie immediately dorsal to the STN. Lesions in this region may well have involved the STN to a greater or lesser extent [7]. Lesions of H2 field of Forel (campotomy) or the posterior subthalamus were reported to produce results similar to those of thalamotomy [8– 10]. The lesions provoked transient hemiballism in some cases but were reported otherwise to be safe [10]. There is currently a debate about the most convenient method for locating the STN for both ablative surgery and DBS. The STN is a small, obliquely oriented structure with an ovoid shape [11, 12]. The dorsolateral STN is implicated in sensory and motor function and probably represents the optimal target [13]. It is therefore imperative that localization of this target be as accurate as possible.

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Several anatomical and physiological targeting methods are commonly used for the localization of the STN. Anatomical methods include both direct and indirect techniques. Direct targeting involves specific T2-weighted MRI sequences that enable visualization of the STN boundaries. The indirect methods are based on brain atlases and typically use the anterior commissure (AC) and posterior commissure (PC) as internal landmarks to co-register the atlas with the patient. The three-dimensional (3-D) coordinates of the AC and PC are variably determined by using ventriculography, computerized tomography scanning, magnetic resonance imaging (MRI) or ventriculography coupled with MRI [14–21]. To compensate for the individual variations when using the indirect method, many centers have developed intra-operative clinical and electrophysiological monitoring procedures that can be used with local anesthesia [3, 20–29], and these are regarded by many to be a pre-requisite for accurate placement of the stereotactic lesion or DBS electrode [30]. In our center, a predominantly MRI-directed method was developed for targeting the STN, with per-operative macrostimulation used purely for adjustment at the target, initially for unilateral subthalamotomy and subsequently for bilateral DBS. However, the STN is now targeted solely by use of the MRI-directed method, guide tubes are implanted and target verification is MRI-based. Because physiological methods are not used, the procedure can be performed completely under general anesthesia. In this article, a description of our method to date, the accuracy of our method as shown from the lesioning data, and interim data on the use of guide tubes for bilateral DBS will be presented.

Materials and Methods Patients Between 1997 and 2000, unilateral subthalamotomies were performed on 26 patients (17 men, 9 women). 22 of the 26 patients had predominantly asymmetric PD and underwent unilateral (contralateral) lesioning of the STN. Four (2 men, 2 women) had significant bilateral PD and had unilateral lesioning with contralateral implantation of electrodes in the STN. Since October 2001, 37 guide tubes for deep brain stimulators (18 bilateral, 1 unilateral) have been implanted in 19 patients (12 men, 7 women). Approval from the Frenchay Hospital Research Ethics Committee was received before both series were commenced. The selection criteria were that the patient should have idiopathic PD that was responsive to levodopa but nonetheless severely disabling despite all drug therapies, and that was not associated with dementia as indicated by a significant drop in cognitive function on neuropsychological testing as compared with estimates of premorbid cognition. In addition, the patient should be able to function at a reasonable level of independence for at least some part of the average day.

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Fig. 1. High-resolution axial T2-weighted MR images delineating the STN bilaterally (arrows).

MRI-Based Target Planning All patients gave fully informed consent and were aware of the potential risks of stereotactic STN targeting, including those of hemiballism and hemorrhagic stroke. The STN was localized with high-resolution MRI T2 scan sequences (1.5 Tesla TR 2,500, TE 150, TSE 11, NSA 12). Under general anesthesia, a modified Leksell stereotactic frame was affixed parallel to the orbito-meatal plane. The anterior (AC) and posterior (PC) commissures were identified in a mid-sagittal planning scan. Axial images (fig. 1a) 2 mm thick were acquired parallel to the AC-PC plane and coronal images (fig. 1b) orthogonal to these then obtained. We found these sequences to give optimum delineation of the STN and related structures. We used magnified hard copies of the MRI scans and overlaid the T2 scans with inverted T2 images to enhance further the definition of STN boundaries, and these were cross-checked with the Schaltenbrand atlas [31]. Stereotactic co-ordinates of the target, the dorsolateral

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STN, were recorded and a trajectory was planned, orientated along the axis of the nucleus in the coronal plane. STN Lesioning: Awake Surgery with Per-Operative Macrostimulation At surgery patients were awake and in an ‘off’ state, antiparkinsonian medications having been stopped 24 h previously. The operation was carried out with the patient in a sitting position and constant saline irrigation of the burr hole was maintained throughout the procedure. A 1.2-mm diameter electrode with a 2-mm exposed tip (Radionics Inc., Burlington, Mass., USA) was guided to the dorsolateral STN. The target was stimulated at 100 Hz, 0.75–2 V, with 1 ms pulse width, during which changes in tremor, rigidity and bradykinesia were monitored. Probe position was adjusted to gain maximal clinical improvement without the development of side effects. A radiofrequency lesion was made at the optimal position. STN DBS: Surgery under GA Using Guide Tubes The guide tube is an in-house investigational device that is manufactured by Ansamed, Roscommon, Ireland. It has a threaded cylindrical hub with a dome-shaped proximal end. When the guide tube has been inserted, the threaded portion of its hub is bonded in the burr hole with acrylic cement. A slot in the dome is in continuity with the bore of the guide tube. The junction between the slot and the bore of the tube is radiused so that when a DBS lead is inserted through it to the target and then bent through 90° for fixation to the skull the therapeutic device will not kink and the type remains at the target. The guide tube has a removable radio-opaque stylette whose T-shaped proximal end fits within the hub and whose distal end projects beyond the guide tube (fig. 2). The guide tube and stylette are injection-molded from radio-opaque implantable polyurethane and the guide tubes are appropriately sized to accept DBS electrodes (3387 and 3389 DBS leads Medtronic Inc., Minneapolis, Minn., USA). For insertion of a DBS electrode using the guide tube technique, the Leksell Stereoguide has been modified (Elekta Instrument AB, Stockholm, Sweden) to allow the guide tube to be inserted to the vicinity of the STN over a probe introduced down to the target. The guide tube is then secured in the burr hole with acrylic cement and the probe is replaced with a stylette cut to length, so that its distal end projects beyond the guide tube into the target. The scalp wound is closed and the patient is transferred to an MRI or CT scanner where the position of the tip of the stylette is defined in relationship to the desired target from images obtained under stereotactic conditions in the same configuration as the planning images. Prior to insertion of a Deep Brain Stimulator electrode, the length to be inserted is marked off by tying a suture around the lead, defined by the length of the stylette that has been withdrawn from the guide tube. The electrode is secured to the skull and proceeds with connection to implanted pulse generator and connection leads. Setting DBS Stimulation Parameters The Kinetra generator is switched on immediately after surgery, with antiparkinsonian medications typically reduced by 50%. The generator is programmed to deliver stimulation through optimal contacts with parameters set at a usual current frequency of 160 Hz, 90 ms pulse width and at amplitudes set between 1.0 and 2.5 V. In the few days following surgery, a clinical evaluation of the effects of stimulation is performed, and the stimulator is optimally

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Fig. 2. Guide tube with a threaded cylindrical hub and a dome-shaped proximal end and adjacent stylette whose T-shaped proximal end fits within the guide tube’s hub and whose distal end projects beyond the guide tube.

programmed. Initially a monopolar electrode setting is used, and subsequently bipolar if a more focal stimulation-maintaining effect exclusive of side effects is required. Target Accuracy Analysis In patients following lesioning, a high-resolution MRI was performed within a few hours of surgery, to confirm lesion position. Axial and coronal T2 images were obtained with the same slice configurations in relation to the AC-PC line as before surgery, allowing direct comparison of the images (fig. 3). In postoperative images, the coagulum corresponded to the lesion and was usually surrounded by a ring of edema. The lesion location and diameter were recorded. Following guide tube implantation for DBS, the per-operative MRI scans were compared with the planning images to assess the difference in the positions of the radio-opaque stylettes in relation to the center of the desired target within the dorsolateral STN (fig. 4).

Results

Unilateral Subthalamotomy Lesion Location Five patients were lost to follow-up. For all of the remaining patients, postoperative MRIs were examined to identify lesion location. All 21 lesions were successfully located in the dorsolateral STN. Nineteen lesions extended dorsally

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Fig. 3. Pre- and post-operative high-resolution coronal T2-weighted image showing lesioning of the right DL-STN.

beyond the STN into the pallidofugal fibers (H2) and ZI. Two lesions were confined to the STN. The mean position of the DL-STN target center of all 21 cases with respect to the AC-PC line midpoint was 12.6 mm lateral (SD = 1.2), 3.7 mm posterior (SD = 1.1) and 2.6 mm inferior (SD = 1.2). In comparison, the mean position of the lesion center of all 21 cases was 12.7 = mm lateral (SD = 1.3), 3.3 mm posterior (SD = 1.4) and 2.1 mm inferior (SD = 1.3). The mean lesion diameter as seen on MRI was 4.2 mm (SD = 1.5). One patient died from angiotropic B-cell lymphoma 18 months post-surgery. At 6 months follow-up he had shown marked improvement in contralateral UPDRS motor scores, with predominant effect on tremor. Examination of the brain after fixation revealed a lesion involving the dorsolateral STN and extending dorsally to involve H2 and ZI (fig. 5). The histologically-defined location of the lesion correlated closely with that determined radiologically on post-operative

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Fig. 4. Per-operative inverted coronal T2 weighted image verifying the position of the radio-opaque stylettes within the planned STN target. Per-operative images are obtained in the same slice configuration as the pre-operative planning images.

MRI. Cryostat sections stained with oil red O and by the Marchi method revealed products of fiber degeneration extending from the lesion towards and into (not shown) the globus pallidus (predominantly interna; GPi), the reticular nucleus of the thalamus, and caudally on the medial aspect of the subthalamus towards the brainstem. In cryostat sections through the midbrain, products of fiber degeneration were visible in the pars reticulata of the substantia nigra (SNr). Histology also confirmed the diagnosis of PD, with Lewy bodies in the substantia nigra and locus ceruleus. Accuracy of Guide Tube DBS Delivery Nineteen patients were implanted with guide tubes and DBS in 37 STN targets. The mean position of the DL-STN target center in these 37 STN with respect to the AC-PC line midpoint was 12.6 mm lateral (SD = 1.1) and 3.0 mm posterior (SD = 0.8). In comparison, the mean position of the stylettes was 12.6 mm lateral (SD = 1.1) and 3.4 mm posterior (SD 0.8). With confirmed depth of the stylette within the target, the exact position of each DBS contact within the target was predictable. The mean target error in the axial plane was 0.4 mm medio-laterally (SD = 0.4) and 0.5 mm anteroposteriorly (SD = 0.4), with a median of 0.5 mm.

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Fig. 5a–c. Autopsy neuropathological findings in the patient who died from angiotropic lymphoma. a Coronal slice through the fixed brain at the level of the stereotactic lesion (arrow), which involves the upper part of the subthalamus and the H2 field of Forel and overlying zona incerta. b The location of the lesion (arrow) is more clearly defined in this crytostat section stained with luxol fast blue and cresyl violet. Streak-like zones of slight myelin pallor (arrowheads) extend dorsolateral and ventromedial to the main lesion. c This section has been stained with oil red O and viewed with polarized light to demonstrate birefringent products of fiber degeneration. An asterisk marks the lesion cavity. Products of fiber degeneration can be seen to extend between the arrowheads, across the internal capsule and towards the globus pallidus interna. There is further evidence of fiber degeneration extending dorsolaterally (upper arrow) towards the reticular nucleus of the thalamus, and ventromedially (lower arrow) towards the brain stem.

Cumulative frequencies (fig. 6) predict that 91.5% of DBS electrodes are placed within 1.0 mm of the planned target in the medio-lateral plane; and 100% of DBS electrodes are within 1.0 mm in the antero-posterior plane. In only 1 target was it required to reposition the guide tube with repeat direct MR verification of target accuracy.

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Fig. 6. Cumulative frequencies of the target errors between the radio-opaque stylette and the planned target in the medio-lateral (x-axis, a) and antero-posterior (y-axis, b) planes.

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Discussion

Our data show that a predominantly MRI-directed method can be used accurately for lesioning or DBS of the STN. The additional use of guide tubes enables accurate delivery of DBS electrodes to the STN, with direct verification and correction if necessary, and allows the whole procedure to be performed under general anesthesia. Prior to our use of guide tubes, we used our MRI-directed method with peroperative macrostimulation for bilateral STN DBS. Due to significant image artefact, direct MRI target verification in this group was not possible. Sixteen patients in this series have thus far been followed for at least 12 months and all have received sustained benefit from the procedure [to be published]. The effect of stimulation on the patients’ motor performance (UPDRS part III) was significant in both the offand on-medication states, resulting in 61% (p ! 0.001) and 40% (p = 0.007) reductions respectively. The patients’ functional performance (UPDRS part II) was significantly improved by 62% (p = 0.001) in the off-medication state with stimulation. Stimulation significantly reduced dyskinesias and motor fluctuations as assessed on complications-of-therapy scores (UPDRS part IV). The score for the duration of the ‘off’ period was reduced by 55% (p = 0.007) (UPDRS part IV, item 39); the duration of dyskinesias decreased by 46% (p ! 0.02) (UPDRS part IV, item 32); and the mean disability related to dyskinesias decreased by 87.5% (p ! 0.01) (UPDRS part IV, item 33). The duration of ‘on’ period was increased correspondingly. Levodopa equivalent intake was reduced by 48%. In addition, in this group of patients there were no procedure- or device-related complications. Our method relies on visualization of the STN on high-resolution T2 images obtained in both the axial and coronal planes. Sensitivity on STN visibility is enhanced by obtaining the images with a long acquisition time and by planning on magnified formats. It involves no manipulation or reformatting of the raw data as with image fusion techniques with either CT or a standard brain atlas. Although MR imaging is potentially susceptible to geometric distortion caused by gradient field nonlinearities and magnetic field inhomogeneities, such effects are reduced by using our modified Leksell stereotactic frame with non-conducting properties, appropriately positioned low on the head, and MR imaging in our 1.5-T Philips Gyroscanner which uses a well-shimmed magnet with a stable field. The frame is applied under general anesthesia, which is maintained during the imaging, and, with the head frame fixed within the head coil, the patient remains immobilized during the acquisition reducing any movement-related distortion. The inherent spatial distortions in the images that result from inhomogeneities in the main magnetic field and non-linearities of the orthogonal field gradients occur mainly at the periphery of the image and are more pronounced in the coronal plane. We have found the axial image to be highly accurate and any coro-

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nal image distortion is corrected by cross-correlation. The coronal image is used to plan the trajectory down the axis of STN and the length of guide tube and stylette to be implanted. At surgery measures are taken to minimise CSF loss and brain shift: these include operating on patients whilst in the sitting position, using a small burr hole and maintaining constant saline irrigation. The surgical procedure, in our experience, takes 20–30 min per side for implantation of the guide tubes, further minimising brain shift. Per-operative imaging following implantation of the guide tubes and stylettes provides a direct measure of target accuracy, which is not possible with intra-operative physiological verification, and with this the exact position of the DBS contacts in relation to the target can be predicted. With examination of images in over 60 cases, we have found marked variability of STN size, shape and orientation [to be published]. This variability is reflected in frequent asymmetry and in differences between individuals. Because of this variability, an indirect targeting method, with atlas-based coordinates generated from a customized map reformatted to the patient’s individual length of the AC-PC line, can occasionally be highly inaccurate, and carries a risk of potentially serious complications. The majority of investigators experienced in performing STN surgery use microelectrode recording to delineate the boundaries of the target per-operatively and therefore ensure optimal placement of the lesion or DBS electrode. MER usually involves 3–6 recording tracts to be made before the lesioning or DBS electrode is inserted. Despite this, the accuracy with which the target can be defined in the coronal plane depends upon the distance between the recording trajectories, which is typically 2 mm. The maximal spatial resolution of the technique is therefore 2 mm, and this is not sufficiently precise to ensure optimal placement of a DBS electrode (typically 1.3 mm in diameter) centrally within the STN (typically 3 mm in diameter). While side effects are not uncommon for both MER- and non-MER-guided procedures, the rate of severe complications, such as intracerebral haematoma, appears to be higher when microelectrodes are used [32, 33]. However, a review of the literature for both MER- and non-MER-guided procedures found reporting among groups using MER techniques to be greater. Consequently, the available literature clearly suggests that MER techniques neither decrease risks nor increase targeting accuracy of ablative surgery or DBS procedures, compared to macrostimulation techniques. Furthermore, MER techniques do not result in smaller lesions or in lower electrical parameters of DBS. Additionally, MER can prolong the overall duration of the procedure by up to 12 h for a bilateral procedure. This increases the likelihood of brain shift, making target localization more difficult. More importantly, this technique exposes patients to many hours of awake surgery, which for Parkinsonian patients in an ‘off’ state can be severely compromising.

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Conclusion

A MRI-directed method can be used accurately, and our interim clinical data show that it can deliver treatment with safety and efficacy. The additional use of guide tubes and radio-opaque stylettes enables direct MRI verification of the target and allows the whole procedure to be performed under general anesthesia. We feel that fine electrophysiological assessment using MER is not necessary. Furthermore, the use of an indirect method is complicated by individual brain asymmetry and variations between individuals that render statistical prediction of the coordinates imprecise and hinder the localization of the optimal target within the STN.

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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; 36:1118–1125; discussion 1125–1127. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Tasker RR, Dostrovsky JO, Dolan EJ: Computerized tomography (CT) is just as accurate as ventriculography for functional stereotactic thalamotomy. Stereotact Funct Neurosurg 1991;57:157– 166. Lanotte MM, Rizzone M, Bergamasco B, Faccani G, Melcarne A, Lopiano L: Deep brain stimulation of the subthalamic nucleus: Anatomical, neurophysiological, and outcome correlations with the effects of stimulation. J Neurol Neurosurg Psychiatry 2002;72:53–58. Starr PA, Vitek JL, DeLong M, Bakay RA: Magnetic resonance imaging-based stereotactic localization of the globus pallidus and subthalamic nucleus. Neurosurgery 1999;44:303–313; discussion 313–314. Benabid AL, Benazzouz A, Hoffmann D, Limousin P, Krack P, Pollak P: Long-term electrical inhibition of deep brain targets in movement disorders. Mov Disord 1998;13(suppl 3):119–125. Bakay RA, Starr PA, Vitek JL, DeLong MR: Posterior ventral pallidotomy: Techniques and theoretical considerations. Clin Neurosurg 1997;44:197–210. Gross RE, Lombardi WJ, Hutchison WD, Narula S, Saint-Cyr JA, Dostrovsky JO, et al: Variability in lesion location after microelectrode-guided pallidotomy for Parkinson’s disease: Anatomical, physiological, and technical factors that determine lesion distribution. J Neurosurg 1999;90:468– 477. 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. Lozano AM, Lang AE: Pallidotomy for Parkinson’s disease. Neurosurg Clin N Am 1998;9:325– 336. Lozano A, Hutchison W, Kiss Z, Tasker R, Davis K, Dostrovsky J: Methods for microelectrodeguided posteroventral pallidotomy. J Neurosurg 1996;84:194–202. Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, et al: Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998;44: 622–628. Guridi J, Gorospe A, Ramos E, Linazasoro G, Rodriguez MC, Obeso JA: Stereotactic targeting of the globus pallidus internus in Parkinson’s disease: Imaging versus electrophysiological mapping. Neurosurgery 1999;45:278–287; discussion 287–289. Guridi J, Rodriguez-Oroz MC, Lozano AM, Moro E, Albanese A, Nuttin B, et al: Targeting the basal ganglia for deep brain stimulation in Parkinson’s disease. Neurology 2000;55(12 suppl 6): S21–28. Schaltenbrand G, Bailey P: Einführung in die Stereotaktischen Operationen mit einem Atlas des menschlichen Gehirns. Stuttgart, Thieme, 1959. Carroll CB, Scott R, Davies LE, Aziz T: The pallidotomy debate. Br J Neurosurg 1998;12:146– 150. Hariz MI, Fodstad H: Do microelectrode techniques increase accuracy or decrease risks in pallidotomy and deep brain stimulation? A critical review of the literature. Stereotact Funct Neurosurg 1999;72:157–169.

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Stereotact Funct Neurosurg 2002;78:146–157 DOI: 10.1159/000068960

Safety and Risk of Microelectrode Recording in Surgery for Movement Disorders Marwan I. Hariz Department of Clinical Neuroscience, Umeå, Sweden

Key Words Microelectrode recording W Pallidotomy W Deep brain stimulation W Parkinson’s disease W Movement disorders W Stereotactic surgery

Abstract There is an ongoing controversy about whether it is necessary to use microelectrode recording (MER) techniques in stereotactic surgery for Parkinson’s disease and other movement disorders. This paper consists of a critical review of the published literature in order to analyze the value of MER in providing safe, efficient and accurate functional stereotactic surgery. Review of the literature revealed that MER techniques do not necessarily improve targeting accuracy or clinical results, compared to techniques using impedance monitoring and macrostimulation. In terms of safety for the patients, however, MER techniques are relatively safe, but non-Mer techniques, based on macrostimulation-guided surgery, are at least five times safer. Copyright © 2002 S. Karger AG, Basel

ABC

© 2002 S. Karger AG, Basel 1011–6125/02/0784–0146$18.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] Accessible online at: www.karger.com/sfn www.karger.com

Marwan I. Hariz, MD, PhD, Professor of Functional Neurosurgery, Department of Clinical Neuroscience University Hospital, SE–901 85 Umeå (Sweden) Tel. +46 90 195631, Fax +46 90 191556 E-Mail [email protected]

‘O let’s never ever doubt what nobody is sure about’ Hillary Belloc

Introduction

Stereotactic surgery for Parkinson’s disease (PD) and other movement disorders (MD) is a ‘primum nil nocere’ surgery. The main aim of a stereotactic procedure for MD is to alleviate the symptoms of the disease, not to cure the disease itself. Stereotactic surgery for MD is not a ‘life-saving’ procedure because MD do not constitute life-threatening conditions, and the patients often have the choice of not undergoing surgery. Since the ultimate goal of surgery for MD is to decrease the symptoms and disability of the patient, the surgical procedure ideally should therefore not provoke any new symptom or neurological deficit in the already disabled patient. The absolute bottom line in functional surgery for MD ought to be that the patient’s symptoms would at the very worst remain the same after surgery as before. To ensure a proper physiological identification of the imaged anatomical target, intraoperative neurophysiological exploration is required prior to lesioning or DBS implant. Intraoperative physiological corroboration can be performed with a variety of methods used alone or in various combinations: These may consist of impedance monitoring, evoked potentials, macroelectrode stimulation, semimicroelectrode recording, single cell microelectrode recording (MER), etc. These different methods have their advantages and disadvantages, depending on what information one needs or requires and for what purpose. It is evident that if one is doing a research study to analyze the variability of the firing rate of the globus pallidus internus (GPi) and subthalamic nucleus (STN) in a PD patient before and after intraoperative injection of apomorphine [1] then one must use single cell microelectrode recording (MER). The same applies if one is to investigate the firing rate of the STN ipsilateral to a previous pallidotomy [2]. However, if one is doing a routine pallidotomy or deep brain stimulation (DBS) procedure, perhaps careful and experienced macrostimulation would be enough to place the lesion or the DBS electrode adequately and safely. The proponents of MER techniques have insisted on the advantages of their method compared to macrostimulation techniques claiming that MER improves the accuracy of lesion or DBS electrode placement, that MER decreases complications and that it improves the clinical results of surgery. A study of the literature, however, disclosed that these claims are often not valid and, as far as complications are concerned, these are far higher when MER is used than when macrostimulation techniques are used. In previously published reviews [3, 4], it was shown that inaccuracies of lesion and DBS lead placements were not uncommon

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in MER publications. The present paper, will emphasise the safety of MER, as illustrated in the literature on pallidotomy and DBS.

Safety of Microelectrode Recording during Pallidotomy

Leksell’s non-microelectrode-guided pallidotomies, performed in the 1950s when modern imaging techniques were lacking, resulted in zero percent mortality in the 81 patients reported by the neurologist Svennilson et al. [5] in the famous paper from 1960. Laitinen’s non-microelectrode-guided pallidotomies performed on a large number of patients between 1985 and 1995 had zero percent mortality and a very low rate of severe morbidity [6]. In two recent publications on microelectrode-guided pallidotomies, high rates of mortality and severe morbidity were reported: in 1998, Brain published a detailed paper presenting pallidotomy experience in 26 patients [7]. In this study, the severe morbidity amounted to 15.4% and mortality to 7.7% of the patients. The authors concluded their study stating: ‘patient selection .... should be based largely on anticipated improvement in LID, (Levodopa Induced Dyskinesias), but this must be balanced against the associated morbidity and mortality’. In 1998, Neurology published a paper describing pallidotomy experience in 26 patients [8]. This study revealed 30.7% morbidity and 3.8% mortality. The authors made the following statement concerning pallidotomy: ‘Morbidity may limit its use’. They concluded their paper by the following sentence: ‘We are concerned that the procedure will gain widespread use outside of PD research centers before its efficacy and safety have been better defined.’ Two papers, both published in June 1998 and both originating from Emory University, showed variable pallidotomy complications. In the paper by Cohn et al. [9] describing 83 patients there were 7 patients with hemorrhage. Cohn et al. [9] wrote: ‘Seven patients had hemorrhage along he probe tract. Of these, three had hematomas 2 to 3 cm in size within the surgical tract in the frontal lobe and four had hemorrhage involving the ipsilateral caudate, internal capsule and putamen. Only one patient had significant mass effect ...’. The paper by Vitek et al. [10], describing 160 patients, reported ‘major complications’ in 5, three of them with hematoma: one was aspirin-related, located ‘superficially in the white matter’, one was in the GPi occurring immediately after lesioning, and one was ‘a subdural hematoma that presented as brain herniation the day after pallidotomy’ and that eventually led to death ‘several months later as a result of the perioperative complications’ [10]. Concerning this last hematoma, Vitek et al. [10] wrote: ‘This hematoma occurred at a site distant from the area of instrumentation and was likely a result of brain shifting secondary to the craniotomy and did not result from the recording or lesioning process.’ In the opinion of the present author,

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perhaps the ‘brain shifting’ was not ‘secondary to the craniotomy’ per se, but secondary to the lengthy MER surgery during which a significant amount of air provoked a large pneumocephalus that in turn provoked the brain shifting. In a recent paper published in Neurosurgery, a MER team detailed their experience in pallidotomy [11]. They used 3–5 microelectrode tracks and lesions with 1 ! 3 mm electrode: thirty-six attempts resulted in 32 pallidotomies. Three attempts aborted (large intracerebral hematoma after first microelectrode pass in 1 patient and GPi could not be identified in 2). They also had one unintentional lesioning of STN (!). Five of 11 patients who were considered as nonresponders (i.e. 15.5% of all pallidotomies) ‘had small or improperly placed lesions despite extensive use of microelectrode mapping ...’. The group of Obeso et al. [12] from Spain, who reported severe hematoma in 7.4% of their first 27 patients operated on with microelectrode pallidotomy, stated that ‘the major risk is intracerebral hematoma’. One year later the same group delivered the following statement: ‘Intraoperative microrecording is considered the best method to avoid side effects and partial results’ [13]. Obeso et al. [14] defined the risks of microelectrode-guided pallidotomy in 1997 as follows: ‘The risks amount to 1% in mortality and 2–6% in severe morbidity-hemiplegia’. A group in Philadelphia published in the American Journal of Radiology in 1997 a MRI figure showing how a brain looked following MER-guided pallidotomy [15]. One could clearly see a wide track of massive frontal edema extending from the cortex to the pallidal area, with bleeding along the track, in the putamen, in the head of the caudate nucleus, etc. Keeping in mind that the aim of the MER-guided surgery was to place an accurate lesion in the PV pallidum precisely to avoid damage to surrounding brain structures, this patient’s brain looked as if he had had an extended frontal leucotomy in one hemisphere! Compared to MER groups, the reported pallidotomy complications of macroelectrode teams were generally milder, the occurrence of hematoma was extremely rare and the mortality was virtually nil [6, 16, 17–22]. Hariz and DeSalles [20] published a paper on the complications of pallidotomy and acknowledged malplacement in some of their macrostimulation-guided lesions. The Harvard group reported on successful repeat surgery using macrostimulation in patients in whom previous macrostimulation-guided pallidotomies done elsewhere resulted in non-accurately placed lesions [23]. In all but one [24] of the publications of the non-microelectrode teams, there were no deaths related to surgery.

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Safety of Microelectrode Recording during DBS Procedures

DBS procedures have gained popularity largely because they are considered safer for the patients [24–27]. Since ablative lesions may result in permanent complications, and since some authors consider that most hemorrhage occur at the time of lesioning [28], DBS should theoretically eliminate the risk of severe morbidity. At the meeting of the Movement Disorder Society in New York in October 1998, the preliminary results of a multicenter study on DBS in advanced PD were presented. Anthony Lang [29] presented the results of DBS in the pallidum in 36 patients (25 bilateral) and reported, among other complications, 28% system complications, 8% hemorrhage, 11% infection, and 3% seizures. He concluded by stating that complications were not uncommon but risk/benefit was quite acceptable. Obeso et al. [30] presented the results of DBS in the subthalamic nucleus (STN) in 36 patients (33 bilateral), and reported 8% hemorrhage and 22% infections, and concluded that the risk cannot be minimized but the benefit is substantial. All centers involved at that time in these studies except the one in Lund, Sweden, used MER techniques for target identification. The non-MER center of Lund, however, had neither hematoma nor infections among their operated DBS patients [Dr. Stig Rehncrona, Department of Neurosurgery, Lund, Sweden, pers. commun]. This was confirmed later in the paper published in the New England Journal of Medicine reporting the outcome of STN and pallidal DBS in 18 centers, in which it was found that the incidence of hemorrhage correlated with the number of microelectrode passes [31]. On the other hand, the group of Benabid in Grenoble, France, has regularly been using MER in their practice of DBS since 1987. In 1998, these workers reported a very low rate of serious complications in their experience of 311 electrode implantations in 199 patients, most of whom had Vim thalamic stimulation [32]. In February 2001, this team reported their experience with 125 STN DBS patients and declared 6.4% infections and 2.4% intracerebral hematomas [33]. Perhaps their technique of MER, using five parallel microelectrode tracks, no intersecting passes, and a plug in the burrhole (the so called ‘Ben Gun’) to avoid CSF leak during the lengthy surgery on a supine patient, contributed to the low rate of permanent complications in their patients. However, the rate of transient confusion was not rare, probably reflecting, in my personal opinion, both the length of surgery and the edema and ‘minor’ hematomas provoked by the trans-dural passage of five guiding cannulae through the frontal lobes bilaterally. The complications of DBS that are related to the hardware and surgical procedure have been alarmingly high in some microelectrode centers. While the Toronto group recently published an incidence of 25% device-related complications in their first 100 DBS [34], the Kansas group presented in 2001 a rather high rate of complications in their total DBS experience in 206 patients who underwent

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Table 1. Percent reduction of UPDRS part III (motor scores, off-medications) in various pallidotomy studies according to whether microelectrode recording (MER) was used or not

Postoperative Author/year follow-up, months

MER

Patients

UPDRS % reduction

6 12 6 6 12 6 12 12 24 12

yes yes yes yes yes no no no no no

29 41 39 29 89 47 58 32 68 32

25 21 31 16 35 31 23 26 20 24

Kopyov 1997 [40] Uitti 1998 [41] Kumar 1998 [42] Melnick 1999 [43] Lai 2000 [44] Giller 1998 [17] Kondziolka 1999 [19] De Bie 2001 [21] Eskandar 2000 [22] Masterman 1998 [39]

275 DBS procedures [35], amounting to a rate of 49% in their specific STN DBS experience in 29 patients [36]. In April 2002, this group described device-related events (infection, electrode misplacement, fracture, dislocation, etc.) occurring in 55% of their 27 patients [37]. Although all these complications are related one way or another to the implant and to the learning curve, the surgical technique used, relying on lengthy MER exploration, should not be neglected, especially with respect to the high rate of infections. In comparison, Hariz et al. [38] reported infection in 1 patient and hardware-related complications in 8.6% of their 56 patients followed for 3–55 months after surgery.

Clinical Results of MER- vs. Macrostimulation-Guided Surgery

Perhaps the increased rate of complications in MER-guided surgery compared to macrostimulation-guided surgery may be justified by the eventually better results of MER-guided procedures. A review of well-performed pallidotomy studies (table 1) shows that the results did not differ significantly whether MER techniques were used or not. Regardless of what surgical technique had been used, the most consistent finding in the literature is that pallidotomy exerts its main effect on limb dyskinesias, dystonia, and tremor, and least on axial symptoms and gait freezing. Although the percentages of improvement in various aspects of UPDRS reported

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Table 2. Percent reduction of UPDRS part III (motor scores, off-medications) in various STN DBS studies according to whether microelectrode recording (MER) was used or not

Postoperative Author/year follow-up, months 12 6 12 16 12 6 6 3 12 21 6 12–50 6 1

Limousin 1998 [46]1 Krack 1998 [47]1 Kumar 1998 [48]1 Moro 1999 [49]1 Pinter 1999 [50] Houéto 2000 [51]1 Molinuevo 2000 [52]1 Lopiano 2001 [53] Volkmann 2001 [54]1 Vingerhoets 2002 [55] Just 2002 [56] Romito 2002 [57] Multicenter 2001 [31]1

MER

yes yes yes no yes and no yes yes no no yes no no yes and no

Patients

20 13 7 7 9 23 15 16 16 20 11 22 102

UPDRS % reduction 58 71 58 42 45 67 66 57 50 45 68 50 52

Patients in these studies are partly included in patients from the multicenter study.

in the literature were rather disparate, this disparity, however, was not between reports from MER groups versus non-MER groups, but within either group, as has been shown by Starr et al. [45] in their comprehensive survey on the effect of unilateral pallidotomy, published in November 1998 in Neurosurgery. For DBS procedures, especially STN DBS, the results published so far do not permit a direct comparison of efficacy between groups using MER and groups not using MER. The main reason is that groups using MER tend to publish more papers and include overlapping patients in their publications. Table 2 shows the UPDRS percentual improvement in various studies of STN DBS, according to whether MER was used or not.

Which Is Safer? MER or Macrostimulation?

In a paper published from Oxford, UK, in 1998, entitled ‘The pallidotomy debate’ [58], the authors compared complications reported in five publications on microelectrode-guided pallidotomy with complications from eight publications on macroelectrode-guided pallidotomies. They showed that intracerebral hemor-

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rhage occurred in 7% of MER-operated patients versus 0.6% in non-MER-operated patients. The Toronto group arrived at the same conclusion in their paper published in 2001 [59]. In 1,959 patients from 85 articles at 40 centers in 12 countries, MER was used in 46.2% and macrostimulation in 53.8%. Cerebral hemorrhage occurred in 2.7% of MER patients and in 0.5% of macroelectrode patients. Overall complications occurred in 26% of MER patients and in 19.2% of macroelectrode patients. A meta-analysis study of results of MER versus macroelectrode-guided pallidotomy was performed by the Vancouver group in Canada [60]. It showed that there were no significant differences between the two techniques in improvement of dyskinesia or UPDRS motor scores. However, this study showed that MER had a significantly higher intracerebral hemorrhage rate (1.3 B 0.4%) compared to macroelectrode stimulation (0.25 B 0.2%). The Amsterdam group [61] performed a systematic literature review of morbidity and mortality following pallidotomy in Parkinson’s disease showing that pallidotomy performed with MER resulted in significantly more morbidity and mortality. In practice of pallidal and STN DBS, the same trend has already been substantiated in the publication of the multicenter group, showing that MER resulted in more hemorrhage than macroelectrode techniques [31]. The numerous examples about misplaced lesions, mislocated DBS electrodes, complications, etc. from the clinical MER literature presented in a survey by Hariz and Fodstad [3] in 1999 are not anecdotal or coincidental reports. They have not occurred once or twice, but too often and in too many centers to not become an evident reality. Does this mean that MER techniques are to be condemned? No! The present author believes that the MER technique is an exquisite method for research on the cellular activity of basal ganglia in several diseases and to study the effect of a treatment. Especially in animal models this technique is irreplaceable to learn more about the behavior of the basal ganglia. What is questionable is the efficacy and safety of the routine application of this technique in humans, when compared to macrostimulation techniques; furthermore, it is dubious whether the MER technique should be imposed on or practised by teams who have neither the training nor the experimental background to be able to use this technique in a way that is safe for the patients. The high rate of complications when using MER in several centers is totally unacceptable for a surgery that is elective, symptomatic, not life-saving, minimally invasive, and the aim of which is to improve the quality of life of the patient. Even if we assume that MER contributes to more optimal placement of the lesion or DBS lead in the functional target, the present author prefers to use macrostimulation and to risk having a suboptimally located or suboptimally sized lesion or even to abort surgery rather

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than to have a nice very well located lesion or DBS electrode in a comatose, hemiplegic or dead patient. The ‘primum nil nocere’ axiom of functional stereotactic surgery should always prevail whenever operating on a patient with a non-mortal disease such as PD or other movement disorder.

Conclusions

MER techniques are not homogeneously used among neurosurgeons. Most MER techniques require several passes of several microelectrodes in the brain. This technique is important for research and detailed cellular study of the basal ganglia, but it may increase surgical risks: prolonged surgery may increase stress reactions, and the patient may become unreliable to assess; prolonged surgery may increase infection risks; multiple passes of sharp probe tips may increase hemorrhage risk. So far there is no evidence that microelectrode technique improves results, but there is accumulating evidence that it increases the rate of severe complications, such as death and hemorrhage. In the absence of a randomized trial on use of macrostimulation versus MER techniques in surgery for MD, comprehensive and critical reviews of the literature remain the only means to evaluate the benefits and drawbacks of either method. Such reviews have now been provided in at least five papers from five different centers [3, 58–61], one of which is a leading MER center [59]. All these reviews, published between 1988 and 2002, and performed independently from each other, concluded that MER techniques were at least five times more dangerous than macrostimulation techniques in terms of provoking serious complications, especially brain hemorrhage. Whether this very significantly increased risk for serious complications is justified by an alledgedly and theoretically better clinical improvement in patients operated on with MER techniques remains to be proven. So far, it seems that the published improvements following surgery using either method do not differ, while the published complication rates definitely do.

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Exploration of the Role of the Upper Brainstem in Motor Control D. Nandi a J.F. Stein a T.Z. Aziz a, b a University

Laboratory of Physiology, Oxford University, Oxford, and of Neurosurgery, Radcliffe Infirmary, Oxford, UK

b Department

Key Words Brainstem W Akinesia W Pedunculopontine nucleus W Primate W Stimulation

Abstract The rostral areas of the brainstem have been extensively studied in higher mammals and to a lesser extent in humans in the last two decades, looking for anatomical, electrophysiological and neurochemical evidence of involvement in the initiation and control of voluntary movement. This has come with the realisation that the axial symptoms of advanced Parkinson’s disease (PD), like akinesia, postural impairment and gait freezing, are relatively less responsive to current medical and surgical treatments directed primarily at the basal ganglia and thalamus. The pedunculopontine nucleus (PPN) is one such area of interest. We have found that lesioning and electrical stimulation at high frequencies of the PPN region in the normal behaving primate induces akinesia, and low frequency stimulation can induce tremor. Micro-injections of gamma-aminobutyric acid (GABA) receptor A agonist, muscimol, into the PPN decreases activity. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated Parkinsonian primate model, bicuculline, a GABAA antagonist, can alleviate akinesia when infused into the PPN region. This may suggest new targets for treating the intractable akinetic symptoms of advanced PD. Copyright © 2002 S. Karger AG, Basel

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Dr. Dipankar Nandi University Laboratory of Physiology, Oxford University Park Road, Oxford, OX1 3PT (UK) Tel. +44 1865 272 539, Fax +44 1865 272 469 E-Mail [email protected]

Introduction

Parkinson’s disease (PD) is characterized by rigidity, resting tremor, bradykinesia (slowness of movement), akinesia (inability to initiate movement), postural instability and gait disturbance. The last three are by far the most disabling and difficult to treat [1]. Current models of the pathophysiology of motor symptoms in PD emphasize the abnormal increase in the activity of the subthalamic nucleus (STN) [2–4] that drives the medial globus pallidus (GPi) to inhibit the thalamus and thalamocortical pathway, which results in reduced cortical activity and accounts for the motor disturbances associated with PD. Several recent studies have suggested that the upper brainstem, and in particular the pedunculopontine nucleus (PPN), may play a significant role in the pathophysiology of some of the motor symptoms in PD, like akinesia, gait dysfunction and postural abnormalities [5–11]. The PPN is a nuclear structure in the rostral brainstem tegmentum with a dense pars compacta (cholinergic neurons) and a loosely spread pars dissipata (glutamatergic, dopaminergic, cholinergic and adrenergic neurons) [12–14]. The PPN receives the bulk of its afferents from the GPi and the substantia nigra pars reticulata (SNr) [15, 16]. It sends mainly glutamatergic ascending efferents to the substantia nigra pars compacta (SNc) and the STN (ventral tegmental tract) and mainly cholinergic ascending efferents to the thalamic nuclei (dorsal tegmental tract) [17, 18]. Descending projections from the PPN target lower brainstem, cerebellar and spinal motor centres [19]. In advanced PD and other neurodegenerative diseases where akinesia is a prominent symptom, like multisystem atrophy (MSA) and progressive supranuclear palsy (PSP), there is degeneration of the PPN [20, 21]. The degree of akinesia in PD has been linked to the extent of loss of the large cholinergic PPN neurons [21]. Stimulating the PPN electrically in decerebrate cats and monkeys elicited stepping movements, and increasing the intensity of the current drove the stepping progressively from a walk to a trot to a gallop [22, 23]. Several studies have demonstrated that unilateral lesions in the PPN in a normal monkey cause temporary hemi-akinesia, while bilateral lesions result in a profound long-lasting akinetic state [5, 7, 8]. In the first experiment, we have conducted preliminary studies with electrical stimulation of the PPN region in a normal freely moving monkey, using a fully internalised deep brain stimulating system. Gamma-aminobutyric acid (GABA) is the predominant afferent neurotransmitter in this region [24, 25]. We have suggested that akinesia in PD may be caused by excessive GABAergic inhibition of the PPN by descending projections from the GPi and SNr. In the second study, therefore, we have investigated the effects on motor function of pharmacologically manipulating the GABA input to the PPN in 2 normal monkeys and subsequently, after treating them with 1-meth-

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yl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP HCl) (Sigma, St. Louis, Mo., USA), to make them Parkinsonian. Two separate sets of experiments were performed in one of these monkeys, after inducing moderate and severe Parkinsonism.

Methods Electrical Stimulation of the PPN Region A farm-bred 5-year-old male macaque monkey weighing 4.5 kg was used for this pilot study. It was housed in accordance with the Home Office, UK regulations under the Animal (Scientific Procedures) Act, 1986. All procedures were performed with the prior approval of the Local Animal Ethics Committee, Oxford University, and the Home Office Inspectorate, UK. The animal was trained to sit in a primate chair and perform a simple reaching task for food reward. 24-Hour activity counts were recorded in the home cage using an infra-red motion detector. Video monitoring was carried out to register spontaneous and provoked facial expression and behaviour. Motor parameters were scored on a clinical scale developed by us. The primate Parkinsonism Motor Rating Scale (PPMRS) described in table 1. This scale is a modification of several existing scales used by other groups. Videos were assessed using a modified version of this scale – video PPMRS (VPPMRS), where the only difference was that tone was not scored. All these parameters were monitored for 10 days to establish a baseline. Under general anesthesia with intravenous alphaxalone/alphadolone (Saffan), using contrast ventriculography and a primate brain atlas [26], we stereotactically implanted a macroelectrode (Medtronic 3389) in the left PPN region in a normal macaque to investigate the effects of electrical stimulation at different frequencies. An extension lead and a pulse generator (Medtronic ITREL 3) were implanted subcutaneously. Activity counts were again recorded using an infra-red detector and behaviour was also videotaped. The pulse generator was activated 3 weeks after the surgery to study the effects of stimulating the normal PPN at different frequencies in a healthy animal. By this time all the parameters being recorded had returned to preoperative levels, including facial expression, which was the last to recover. Response was measured in terms of 2-hour activity counts (5 trials on separate days for each frequency of stimulation) in a glass fronted observation cage (with three infra-red detectors distributed to cover the available space) compared with control readings at similar times during the day. This was supplemented with video recording of spontaneous and provoked facial expression and behaviour. Micro-Injections into the PPN In this series of experiments, after recording baseline motor parameters, as detailed above, a stainless steel cannula was stereotactically implanted in the unilateral PPN in 2 macaque monkeys. The operative technique was similar to that used to implant the DBS electrode and relied upon contrast ventriculography and a primate brain atlas [26]. The cannula was fixed to the skull with dental acrylic and was used to inject muscimol, bicuculline and saline as control.

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Table 1. Primate Parkinsonian motor rating scale (PPMRS)

Parameter

Score

Definition

Spontaneous activity

0 1 2 3 4

normal walks, but reduced does not walk; actively moves limbs and trunk moves eyes and head only no movement

Speed of movement

0 1 2

normal moderately reduced severely reduced

Facial expression

0 1 2

normal moderately reduced severely reduced

Provoked response

0 1 2 3 4

normal slow; reduced activity and expression does not walk; moves limbs and trunk moves eyes and head only no response

Posture

0 1 2 3 4

normal stands/sits up with support moderately stooped severely stooped flat

Stability

0 1 2

normal leans; unsteady topples over

Tone

0 1 2

normal moderately increased severely increased

Because the predominant input to the PPN region is GABAergic, we confined our studies to manipulation of this pathway. Activity counts were recorded with an infra-red detector before and after implantation of the cannula to confirm that the procedure had no adverse motor effects. The monkey was also videotaped in its home cage to record spontaneous and evoked behaviour. Two microlitres each of solutions of muscimol (1 Ìg/Ìl in sterile water) and bicuculline (1 Ìg/Ìl in saline) were injected. Two microlitres of saline was injected as control. Injections were separated by at least 24 h to allow full recovery from effects of the previous injection. Activity counts were recorded for 4 h following each injection and behaviour videotaped. We gave 5 micro-injections of each substance.

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Fig. 1. Difference in response to low- and high-frequency stimulation of the unilateral PPN in a normal monkey. Activity counts with low-frequency stimulation (5, 10 and 30 Hz) were significantly higher compared to high-frequency stimulation (45, 60 and 100 Hz).

Results

Electrical Stimulation of the PPN at Different Frequencies In comparison with the base line, stimulation at all frequencies from 5 to 100 Hz significantly reduced activity counts (fig. 1, mean B SD, n = 5, paired t test, p ! 0.05, but at frequencies above 45 Hz the akinesia was significantly more severe than at lower frequencies (paired t test, n = 15, p ! 0.01). During 100-Hz stimulation there was also gross impairment of postural control. In addition, stimulation at low frequencies (5–30 Hz) induced a 5-Hz tremor in the contralateral arm. The frequency of the tremor remained at 5 Hz over this wide range of stimulation frequencies. These effects were quickly reversible and there was neither impairment of alertness nor limb weakness. Micro-Injections into the PPN Following the operations to implant indwelling cannulae in the monkeys’ skull stereotactically targeted on the unilateral PPN, the daily and half-hourly activity counts, motor assessments and videoclips were repeated over the next 2 weeks. This revealed that there was no effect of surgery on the mean half-hourly activity counts and on the clinical motor scores. Then intracerebral micro-injections of GABA agonist (muscimol), GABA antagonist (bicuculline) and saline

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were delivered sequentially into PPN through the cannula. Videotape, PPMRS and activity count records were maintained. Muscimol significantly reduced the mean half-hourly activity counts of both monkeys A and B. There was no effect following saline or bicuculline micro-injection. However, bicuculline caused some axial motor effects like sustained titubation and vertical nystagmus, more prominent in monkey A. The clinical motor rating scores showed a consistent significant decrease in motor function in both monkeys following injection of muscimol (fig. 2a, b). Moderate Parkinsonism In the next stage of the experiment (conducted only in monkey A), the animal was rendered Parkinsonian by weekly intravenous injections of MPTP. Parkinsonism was rated on the clinical rating scale. After three injections the monkey slowed down markedly and developed limb and head tremor as well as a stooped posture. It scored 10.6 B 1.35 (n = 5) on the PPMRS (baseline score 1.3 B 0.67, n = 5) and 11 B 1 (n = 5) on the VPPMRS (baseline score 1.6 B 0.58, n = 5), which suggests moderate Parkinsonism. The mean half-hourly activity counts were significantly reduced. The reduction in activity was reversed by an oral suspension of L-Dopa. The series of intracerebral micro-injections were then repeated. There were significant increases in the activity counts following the bicuculline injections (fig. 2a). The tremors were unaffected by the bicuculline. Saline and muscimol did not have any effect. Motor scores also demonstrated significant improvement in activity following intracerebral bicuculline and oral L-Dopa. Severe Parkinsonism In the final stage of the experiment, both the monkeys were given a bolus dose of intravenous MPTP (2 mg/kg in monkey A and 1 mg/kg in monkey B). This made the animals severely akinetic, stooped and rigid. The clinical scores (18.1 B 1.6, n = 5, monkey A; 17 B 0.35, n = 5, monkey B) on the PPMRS (fig. 2a, b) and those (16.3 B 1.3, n = 5, monkey A; 16.6 B 0.54, n = 5, monkey B) on the VPPMRS, confirmed severe Parkinsonism. They required intensive nursing and had to be hand-fed regular doses of L-Dopa in order to feed and groom themselves. The mean half-hourly activity counts were very markedly reduced. The series of intracerebral micro-injections were repeated. Due to its severely affected condition, the number of injections was reduced in monkey A. There was a remarkable increase in the animals’ activity following the bicuculline injections (fig. 2a, b). But there was no effect with saline or muscimol. Within 5 min after the bicuculline micro-injection the animals were able to sit up from their previous flat positions, reach out and grasp food and were able to feed and groom themselves. The peak effects lasted for about 45 min before gradual slowing of activity

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over the next 30 min. There was some evidence of contralateral turning behaviour in monkey B. Videotaping was done through the glass front before and after every intracerebral micro-injection. The clinical scores of motor function (PPMRS and VPPMRS) revealed a highly significant increase following injection of bicuculline which matched the degree of increase seen with oral L-Dopa. Histological Examination After the conclusion of the experiments, the site of the micro-injections was marked by a thermal lesion in one monkey and by India ink dye in the other. The animals were then sacrificed and the brains were blocked, fixed and processed histopathologically. Coronal sections through the area of the brainstem were stained with haematoxylin and eosin, cresyl violet and luxol fast blue and examined. The sections were referenced to the primate brain atlas [26]. This confirmed the site of the micro-injections as the right PPN in monkey A and left PPN in monkey B.

Conclusions

Review of the literature and these experiments suggest that the descending projections from the basal ganglia, especially those targeting the upper brainstem nuclei like the PPN, play a more important role in the control of movement and the generation of motor symptoms in movement disorders than previously realised. They support the case for the involvement of the PPN in akinesia and suggest a possible clinical application for surgical or pharmacological excitation of the PPN region for the treatment of advanced PD.

Fig. 2. Motor scores on the PPMRS (mean and SD, n = 5; except as indicated in a stage 3, where n = 3) recorded during the different sessions in the pre-MPTP, post-MPTP (moderate Parkinsonism, monkey A) and post-MPTP (severe Parkinsonism) stages of the experiment. Each session was 15 min long. Each score for each session represents the mean of the scores of two independent observers (one blinded). The controls in the 3 stages (2 stages b for monkey B) are the post-op scores, the post-MPTP (1st set) and post-MPTP (2nd set), respectively. C = Control; M = muscimol; B = bicuculline; S = saline; L = L-Dopa (Madopar); C (end) = control at the end of that stage of the experiment.

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Acknowledgements We are grateful to Ms Victoria Metcaffe and Ms Jane Sutcliffe for scoring on the PPMRS and to Ms Nicola Sullivan for helping with the histological processing. Mr. Brian Howse and Mr. Jonathan Winter provided invaluable technical assistance. This work was supported by grants from the Medical Research Council, UK, and the Norman Collisson Foundation.

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Deep Brain Stimulation for Dystonia in Adults Overview and Developments

Joachim K. Krauss Department of Neurosurgery, University Hospital, Klinikum Mannheim, Mannheim, Germany

Key Words Deep brain stimulation W Dystonia W Functional neurosurgery W Pallidum W Stereotactic

Abstract The renaissance of functional neurosurgery in the treatment of Parkinson’s disease has sparked also the interest in other movement disorders which are refractory to medical treatment. Deep brain stimulation (DBS) has been used only since a few years in dystonia patients. This review summarizes the available data on pallidal and thalamic DBS for various dystonic syndromes. The major advantage of DBS as compared to radiofrequency lesioning is that it allows performing contemporaneous bilateral surgery with relatively low morbidity in these patients. The posteroventral lateral globus pallidus internus (GPi) has been the preferred target in most instances, thus far. While phasic dystonic movements may improve early after surgery, the response of tonic dystonic movements to chronic stimulation may be delayed. The most beneficial results have been achieved in patients with primary genetic generalized and segmental dystonia, myoclonic dystonia, and complex cervical dystonia. Outcome has been varied in patients with other dystonic disorders, in particular those with secondary dystonia. Most studies have reported on relatively short follow-up periods,

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Prof. Dr. Joachim K. Krauss, Dept of Neurosurgery University Hospital, Klinikum Mannheim Theodor-Kutzer-Ufer 1–3, D–68167 Mannheim (Germany) Tel. +49 621 383 3142, Fax +49 621 383 2004 E-Mail [email protected]

on single cases, or were retrospective. Pallidal DBS has been shown to be effective in complex cervical dystonia yielding both symptomatic and functional benefit for up to 2.5 years of follow-up. Dramatic improvement has been obtained in children and in adults with DYT1 positive dystonia. Also, patients with non DYT1 genetic dystonia achieved sustained benefit for up to 2 years of follow-up. Preliminary experience indicates that choreoathetosis in patients with cerebral palsy responds less well to pallidal DBS, and that it may not be effective at all in some patients. In single instances unilateral pallidal DBS has been shown to yield valuable benefit in patients with hemidystonia. The experience with DBS for treatment of Meige syndrome and other focal dystonias has been explored only recently. There is much less experience with thalamic DBS for dystonia. Thalamic DBS has been shown to be effective in single cases with posttraumatic dystonia, postanoxic dystonia and paroxysmal nonkinesigenic dystonia. Future perspectives of DBS for treatment of dystonia include the development of new technology, the evaluation of the possible role of other targets, and carefully planned studies to further establish the role of surgery. Copyright © 2002 S. Karger AG, Basel

Deep brain stimulation (DBS) has widened considerably the spectrum of movement disorder surgery within the past decade. It has been used predominantly in Parkinson’s disease (PD) and in patients with essential tremor. Targets most commonly selected nowadays include the thalamus, the subthalamic nucleus, and the globus pallidus internus (GPi). The mechanisms of DBS thus far have not been fully elucidated [1, 2]. While local inhibition of neuronal activity has been assumed to be the primary mode of its action, stimulation of fiber tracts might also be relevant. DBS offers several potential benefits over ablative functional stereotactic neurosurgery. There appears to be less peri- and postoperative morbidity with DBS, although this has only been formally assessed in patients with tremor [3]. DBS may be performed bilaterally in one operative session without significant morbidity. Most importantly, the functional size of the focus of stimulation (and even its location) can be changed and adjusted over time. With that regard, DBS is a most useful tool to explore new options for otherwise medically-intractable movement disorders. DBS has been introduced only recently for treatment of dystonia [4–6]. Since then, several studies with promising results have been published. Based on the experience that pallidotomy improved contralateral dystonic dyskinesias in patients with PD and also on historic accounts of pallidal surgery in dystonia, the GPi is being used most frequently, nowadays, as the target for DBS in dystonia. It has been shown that midline dystonic symptoms in patients with generalized dys-

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tonia are improved with chronic DBS, and also that cervical dystonia (CD) responds well. Most studies, thus far, however, have reported on relatively short follow-up periods, on single patients, or were retrospective. Here, a brief overview on the published data and some comments on the author’s personal experience with DBS for dystonia will be given.

Historical Aspects of Deep Brain Stimulation for Dystonia

The animal experiments of the neurophysiologist W.R. Hess in Zürich, for which he was awarded the Nobel prize, probably present the first traces in the history of DBS for treatment of dystonia [7]. In the early 1950s, the German neurologist R. Hassler, who is known today chiefly for his thalamic nomenclature, travelled to Zürich to review the kinematographic data and the histologic serial cuts from Hess’ experiments in cats. Based on the effects of electrical stimulation of chronically implanted electrodes in various thalamic and basalganglia nuclei, Hassler proposed an elaborate model to explain the deviation of the head along different axes in human CD [8]. The first target for chronic electrical stimulation for treatment of dystonia, decades later, however, were the dorsal columns of the cervical spine in patients with CD. Spinal cord stimulation for CD required very high frequency that is not available on present day stimulators [Gildenber, pers. commun.]. As early as in 1977, Mundinger [9] reported his experience with thalamic stimulation for CD. However, the results were not published in the English literature and the study went almost completely unnoticed. Thalamic DBS was not pursued further then, because of technical problems with the equipment.

Lessons Learned from Lesioning Procedures

Over decades, the thalamus was considered the preferred target for radiofrequency lesions to treat dystonia [10–12]. Variable results were reported with improvement in about 50% of patients. The results of most studies, however, are difficult to appreciate nowadays regarding various technical and methodological issues. It is only for the past few years that pallidal surgery has been reaccepted as a valuable tool in the treatment of dystonia [13–17]. Pallidotomy has been shown to be effective in generalized dystonia, segmental dystonia and hemidystonia in several studies with varying benefit. In most recent studies, bilateral pallidotomy yielded a 50–80% improvement in dystonia scores. In some studies, however, a partial recrudescence of dystonic symptoms has been noted over time.

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Deep Brain Stimulation for Dystonia: Overview

The number of publications on chronic DBS for treatment of dystonia has grown slowly but steadily over the past few years. The available data on pallidal [4–6, 18–35] and thalamic [29, 31, 36–38] DBS for dystonia is summarized in tables 1 and 2. While it has been established that chronic DBS renders dramatic improvement in children with genetic DYT1 positive dystonia [19], investigation of the long-term efficacy in DYT1 negative generalized dystonia and in choreoathetosis has received much less attention. Improvement of dystonia with pallidal stimulation may be delayed. Sometimes it may take even months before the full benefit is noticeable. In our experience, phasic dystonic movements may respond almost immediately to stimulation, while there may be some early effect on tonic components, which show gradual progressive improvement thereafter. In contrast, dystonia may reoccur within minutes or hours when the implantable pulse generators (IPG) are switched off. Since both pulse width and voltage are higher in dystonia patients than in PD, depletion of the IPG batteries may occur within 2 years, in particular when using the Itrel II stimulator (Medtronic, Minneapolis, Minn., USA). The power consumption of the Itrel II is linear up to 3.6 V, but then rises abruptly because a second capacitor is activated. Since power consumption is linear with the dualchannel Kinetra (Medtronic), this IPG may be more advantageous regarding battery life under such circumstances. Modifications in the techniques of stimulation should be explored. Battery life might be prolonged for example by cyclic stimulation modes. Most centers perform contemporaneous bilateral surgery to implant the electrodes. Some surgeons use general anesthesia in patients with dystonia, in particular in children. We, as others, prefer to operate under local anesthesia in adult patients. A short-acting benzodiazepine may be given for stereotactic imaging. The target in the posteroventral lateral GPi usually is chosen 20–22 mm lateral to and at 4 mm below the intercommissural line, and 2–3 mm anterior to the intercommissural midpoint. We find microelectrode recording with high-impedance microelectrodes very helpful to assess the spatial morphology of the target and the trajectory to it. We use one to three trajectories to further refine the target. We also use macrostimulation directly via the DBS electrode to check for thresholds of intrinsic and extrinsic responses, and to determine the final electrode position [39]. Since depletion of the batteries on long-term use may result in abrupt reappearance of the dystonia, which then may be even worse than preoperatively, we prefer to implant two IPGs (Itrel II, Itrel III or Soletra) instead of the dual channel IPG Kinetra. Our initial DBS settings are always based on a bipolar stimulation mode. Amplitudes below thresholds that produce undesired side effects are pro-

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Table 1. Pallidal deep brain stimulation for dystonia Author year

Patient(s) Dystonia Age etiology

Distribution

Surgery

Reported outcome

Follow-up Comments

Krauss 1999

3 42–53

primary

cervical

B

TWSTRS 1 50% imp of dystonia, pain + disability

6–15 m

–

Kumar 1999

1 49

primary

generalized

B

BFMDMS 65% imp

18 m

reduced PET activation of certain motor cortical areas during stim

Coubes 1999

1 8

primary, DYT-1

generalized

B

excellent

30 m

–

Islekel 1999

1 42

primary

cervical

U

marked imp

NA

–

Coubes 2000

7 8–27

primary, DYT-1

generalized

B

BFMDMS 60–100% imp; mean 90%

1y (at least)

–

Angelini 2000

1 13

secondary, generalized, CP (postvacc) choreoathetotic

B

excellent

7m

life-threatening ‘dystonic storm’ preoperatively

Tronnier 2000

3

primary (2), secondary, CP (1)

generalized

B

marked relief in primary, mild relief in secondary dystonia

6–18 m

–

Loher 2000

1 24

secondary

hemidystonia

U

marked imp of dystonic posture, movements + pain

4y

after previous thalamotomy imp of tremor, but not of dystonia

Coubes 2001

17 8–26

primary, DYT-1 (7)

generalized

B

BFMDMS mean 81% imp

3–36 m

extended series

Andaluz 2001

1 61

primary

cervical + truncal

B

TWSTRS 50% imp

8m

–

Kulisevsky 2001

2 35 + 65

primary

cervical

B

mild imp of dystonia, but marked imp of pain

17–24 m

–

Brin 2001

4 NA

primary

generalized (2), cervical (1), seg (1)

U

mild imp (2), failure (2)

12 m

wound healing problems in 3 patients, device removed in 2

Gill 2001

1 11

secondary, CP

generalized, choreoathetotic

B

‘disappearance of hyperkinesia, modest imp of dystonia’

NA

–

Parkin 2001

3 23–67

primary

cervical

B

marked imp of dystonia, pain + disability

2–6 m

–

Trottenberg 2001

1 70

secondary, tardive

segmental

B

BFMDMS 73% imp

6m

patient had no effect with thalamic DBS

Muta 2001

1 61

primary

segmental axial and facial (Meige)

B

BFMDMS 80% imp

NA

prior bilateral thalamotomy without beneficial effect

Vercueil 2001

8 12–59

primary (5), secondary (3)

generalized (5), seg (2), hemidystonia (1)

B (7) BFMDMS 1 50% mean U (1) imp

6–24

thalamic DBS was not successful in 3 patients previously

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Table 1 (continued) Author year

Patient(s) Dystonia Age etiology

Distribution

Surgery

Reported outcome

Follow-up Comments

Bereznai 2002

6 22–78

primary, DYT-1 (1)

generalized (1), seg (3), cervical (2)

B

BFMDMS 73% mean 3–12 m imp, Tsui score 63% mean imp

Krauss 2002

8 28–53

primary (6), secondary, CP (2)

cervical (6), B (7) TWSTRS 63% imp of choreoathetotic (2) U (1) severity, 50% imp pain, 69% imp disability

12–30 m

extended series of cervical dystonia, DBS adjunct to spinal surgery

Vesper 2002

1 26

primary

generalized

B

BFMDMS 1 90% imp

2y

continued use of intrathecal baclofen during DBS (at reduced dosage)

Liu 2002

1 28

primary

cervical (myoclonic)

B

marked imp of dystonic posture and myoclonic jerks

20 m

–

–

B = Bilateral; U = unilateral, TWSTRS = Toronto western spasmodic torticollis rating scale; BFMDMS = Burke-Fahn-Marsden dystonia movement scale, imp = improvement; stim = stimulation; m = month(s); y = year(s); NA = not available; CP = cerebral palsy; seg = segmental.

Table 2. Thalamic deep brain stimulation for dystonia Author year

Patient(s) Dystonia age etiology

Distribution

Surgery

Reported outcome

Follow-up

Comments

Sellal 1993

1 16

secondary, head injury

hemidystonia

U

excellent, intermittent stim producing dysaesthesias

8m

target nucleus: VPL, poor wound healing: DBS removed

Loher 2001

1 37

secondary, after plexopathy

paroxysmal nonkinesigenic

U

marked decrease of frequency, intensity and duration of attacks

4y

–

Trottenberg 2001

1 60

primary

generalized myoclonic dystonia

B

myoclonus score 80% 24 m imp, no imp of dystonia

–

Vercueil 2001

12 18–25

primary (4), secondary (8)

generalized (9), seg (2), hemidystonia (1)

B (7) U (5)

mean BFMDMS unchanged, but good functional result in 6 patients

4 m–11 y

pallidal stim in 3 patients later

Ghika 2002

1 26

secondary, postanoxic

generalized

B

UDRS 50% imp

4m

patient committed suicide, previous pallidal stim was unsuccessful

B = Bilateral; U = unilateral; BFMDMS = Burke-Fahn-Marsden dystonia movement scale; imp = improvement; stim = stimulation; m = month(s); y = year(s); VPL = ventroposterolateral thalamic nucleus; seg = segmental; UDRS = unified dystonia rating scale.

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grammed at the follow-up visits with a gradual increase of the intensity of the stimulation. The stimulation of a combination of different contacts and settings is assessed in case no optimal effect on the movement disorders was achieved. DBS settings are adjusted within the first year after surgery, and in some patients minimal adjustments of stimulation voltage are performed also later on. We usually select a frequency of 130 Hz and a pulse width of 210 Ìs for chronic DBS. The voltages are much higher than those used in PD patients, and have ranged between 2.2 and 6.3 V in our patients with dystonia. In patients with an Itrel II or a Soletra, bipolar stimulation is changed to monopolar stimulation when the amplitude is set higher than 3.6 V, in order to avoid rapid battery depletion. Some patients experience a feeling of perioral tightness during adjustment of DBS settings. Other transient side effects include increase of preoperative dysarthria, dizziness and rarely tingling. Usually, side effects are completely reversible upon readjustment of DBS settings. Weight gain appears to be an unspecific side effect, which has also been observed in pallidal surgery for other indications. Lead fractures occur more frequently in dystonia patients than in patients with other movement disorders in our experience.

Pallidal DBS for Cervical Dystonia

Regarding the fact that CD is the most frequently encountered dystonic disorder, it becomes evident that DBS could be of particular importance in CD. The indications for chronic bilateral pallidal stimulation for CD remain to be further elaborated. At the present time, patients with complex CD who do not achieve satisfactory improvement with botulinum toxin injections and who are poor candidates for peripheral procedures such as selective denervation are considered for DBS. Such patients include those with continuous phasic movements, marked dystonic head tremor or myoclonus; severe retrocollis, sagittal and lateral translations, and anterocollis with involvement of deep cervical muscles. Chronic bilateral pallidal stimulation may also become an alternative in patients with less complex forms of CD. One advantage is that other manifestations of dystonia can possibly be treated in the same patient (for example, shoulder elevation). Furthermore, a single operation might produce the same or greater benefit than serial procedures, which can be necessary in CD patients who undergo peripheral surgery. CD is thought to arise from pathological mechanisms within the basal ganglia circuitry. There is evidence that involvement is bilateral, regardless of the specific pattern of CD. PET investigations of patients with CD have shown increased bilateral glucose metabolism in the lentiform nucleus [40]. There were

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no significant differences concerning the laterality, the specific pattern, or the severity of CD in individual cases. Bilateral basal ganglia involvement has also been suggested by SPECT studies showing that striatal D2 receptor binding was significantly reduced in patients with CD when compared with normal controls [41]. Bilateral rather than unilateral DBS is also supported by knowledge accumulated regarding the innervation of neck muscles [42]. About 300 patients with CD were reported to have undergone functional stereotactic surgery in the 1960s and 1970s [7]. Historical reports are difficult to interpret, but it appears that most patients experienced mild to moderate benefit. Targets used by different surgeons included the ventral lateral nuclei of the thalamus (ventro-oralis anterior, ventro-oralis posterior, and ventro-oralis internus), the center median nucleus, the ventralis intermedius, the ventralis posteromedialis and posterolateralis, the pulvinar, Forel’s fields H1 and H2, the zona incerta, the interstitial nucleus of Cajal, and the red nucleus. The difficulties in choosing the appropriate side and site are exemplified by the contradictory recommendations of two historic authorities. While Cooper recommended lesioning contralateral to the dystonic sternocleidomastoid muscle, Hassler stated that the ipsilateral side should be targeted. We have shown that bilateral pallidal stimulation for CD produces symptomatic and functional improvements, including marked relief of pain for up to 2.5 years of follow-up [4, 33]. The gradual postoperative improvement of CD was reflected by evaluation with the modified Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). All subscores were improved substantially by 3 months after surgery: the severity score improved by 38%, the disability score by 54%, and the pain score by 38%. At the last follow-up, all scores were further improved. The severity score had improved by 63%, the disability score by 69%, and the pain score by 50%, as compared to preoperative scores. The difference in the subscores at the last follow-up, as compared to the 3-month follow-up, was significant for the severity and functional disability subscores, but not for the pain subscore. One patient was completely pain free at the last follow-up; all other patients still complained of residual neck pain or tension. The first patient in this series experienced several exacerbations of CD during late follow-up (i.e. after 18 months). Two such episodes were due to unilateral electrode fractures, and two to IPG battery depletion. Each time, CD worsened within a few hours. After replacement of the non-functioning hardware, clinical improvement occurred with much less delay than before. No patient experienced a permanent complication due to the surgical procedures or chronic DBS. We have applied pallidal DBS as an adjunct in single patients with severe cervical dyskinesias with cervical myelopathy undergoing spinal surgery and spinal stabilization. Several other groups have also published their experience with pallidal DBS for CD [18, 24, 25, 28, 32]. The results are summarized in table 1. With the excep-

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tion of one case, all patients underwent bilateral stimulation. The cost of chronic stimulation for patients with CD is relatively high. This is due, in particular, to shorter battery life and the younger age of the patients, as compared to those with other movement disorders. Parkin et al. [28] stressed the importance to consider new DBS strategies in these patients in order to reduce costs.

Pallidal DBS for Generalized and Segmental Dystonia

It has been suggested that the response of dystonia to pallidal DBS may depend on etiology, similar to the experience with pallidotomy [43]. In general, patients with primary dystonia respond well, patients with secondary dystonia appear to respond less well, and poorer results are expected in patients with secondary dystonia and structural lesions. Nevertheless, in single instances of secondary dystonia, with or without structural lesions, remarkable benefit has been achieved with pallidal DBS. Regarding the bilateral involvement of the basal ganglia circuitry in generalized and segmental dystonia, contemporaneous bilateral DBS should be preferred over unilateral surgery. Adverse events, have been minimal and can be easily managed. The most beneficial results in generalized dystonia were obtained in children with genetic DYT1 positive dystonia. Coubes et al. [19] described a mean improvement of 90% in the BFMDMS in 7 patients (mean age at surgery 14 years) at a follow-up of at least 1 year after surgery. Several other groups have found similar improvement (table 1). So far, only single cases with DYT1 positive dystonia were reported to not have responded to pallidal surgery. DBS for DYT1 positive and for pediatric dystonia is reviewed elsewhere in this volume. To date, there are only limited published data on the efficacy of pallidal DBS for primary DYT1 negative generalized dystonia in adults, and little information is available on long-term outcome. Overall, it appears that remarkable benefit is also achieved in patients with primary non-DYT1 dystonia, but the results are slightly inferior to those seen in patients with DYT1 positive dystonia, in particular in the pediatric population. In our experience, chronic GPi stimulation rendered marked symptomatic and functional improvement in 2 adult patients with primary non-DYT1 generalized dystonia. Both patients had a positive family history of dystonia, but the patients and several family members tested negative for DYT1. Both patients benefited markedly from chronic bilateral DBS as was reflected in improvement of their dystonia scores. The mean preoperative BFM dystonia scores (81 B 14) were improved by 74% at 3 months postoperatively, by 75% at 1 year, and by 74% at 2 years postoperatively (p ! 0.05, respectively). Blepharospasm improved markedly in 1 patient; while eyes were closed about 90% of the day before the operation, at the 2-year follow-up blepharospasm was

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present for less than 10% during the day. Improvement of motor scores was paralleled by amelioration of disability, reflected by a mean improvement of 67% in the BFM disability score. In some patients with secondary dystonia, pallidal DBS was reported to be of no or only of little benefit [21, 38].

Pallidal DBS for Choreoathetosis

There is little contemporary experience with functional stereotactic neurosurgery for treatment of choreoathetosis. Pallidotomy has been used only in single centers, but it did not gain more widespread acceptance. Teo [44] reported that in a series of 24 patients of whom most underwent bilateral pallidotomy, 67% of patients reported subjective improvement, but objective improvement was seen in only 42%, and there was a high complication rate. Lin et al. [45] reported on limited benefit in secondary generalized dystonia and choreoathetosis after bilateral pallidotomy. Bilateral GPi DBS for choreoathetosis was described to be successful in two recent case studies. Excellent improvement of generalized choreoathetosis secondary to cerebral palsy was reported in a 13-year-old boy [20]. The patient presented with lifethreatening ‘dystonic storm’. Seven months postoperatively, there was only residual dystonia. Marked postoperative improvement of ‘hyperkinetic elements’ and moderate improvement of dystonia with pallidal DBS was noted in an 11-yearold boy with generalized choreoathetosis secondary to cerebral palsy [27]. In our experience, the effect of pallidal DBS in patients with choreoathetosis secondary to cerebral palsy has been more varied, and it was minimal or irrelevant in some patients. We have followed prospectively 4 patients with infantile cerebral palsy subsequent to various etiologies who underwent bilateral GPi DBS. Two patients thought they had achieved marked improvement 2 years postoperatively, while the 2 other patients thought they had no overall benefit from pallidal DBS. The mean preoperative BFM dystonia score for all patients (70.5 B 21) was improved by 12% at 3 months postoperatively, by 29% at 1 year, and by 23% at 2 years postoperatively, the differences being not statistically significant (p 1 0.05, respectively). Those 2 patients who rated their subjective improvement as marked had a minor but stable improvement of 12% in the BFM disability score at 2 years postoperatively, while there was no change in disability scores in the other 2 patients. The discrepancy between objective and subjective ratings is remarkable, and may indicate that little improvement can mean a lot for these severely handicapped patients who are barely able to take care of themselves preoperatively. Clearly, more experience is needed before GPi DBS can be recommended for treatment of choreoathetosis.

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Pallidal DBS for Hemidystonia

Hemidystonia usually is a manifestation of secondary dystonia. It has been shown to respond favorably to thalamic lesioning in the past with a long-lasting improvement in individual patients [11]. There is much less experience with pallidal surgery in these patients. Pallidotomies were ineffective in several instances of hemidystonia [43, 46]. In single instances, however, pallidal DBS was noted to achieve valuable benefit. We have reported long-term follow-up on a patient who underwent pallidal stimulation for treatment of posttraumatic hemidystonia [22]. The patient had developed left-sided low-frequency tremor and hemidystonia after severe head injury. He had relief of his tremor after a thalamotomy, but not of the hemidystonia. At age 24, he underwent DBS of the right posteroventral GPi. Chronic stimulation resulted in remarkable improvement of dystonia-associated pain, phasic dystonic movements, and dystonic posture, which was paralleled by functional gain. At a recent follow-up, 6 years postoperatively, improvement was sustained. Similar amelioration of hemidystonia has been observed in 2 other patients by the Grenoble group [31].

Pallidal DBS for Meige Syndrome and Other Focal Dystonias

The excellent improvement of blepharospasm in one of our patients with DYT1 negative dystonia raises hope that pallidal DBS might also be beneficial for patients with isolated blepharospasm or Meige syndrome. Cranial dystonias also were described to be alleviated in other patients with generalized or segmental dystonia who underwent pallidal DBS. In a pilot study, we have performed bilateral pallidal DBS in a patient with Meige syndrome who benefits from continued improvement at 21 months postoperatively. The exploration of DBS for treatment of Meige syndrome and other focal dystonias will be an exciting task for the future.

Thalamic DBS for Dystonia

Thalamic DBS might be considered an alternative treatment option in patients with secondary dystonia and choreoathetosis. Data published on DBS thus far, however, do not allow us to give any recommendations regarding patient selection or the choice of the target within the thalamus (table 2). Sellal et al. [36] were the first to report the effect of thalamic stimulation for treatment of hemidystonia. Unilateral stimulation in the contralateral somatosensory thalamus resulted in excellent improvement of posttraumatic hemidystonia in a 16-year-

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old boy. Before the advent of pallidal DBS, patients with medically intractable dystonia underwent thalamic DBS in Grenoble. The experience accumulated over the years showed that overall mean BFMDMS scores were unchanged, but that nevertheless about half of the patients achieved a good functional result [31]. Recently, a patient with severe postanoxic dystonia and bilateral necrosis of the basal ganglia was reported to have major improvement 4 months after bilateral thalamic DBS [38]. Previous pallidal stimulation had been unsuccessful. In a patient with essential myoclonic dystonia, thalamic DBS resulted in marked improvement of myoclonus scores, but not of dystonia [29]. We have reported our experience with chronic stimulation of the ventrointermediate thalamus in a patient with dystonic paroxysmal nonkinesigenic dyskinesia [37]. This patient, a 37-year-old man, had a 4-year history of severe and painful paroxysmal dystonia of the right arm. Chronic stimulation resulted in a decrease of the frequency, duration, and intensity of the paroxysmal movement disorder. These positive results were maintained over the 4 years of follow-up.

Future Perspectives

Regarding the relatively low risk of side effects with bilateral DBS, it is likely that DBS will replace pallidotomy for treatment of generalized dystonia in the near future. Thus far, the cost of DBS in dystonia patients has been a limiting factor for the more widespread use of this new technology. The relatively frequent replacements in dystonia patients who, in general, are much younger than PD patients are chiefly responsible for the high costs of this therapy for dystonia in the long run. Newer IPGs are supposed to be useful in prolonging battery life with linear power consumption throughout the voltage range. The development of new hardware such as rechargeable pacemakers would be desirable for the treatment of dystonia. The possible role of components of the basal ganglia circuitry which are not commonly included in the present diagrams on the pathophysiology of movement disorders have to be considered in dystonia, both with regard to etiology and possibly also with regard to treatment. In particular, the thalamic center medianparafascicular (CM-Pf) complex and the interstitial nucleus of Cajal (INC) may be of interest. The CM-Pf has multiple connections with other basal ganglia components, and constitutes one of the ‘forgotten’ thalamic nuclei [47]. It has been the target for lesioning surgery for a variety of movement disorders, previously, mostly in combination with other targets, and it has been shown that CM-Pf DBS for treatment of neuropathic pain may have an impact on concomitant movement disorders [48]. Klier et al. [49] have recently demonstrated that the INC acts as a midbrain neural integrator, not only for eye movements but also for head orienta-

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tion. The INC inputs include signals from the vestibular apparatus while the interstitiospinal tract that controls neck muscles is a key output. In an experimental setting in macaque monkeys, it was found that inactivation of the INC caused head-tilt toward the opposite side, whereas stimulation produced a same-sided tilt. The authors suggested that disorders which affect the bilateral balance of INC activity, either by direct damage or by imbalance of input, could be involved in the pathophysiology of CD. These findings are reminding of the human studies in the 1970s by Sano et al. [50] who tried to use the INC as a target for treatment of CD. INC lesioning appeared to be beneficial in some patients but it was abandoned later on. Pallidal DBS most likely will become the mainstay in the surgical treatment of disabling and medically refractory dystonia within the next few years. Due to the rarity of dystonia it is important to document the outcome of surgery within the frame of carefully planned studies.

Disclosure Joachim K. Krauss is a consultant to Medtronic.

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Krauss

Stereotact Funct Neurosurg 2002;78:183–191 DOI: 10.1159/000068962

Deep Brain Stimulation for Dystonia Surgical Technique

Philippe Coubes a Nathalie Vayssiere a Hassan El Fertit a Simone Hemm a Laura Cif a Jacques Kienlen b Alain Bonafe c Philippe Frerebeau a Departments of a Pediatric Neurosurgery (Research Group on Movement Disorders in Children), b Anesthesiology and c Neuroradiology, Centre Gui de Chauliac, Montpellier University Hospital, Montpellier, France

Key Words Dystonia W Brain stimulator W Deep brain stimulation W GPi stimulation

Abstract Stimulation electrodes are implanted under general anesthesia, without intra-operative electrophysiology or clinical testing, based only on stereotactic MRI and direct anatomical localization of the postero-ventro-basal GPi. We retrospectively analyzed the surgical procedure that has been designed and implemented in our center, using the Leksell G frame, for initiating deep brain stimulation in 65 dystonic patients. We report the surgical technique and the hardware and software complications. We recommend immediate postoperative stereotactic MRI under general anesthesia as a prerequisite to check the reliability of MR acquisition (magnet stability) and the exact localization of each electrode. This technique allowed us to reduce the duration of the operation to 4 h, including general anesthesia, frame fixation, MRI acquisition, implantation of two electrodes under radioscopic control, immediate postoperative stereotactic MRI and frame removal. Surgery-related morbidity was very low with a 0% hemorrhage rate and three delayed unilateral infections re-operated 6 months later. Hardware and software complications were rare. The advances in 3D-MR imaging permit the

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Philippe Coubes, MD, PhD Neurochirurgie B, Centre Gui de Chauliac CHU Montpellier F–34295 Montpellier Cedex 5 (France) E-Mail [email protected]

electrode implantation for deep brain stimulation without resorting to intraoperative localization techniques, which is especially helpful in children and for treating dystonia. The maximum follow-up period is 58 months (first case: November 1996). GPi stimulation has proven to be an effective treatment for most dystonic syndromes with particular efficacy in the disease due to the DYT1 mutation. Copyright © 2002 S. Karger AG, Basel

Introduction

Chronic deep brain stimulation (DBS) has proven over the past 10 years to be an efficient and safe treatment of movement disorders in Parkinson disease and, most recently, of most dystonic syndromes [1, 2]. The different targets to be stimulated are the same that have been used for lesional surgery [1, 3–5]. There is presently neither consensus about the respective specificity of each target nor about the technique for electrode implantation. In our center, considering the young age, the poor general condition, and the permanent restless situation of most patients presenting with movement disorders, especially children, we developed a stereotactic procedure under general anesthesia to be completed during a 1-day, single session procedure [6–11]. It is based solely on 3D-MR imaging for target localization without intra-operative microelectrode recording or clinical control, allowing the procedure to be shortened to 1 h per electrode. We describe the surgical methodology which has been developed in our center for the management of dystonic patients.

Patients and Methods First Operation: Stereotactic Implantation of Two Electrodes Fixation of the Leksell G-Frame Under general anesthesia, the hair is shaved transversally in a 1-cm-wide, 16-cm-long line, just in front of the coronal suture. The Leksell G-frame is first stabilized using ear plugs (second hole) and then fixed to the patient’s head, using constant settings of the fixation posts. The variety of exchangeable front pieces provide sufficient flexibility (Elekta Instruments, Stockholm, Sweden) to assure a good fit. This procedure aims at a reproducible, symmetrical and optimal positioning of the frame on the patient’s head to align the inferior side of the localizer as parallel as possible to the AC-PC plane. This appeared to be important for the localization of the axial-transverse plane (raw data) in which the image of the target was selected without any supplementary reconstruction.

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Table 1. MRI acquisition protocol

Head first Patient position Landmark Coil Scan plane Image mode Pulse sequence

Imaging options

Scan timing

Scan setup

Scanning range Acquisition matrix Frequency direction Phase FOV Imaging time Contrast

supine on the frame head coil axial 3D SPGR variable bandwidth extended dynamic range graphic RX flip angle: 25° TE: 9.0 ms TR: 29.0 ms pre-scan options auto-shim auto CF water receive bandwidth: 15.63 kHz scan thickness: 1.5 mm number of scan locs: 124 (frequency): 256 (phase): 256 A/P 1.00 26 cm 1 Nex 16.43 no

The MRI localizer is then fixed to the frame after having been filled-up with copper sulfate and checked for absence of air bubbles just before acquisition. Magnetic Resonance Acquisition Stereotactic MR imaging is performed on a 1.5-tesla MR unit (General Electric, Paris, France). One 3D-SPGR sequence is implemented without injection of gadolinium (table 1). Images are transmitted to a separated computer through an Ethernet network. Reconstruction is performed on a graphic card of 8 Mb. Since the 256 ! 256 matrix produces 124 images, 1.5-mm-thick sections were chosen to cover the whole cerebral volume.

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Software for Surgical Planning We used the stereotactic software developed by the departments of neuroradiology (Pr. Cordoliani) and neurosurgery (Pr. Desgeorges) in the Val de Grâce hospital, Paris [12, 13]. This software provides an excellent display of the brain on a Sun-Vax station and allows quick and reproducible target coordinate calculation. It meets, in our opinion, the criteria for suiting the requirements of a high-quality stereotactic operation solely based on MR imaging. Control of Distortion Control studies used to assess the homogeneity of the main magnetic field and the calibration of the gradients were obtained the day before the stereotactic operation, according to European standards. The procedure included a control with a quality-assessment phantom and Quick Shim software, under the responsibility of the maintenance department of General Electric, France. For evaluating the accuracy of MR imaging when the frame is fixed in the head-coil, we designed a complementary simple procedure using the G-frame localizer as a phantom [11]. We checked that 3D-MR imaging of the localizer was consistent with its actual dimensions (120–190 mm) and angles (cubic volume). With the stereotactic software measurement distance function, we calculated the mean distance between fiducial markers. These measurements were made routinely on the axial slice on which the target was to be chosen. The difference between the measured and theoretical distance (dt – dm) was designated as error. The error has to be less than twice the pixel size (2 mm) in order to accept the acquisition as reliable enough to determine the target coordinates. To calculate the error caused by distortion in the center of the FOV, the coordinates of the AC and PC, as well as the AC-PC distance (distance between the corresponding midpoints), were calculated and compared pre- and postoperatively. Target and Trajectory Determination from 3D-MR Imaging The software allowed simultaneous visualization of the three orthogonal sections and the position of the cursor in all directions, as well as the trace of a vector linked to the point that defined the trajectory. The best electrode trajectory was selected after varying the planes and orientations according to anatomical landmarks. The corresponding line was then displayed point by point in the cerebral volume. The neurosurgeon selected the target by using a 3D-cursor, following visual recognition of the GPi boundaries on the 1.5-mm-thick transverse axial section including the inferior border of the anterior commissure. On this slice, the GPi appears as an ellipse whose long axis can be divided into four equal parts. From the front, the center of the third quarter was the target. The coordinates were then automatically calculated by the software (Val de Grâce Hospital, Paris, France). Coordinate calculations were performed without reference to an atlas [14]. The trajectory was drawn from this point to the coronal suture on the sagittal plane which includes the target. This action modifies the final localization of the two inferior contacts when the middle of the electrode array is coincident with the target. The target lies in the extreme posteroventrolateral part of the GPi, just above the outer optic tract, which superimposes it closely with the ansa lenticularis. At the end, the final coordinates are fixed when the trajectory intersects exactly the center of the target volume as displayed on recon-

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structed images along the electrode axis. The procedure is repeated until an optimal electrode position is obtained. First Operation: Surgical Procedure The patient lies supine, and the Leksell frame is secured to the patient’s head. The multipurpose arch is fixed to the frame, and the coordinates and angles are set and doublechecked. A transverse curved incision is made exposing the coronal suture. Two 14-mm burr holes are made. A cruciate small incision of the drug allows sufficient visual control of the cortex. A small corticotomy is performed using the bipolar coagulator. The fixation system (Medtronic, Minneapolis, Minn., USA) is adjusted and the twopiece hollow guide (2.1-mm diameter) slowly lowered to the target. The electrode is an MR compatible quadripolar device on which the contacts are numbered as follows: lower contact = 0; upper contact = 3 (model: 3389, Medtronic, RueilMalmaison, France). The upper border of contact 1 is strictly aligned with the target position and secured under continuous radioscopic control. The temporary extension was cut and left under the galea, close to the lateral extremity of the incision, so it must easily be found during the second operation (connection to the IPG). Post-Operative Stereotactic MRI Control Immediately after surgery, the patient is again transported to the MR unit and a control study is obtained with the stereotactic frame on, which allows one to check the electrode position and to measure the possible error, using the same imaging protocol as that used for the planning [11].

Second Operation: Internal Pulse Generator (IPG) Implantation The second operation is performed separately on the 5th day, also under general anesthesia. The connector is found through the first incision. The 95-cm extension (Medtronic) connects the electrode with the IPG (Itrell II or III or Kinetra, Medtronic). The residual length is enrolled behind the IPG to compensate for growth in children and to provide some flexibility with movements in the system. Electrical Settings The following settings were first implemented: contact 1 as cathode, stimulator as anode, rate 130 Hz, pulse width 450 Ìs, voltage 0.8 V continuous bilateral stimulation. The settings were then adapted by progressively increasing the voltage according to the clinical response to reach a mean value of 1.6 V. If necessary, after 6 weeks the volume to be stimulated may be increased by activating an additional contact (usually contact 2). It is recommended not to modify the medical treatment at the initial phase of stimulation in order not to interfere with the evaluation of dystonia.

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Results

Surgical Experience Between November 1996 and April 2002, 65 patients (31 men and 34 women) from 6 to 63 years of age (average age, 21.13 years) underwent bilateral electrode implantation for continuous stimulation of the GPi [6–10]. For precise assessment of therapeutic efficacy, each patient was evaluated using the BurkeMarsden-Fahn dystonia rating scale (BMFDRS) [15–17] pre- and postoperatively, at given intervals, and at the latest follow-up. From this series, we selected the group of 32 patients for which a 2-year follow-up could be studied. All suffered from primary generalized dystonia (17 girls, 20 children). At the time of surgery, all patients were severely disabled and could not perform daily activities. The mean BMFDRS score, indicating the extent and the severity of the disease, was 58.7 B 22.5. All patients were under pharmaceutical treatment with various medications (benzodiazepine, anticholinergic drugs, L-DOPA). All patients or their guardians gave written informed consent. The protocol was approved by the French National Ethical Committee (reference No. 98.07.02). Complications We observed 3 cases of delayed unilateral infection around the device (Staphylococcus epidermidis). The whole system had to be explanted under general anesthesia in 1 patient, and only the IPG for the 2 others. The patients were re-operated 6 months later with subsequent excellent clinical improvement. One patient suffered a head trauma, with a post-traumatic fracture of both electrode and extension due to a direct blow to the connector, which was visible in the wound. In another case, a re-operation was performed in anticipation of a skin opening after a skin erosion had been detected during the monthly control. No electrode migration was noticed. No surgery-related hemorrhage and no case of hardware malfunction was found. The most frequent software complication was the unexpected and unexplained IPG switch-off resulting in every case in a quick worsening of the dystonic symptoms. Clinical Results The evolution of the clinical score of the Burke-Marsden-Fahn Dystonia Rating Scale (BMFDRS) is reported for the 32 patients separated into two groups: group 1 (primary generalized dystonia, PGD, due to the DYT1 mutation) and group 2 (PGD of unknown etiology) (table 2). In both groups, the improvement is highly significant (p ! 0.01).

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Table 2. Clinical scores (BMFDRS) of 32 dystonic patients treated by DBS Clinical score

Before surgery (n = 32) /120

3 months after surgery (n = 32) /120 (%)1

6 months after surgery (n = 32) /120 (%)1

1 year after surgery (n = 26) /120 (%)1

2 years after surgery (n = 12) /120 (%)1

PGD2 DYT1+3 PGD2 DYT1–

60.8B22.7 56.8B21.7

21.3B21.1 (65) 17.8B10.1 (65)

10.8B10.5 (83) 18.2B12.2 (67)

14.1B16.8 (71) 15.1B12.0 (74)

6.8B8.3 (93) 13.5B7.5 (84)

All

58.7B22.5

19.8B15.2 (65)

15.0B11.5 (74)

14.7B14.3 (73)

10.1B9.6 (88)

Mean values B SD. The values in parentheses represent the mean improvement in percent. A reduction in the score indicates an improvement in function. BMFDRS denotes Burke-Marsden Fahn’s Dystonia Rating Scale. 1 The improvement in percent is calculated based on the maximal possible gain (Score preop – Scorepostop)/ (Scorepreop). 2 Primary generalized dystonia. 3 DYT1 mutation.

Table 3. Functional scores (BMFDRS) of 32 dystonic patients treated by DBS Functional score

Before surgery (n = 32) /30

3 months after surgery (n = 32) /30 (%)1

6 months after surgery (n = 32) /30 (%)1

1 year after surgery (n = 26) /30 (%)1

2 years after surgery (n = 12) /30 (%)1

PGD2 DYT1+3 PGD2 DYT1–

16.7B5.2 16.4B7.4

9.1B7.5 (40) 11.4B6.9 (35)

5.8B5.6 (62) 10.5B7.1 (40)

5.7B5.4 (63) 9.5B6.6 (49)

1.2B1.6 (95) 11.2B3.8 (57)

All

16.5B6.4

10.3B7.2 (39)

8.8B6.9 (49)

7.7B6.5 (55)

6.2B5.2 (76)

Mean values B SD. The values in parentheses represent the mean improvement in percent. A reduction in the score indicates an improvement in function. BMFDRS denotes Burke-Marsden Fahn’s Dystonia Rating Scale. 1 The improvement in percent is calculated based on the maximal possible gain (Score preop – Scorepostop)/ (Scorepreop). 2 Primary generalized dystonia. 3 DYT1 mutation.

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The difference in the functional pre- and postoperative scores (BMFDRS) is also highly significant (table 3). We did not find a significant difference of the overall improvement in children (functional: 75%; clinical: 90%) when compared to adults (functional: 82%; clinical: 84%) (p 1 0.01).

Conclusion

Our data demonstrate that a MR imaging-based operation can be considered reliable for target localization on the basis of real-time and continuous quality control procedures at every step of the surgery. In a series of 65 patients, a very low morbidity and a clear efficacy of GPi stimulation is reported, which is a conservative, adaptable and reversible method for treating most cases of severe intractable dystonia. Blinded control study was very difficult to envisage, especially in children, and probably not acceptable in all cases from an ethical point of view.

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Hariz MI: Decrease in akinesia seems to result from chronic electrical stimulation in the external (GPe) rather than internal (Gpi) pallidum. Mov Disord 1999;14:536–540. Benabid AL, Benazzouz A, Hoffmann D, Limousin P, Krack P, Pollak P: Long-term electrical inhibition of deep brain targets in movement disorders. Mov Disord 1998;13(suppl 3):119–125. Laitinen LV: Brain targets in surgery for Parkinson’s disease: Results of a survey of neurosurgeons. J Neurosurg 1985;62:349–351. Laitinen LV, Bergenheim AT, Hariz MI: Ventroposterolateral pallidotomy can abolish all parkinsonian symptoms. Stereotact Funct Neurosurg 1992;58:14–21. Burns JM, Wilkinson S, Kieltyka J, Overman J, Lundsgaarde T, Tollefson T, Koller WC, Pahwa R, Troster AI, Lyons KE, Batnitzky S, Wetzel L, Gordon MA: Analysis of pallidotomy lesion positions using three-dimensional reconstruction of pallidal lesions, the basal ganglia, and the optic tract. Neurosurgery 1997;41:1303–1316; discussion 1316–1318. Coubes P, Echenne B, Roubertie A, Vayssiere N, Tuffery S, Humbertclaude V, Cambonie G, Claustres M, Frerebeau P: Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus: A propos of a case. Neurochirurgie 1999;45:139–144. Coubes P, Roubertie A, Vayssiere N, Hemm S, Echenne B: Treatment of DYT1-generalised dystonia by stimulation of the internal globus pallidus. Lancet 2000;355:2220–2221. Coubes P, Cif L, Azais M, Roubertie A, Hemm S, Diakonoya N, Vayssiere N, Monnier C, Hardouin E, Ganau A, Tuffery S, Claustre M, Echenne B: Traitement des syndromes dystoniques par stimulation électrique chronique du globus pallidus interne. Arch Pediatr 2002:9(suppl 2):84s–86s. Hemm S, Cif L, Monnier C, Diakonova N, Hardouin E, Ganau A, Vayssiere N, Roubertie A, Azais M, Tuffery S, Mansour M, Claustres M, Echenne B, Coubes P: Dystonies généralisées primitives: Traitement par stimulation électrique chronique du globus pallidus interne. Mouvements 2001;8: 4–13. Roubertie A, Echenne B, Cif L, Vayssiere N, Hemm S, Coubes P: Treatment of early-onset dystonia: Update and a new perspective. Childs Nerv Syst 2000;16:334–340.

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Vayssiere N, Hemm S, Zanca M, Picot MC, Bonafe A, Cif L, Frerebeau P, Coubes P: Magnetic resonance imaging stereotactic target localization for deep brain stimulation in dystonic children. J Neurosurg 2000;93:784–790. Derosier C, Buee C, Ledour O, Horf F, Desgeorges M, Cosnard G: MRI and stereotaxis: Choice of an approach route on an independent console. J Neuroradiol 1991;18:333–339. Dormont D, Cornu P, Pidoux B, Bonnet AM, Biondi A, Oppenheim C, Hasboun D, Damier P, Cuchet E, Philippon J, Agid Y, Marsault C: Chronic thalamic stimulation with three-dimensional MR stereotactic guidance. Am J Neuroradiol 1997;18:1093–1107. Vayssiere N, Hemm S, Cif L, Picot MC, Diakonova N, El Fertit H, Frerebeau P, Coubes P: Comparison of atlas- and magnetic resonance imaging-based stereotactic targeting of the globus pallidus internus in the performance of deep brain stimulation for treatment of dystonia. J Neurosurg 2002; 96:673–679. Burke R, Fahn S, Marsden C: Validity and reliability of a rating scale for primary torsion dystonia. Neurology 1985;35:73–77. Fahn S: The varied clinical expression of dystonia. Neurol Clin 1984;2:541–553. Fahn S: Concept and classification of dystonia. Adv Neurol 1988;50:1–8.

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Stereotact Funct Neurosurg 2002;78:192–196 DOI: 10.1159/000068965

Transcranial Magnetic Cortical Stimulation Relieves Central Pain S. Canavero V. Bonicalzi M. Dotta S. Vighetti G. Asteggiano D. Cocito Pain Relief Unit, Department of Neurosciences, Molinette Hospital, Turin, and Service of Clinical Neurophysiology, City Hospital, Alba, Italy

Key Words Central pain W Transcranial magnetic stimulation W Motor cortex stimulation W Propofol

Abstract Extradural cortical stimulation for neurogenic pain is a recent addition to the field of functional neurosurgery. About 50% of patients with central pain draw benefit in the long run. However, there is an urgent need for prognostic factors in order to cut the costs of the procedure. In this paper we report a statistically significant correlation between the subhypnotic propofol test, transcranial magnetic cortical stimulation (TMS) and the actual short-term outcome of extradural cortical stimulation in 9 patients. The propofol test and TMS appear to predict short-term effects of extradural cortical stimulation. Copyright © 2002 S. Karger AG, Basel

Introduction

Extradural motor cortex stimulation (MCS) is known to allay central pain (CP) [1]. Yet, not all series found a benefit and in several cases this was soon lost [1]. In 1995, Migita et al. [2] reduced CP in 1 patient but not in another with single-pulse transcranial magnetic cortical stimulation (TMS). TMS is a tech-

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S. Canavero, MD Via Montemagno, 46 I–10132 Torino (Italy) Tel./Fax +39 011 819 3776 E-Mail [email protected]

nique currently employed for both diagnostic and therapeutic purposes [3]. In 1998, we reported that TMS can allay both CP (5 patients) and neuropathic pain (4 patients) [4]. These results have been confirmed [5–7]. We submitted 9 new patients suffering CP to TMS in order to correlate this with the propofol test, a procedure known to predict short-term benefit of MCS [1]. The propofol test is cheaper than TMS and widely available.

Patients and Methods Between March 2001 and May 2002, 9 patients suffering CP were treated with TMS. There were 3 women and 6 men (age range: 40–66). Their CP was due to brain ischemia (1), brainstem ischemia (1), both (1), thalamic hemorrhage (2), spinal cord ischemia (1), spinal cord injury (2), or syringomyelia (1). Their syndromes fulfilled IASP criteria for CP. Maximal pain was generally referred to the upper or lower limbs. After obtaining written informed consent, these patients were assessed for quality and intensity of their pain and presence of allodynia. Intensities were rated on a Visual Analog Scale and Numerical Rating Scale. Each patient was submitted to TMS with a Magstim Bistim module (Spring Gardens Wales, UK) which delivers 90% of maximal power of the Model 200 unit which we performed our previous study [7]. Two trains of 10 stimuli at maximal power (100% of machine capability) with a maximal frequency of 0.2 Hz and an intertrain interval of 10 s (time for intermodule switch) were delivered to the motor cortex contralateral to the pain. The arm or leg areas were identified anterior to the scalp projection of the rolandic fissure [1], and motor responses were sought by visual inspection of the patient’s movements. Stimulation was applied where the strongest responses were obtained. A figure-of-eight and a double-cone coils were used, respectively, for arm and leg stimulation. Pain was assessed by a VAS/NRS scale starting at the end of the first train, then every 10 min for an hour; the presence of allodynia was specifically explored. Patients were instructed to self-assess their pain and presence of allodynia for the following 24 h. In responsive cases, a placebo effect was excluded by sham stimulation of the contralateral side (same parameters as above). It was explained that, even though motor responses could be elicited on the unaffected limbs, pain elaboration in the brain took place in both hemispheres and thus that both sides had to be explored. Prior to TMS, all patients submitted to a propofol test (0.2 mg/kg i.v. bolus) and placebo match (see full description in ref. [8]). Propofol is completely cleared from the bloodstream in about 5 min, and in these patients all benefits for pain disappeared within 30 min during which pain was assessed. Efficacy of both TMS and propofol was broken down into 4 categories: no relief (0– 25% reduction), fair (26–50% reduction), good (51–75% reduction), and excellent (76– 100% reduction). A test had to produce at least 26% pain reduction to be considered positive. An a priori 15% difference between results from the two tests is considered acceptable in this preliminary study, as it would not interfere with patients’ management. The strength of correlation between pain relief obtained with the propofol test and TMS was accessed with the non-parametric Spearman rank correlation coefficient. The agreement between the two methods was assessed with the Bland-Altman method [9]. In all cases, p ! 0.05 was considered significant.

Transcranial Magnetic Cortical Stimulation Relieves Central Pain

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Fig. 1. Correlation of pain relief.

Results

Sham stimulation was always ineffective. Two patients were temporarily worsened by TMS stimulation, 3 patients obtained no benefit (0–25%), 1 had his allodynia but not his spontaneous pain totally abolished for about 30 min, while 3 had both spontaneous pain and allodynia relieved (2 fair, 1 good). In these last 3 patients, relief lasted, respectively, for less than 1 h, 4 h and 16 h. There was no difference in the non-responders in terms of pain localization compared to responders (i.e. upper and lower limbs were equally distributed in the two groups). Patients who had their pain worsened returned to baseline within 30 min. No epileptic seizures were elicited. The procedure was well tolerated by all patients. The propofol test, but not placebo, reduced the pain and/or allodynia in the same patients as TMS (it abolished allodynia but not spontaneous pain: 1 patient; fair 2; good 1), while it had no effect in the others. The strength of correlation between propofol test and TMS was significant (Spearman rank correlation coefficient, r = 0.892, p = 0.002; fig. 1). The BlandAltman analysis demonstrates a good agreement between the two tests (fig. 2). One patient who obtained no benefit and one who obtained fair relief went on to implantation of an extradural motor cortex stimulator (RESUME, Med-

194

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Canavero/Bonicalzi/Dotta/Vighetti/Asteggiano/ Cocito

Fig. 2. Bland-Altman curve.

tronic Inc., Minneapolis, Minn., USA) (see description of procedure in ref. [1]). The same results were observed at short-term follow-up (no effect and fair relief).

Discussion

TMS may partially and temporarily relieve CP up to 16 h. Unlike previous studies [2, 6–7], we specifically assessed any possible effects on allodynia and observed that TMS may reduce allodynia but not spontaneous pain. Pain was reduced with our protocol despite a much lower frequency, as observed by the French group [6, 7] with rTMS. Likely, the different power outputs of the Bistim Set-up (and also the Model 200) are to be allowed for. How TMS works to allay pain is a matter of speculation. It is possible, in view of the correlation with propofol, a GABA A agonist, that TMS brings about a GABA-mediated renormalization of cortical activity. Our preliminary data in 2 patients plus another from our previous series [4] suggest that there exists a correlation between relief by TMS and MCS, although the magnitude of relief may not be the same. Importantly, in our series, responsiveness to the propofol test [8]

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predicted response to TMS. If confirmed, this might spare the patient the TMS trial before surgical MCS. In fact, we found that TMS analgesia may be 17.5% below or 4.1% greater than the propofol test, which would be acceptable for such clinical purposes. In conclusion, this preliminary study shows that both propofol and TMS may temporarily reduce central pain in some patients and might also predict which patients will obtain benefit from MCS.

References 1 2 3 4

5 6 7

8

9

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Canavero S, Bonicalzi V: Therapeutic extradural cortical stimulation for central and neuropathic pain: A review. Clin J Pain 2002;18:48–55. Migita K, Uozumi T, Arita K, Monden S: Transcranial magnetic coil stimulation of motor cortex in patients with central pain. Neurosurgery 1995;36:1037–1040. Wassermann EM, Lisanby SH: Therapeutic application of repetitive transcranial magnetic stimulation: A review. Clin Neurophysiol 2001;112:1367–1377. Canavero S, Bonicalzi V, Paolotti R, Cerutti A: Extradural cortical stimulation for neurogenic pain and Parkinson’s disease: The Turin experience. Proc 4th Int Congr International Neuromoulation Society, Luzern, 1998. Reid P, Pridmore S: Improvement in chronic pain with transcranial magnetic stimulation. Aust NZ J Psychiatry 2001;35:252. Lefaucheur J-P, Drouot X, Keravel Y, Nguyen J-P: Pain relief by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport 2001;12:2963–2965. Lefaucheur J-P, Drouot X, Nguyen J-P: Interventional neurophysiology for pain control: Duration of pain relief following repetitive transcranial magnetic stimulation of the motor cortex. Neurophysiol Clin 2001;31:247–252. Canavero S, Bonicalzi V, Pagni CA, Castellano G, Merante R, Gentile S, Bradac GB, Bergui M, Benna P, Vighetti S, Coletti Moia M: Propofol analgesia in central pain: Preliminary clinical observations. J Neurol 1995;242:561–567. Bland JM, Altman DG: Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;i:307–310.

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Author Index Vol. 78, 2002 (B) = Book Review

Hariz, M.I. 146 Heinze, H.-J. 3 Hemm, S. 183 Heywood, P. 132 Honey, C.R. 49

Asteggiano, G. 192 Aziz, T.Z. 158 Berk, C. 49 Bonafe, A. 183 Bonicalzi, V. 192 Bulsara, K.R. 53

Jiang, R. 84

Canavero, S. 192 Chu, W.F. 39 Cif, L. 183 Cocito, D. 192 Coubes, P. 183 Couldwell, W.T. 95

Kanowski, M. 3 Karger, S. 2 Karger, T. 2 Kienlen, J. 183 Kocuj, F. 29 Krauss, J.K. 168

Das, K. 95 Dotta, M. 192

Lee, J.S. 39 Liu, Z. 84 Love, S. 132

El Fertit, H. 183 Epple, J. 29

McGirt, M.J. 53 Martin, E. 29 Mita, S. 64

Fan, F.Y. 70 Frerebeau, P. 183 Gildenberg, P.L. 113 (B), 114 (B) Gill, S.S. 132 Gorecki, J. 53 Goto, S. 64 Guo, W.Y. 39 Guo, Y. 70

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Nandi, D. 158 Nishikawa, S. 64 O’Sullivan, K. 132

Roberts, D.W. 1 Rosenow, J. 95 Rotte, M. 3 Rovit, R.L. 95 Shi, M. 70 Song, S.J. 70 Stein, J.F. 158 Tronnier, V.M. 29 Ushio, Y. 64 Vayssiere, N. 183 Vighetti, S. 192 Villavicencio, A.T. 53 Vitek, J.L. 119 Wang, L.G. 70 Wei, L.C. 70 Williams, J.A. 17 Wu, H.M. 39 Wu, T.H. 39 Xia, J.L. 70 Zhang, X. 70 Zhu, C. 84

Patel, N.K. 132 Polarz, H. 29

© 2002 S. Karger AG, Basel

Accessible online at: www.karger.com/sfn

197

Subject Index Vol. 78, 2002

Acoustic neuroma 17 Akinesia 158 Biopsy, percutaneous 49 Bleomycin 84 Brain 3 – metastases 70 – stimulator 183 Brainstem 158 Cavernous sinus 49 Central pain 192 Cerebellar stimulation 95 Cordotomy, percutaneous 53 Craniopharyngioma 84 Deep brain stimulation 95, 119, 132, 146, 168, 183 Direct targeting 132 Dystonia 168, 183 Foramen ovale 49 Fractionation 17 Geometric accuracy 39 Globus pallidus 64, 119 GPi stimulation 183 Guide tubes 132 Hearing preservation 17

Microelectrode recording 146 Motor cortex stimulation 192 – system 3 Movement disorders 146 Nerve blocks 29 Neurosurgery 29, 70 – functional 168 Pain relief 53 Pallidotomy 64, 146 Pallidum 168 Parkinson disease 64, 119, 146 Pedunculopontine nucleus 158 Phosphorus-32 84 Primate 158 Propofol 192 Radiosurgery 17, 39, 70 Radiotherapy 17 – whole brain 70 Stereotactic 168 – X-ray imaging 39 Stereotaxy 29 – frameless 53 Stimulation, electrical 158 Subthalamic nucleus 119, 132 Subthalamotomy 132 Surgery, stereotactic 29, 146 Survival in metastatic brain tumor 70

Irving Cooper 95 Local anesthesia 29

Thalamotomy 64 Transcranial magnetic stimulation 192 Tremor 64

Magnetic resonance imaging 53, 132 – functional 3 – stereotactic 39

XKnife radiosurgery 70

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2002 S. Karger AG, Basel

Accessible online at: www.karger.com/sfn

Contents Vol. 78, 2002

84

No. 1 1

Jiang, R. (Tianjin); Liu, Z. (Beijing); Zhu, C. (Shanghai)

Editorial Roberts, D.W. (Lebanon, N.H.)

2

Publisher’s Note Karger, T.; Karger, S. (Basel)

Original Papers 3

Preliminary Exploration of the Clinical Effect of Bleomycin on Craniopharyngiomas

95

Irving S. Cooper and His Role in Intracranial Stimulation for Movement Disorders and Epilepsy Rosenow, J.; Das, K.; Rovit, R.L.; Couldwell, W.T. (Valhalla, N.Y./New York, N.Y.)

113 Book Reviews

Functional Magnetic Resonance Imaging for the Evaluation of the Motor System: Primary and Secondary Brain Areas in Different Motor Tasks

No. 3–4

Rotte, M.; Kanowski, M.; Heinze, H.-J. (Magdeburg) 17

Fractionated Stereotactic Radiotherapy for Acoustic Neuromas Williams, J.A. (Baltimore, Md.)

29

Nerve Blocks in Stereotactic Neurosurgery Kocuj, F.; Epple, J.; Polarz, H.; Tronnier, V.M.; Martin, E. (Heidelberg)

39

Evaluating Geometric Accuracy of Multi-Platform Stereotactic Neuroimaging in Radiosurgery Wu, T.H.; Lee, J.S.; Wu, H.M.; Chu, W.F.; Guo, W.Y. (Taipei)

49

Percutaneous Biopsy through the Foramen ovale: A Case Report Berk, C.; Honey, C.R. (Vancouver)

119 Deep Brain Stimulation for Parkinson’s Disease.

A Critical Re-Evaluation of STN versus GPi DBS Vitek, J.L. (Atlanta, Ga.) 132 MRI-Directed Subthalamic Nucleus Surgery for

Parkinson’s Disease Patel, N.K.; Heywood, P.; O’Sullivan, K.; Love, S.; Gill, S.S. (Bristol) 146 Safety and Risk of Microelectrode Recording in

Surgery for Movement Disorders Hariz, M.I. (Umeå) 158 Exploration of the Role of the Upper Brainstem in

Motor Control Nandi, D.; Stein, J.F.; Aziz, T.Z. (Oxford) 168 Deep Brain Stimulation for Dystonia in Adults.

Overview and Developments

No. 2

Krauss, J.K. (Mannheim) 183 Deep Brain Stimulation for Dystonia. Surgical

Original Papers 53

Technique

MRI-Guided Frameless Stereotactic Percutaneous Cordotomy McGirt, M.J.; Villavicencio, A.T.; Bulsara, K.R.; Gorecki, J. (Durham, N.C.)

64

Impact of Posterior GPi Pallidotomy on Leg Tremor in Parkinson’s Disease

Coubes, P.; Vayssiere, N.; El Fertit, H.; Hemm, S.; Cif, L.; Kienlen, J.; Bonafe, A.; Frerebeau, P. (Montpellier) 192 Transcranial Magnetic Cortical Stimulation Relieves

Central Pain Canavero, S.; Bonicalzi, V.; Dotta, M.; Vighetti, S.; Asteggiano, G.; Cocito, D. (Turin/Alba)

Goto, S.; Nishikawa, S.; Mita, S.; Ushio, Y. (Kumamoto) 70

Brain Metastasis: Experience of the Xi-Jing Hospital Wang, L.G.; Guo, Y.; Zhang, X.; Song, S.J.; Xia, J.L.; Fan, F.Y.; Shi, M.; Wei, L.C. (Xian)

© 2002 S. Karger AG, Basel Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/sfn_issues

197 Author Index Vol. 78, 2002 198 Subject Index Vol. 78, 2002