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Movement Disorders
Contents Preface
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Joseph Jankovic Etiology and Pathogenesis of Parkinson Disease
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Anthony H.V. Schapira The etiology of Parkinson disease (PD) is multifactorial and is likely to involve different causes in different patients. Several different genes have been identified as causes of familial PD, including alpha-synuclein gene mutations and multiplications, and mutations of parkin, PINK1, DJ1, and LRRK2. The biochemical consequences of these mutations have served to reinforce the relevance of the pathways to pathogenesis previously characterized, for example, mitochondrial dysfunction, oxidative stress, and protein misfolding and aggregation. The recognition that glucocerebrosidase mutations represent a significant risk factor for PD has focused attention on lysosomal function and autophagy as relevant to PD. Several environmental factors have also been shown to influence the risk for PD, although odds ratios remain relatively modest. Specific toxins can cause dopaminergic cell death in man and animals, but they probably have limited relevance to the etiology of PD. Medical Treatment of Parkinson Disease
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Mark Stacy The cardinal characteristics of Parkinson disease (PD) include resting tremor, rigidity, and bradykinesia. Patients may also develop autonomic dysfunction, cognitive changes, psychiatric symptoms, sensory complaints, and sleep disturbances. The treatment of motor and non-motor symptoms of Parkinson disease is addressed in this article. Surgical Treatment of Movement Disorders
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Benzi M. Kluger, Olga Klepitskaya, and Michael S. Okun Surgical approaches are an important consideration in the management of many movement disorders, particularly for patients refractory to medications. In this article, we review the history, pathophysiology, risks and indications for surgical treatment. Summaries of case studies, case series and clinical trials performed using deep brain stimulation are provided for Parkinson’s disease, dystonia, essential tremor and other movement disorders. Tremor: Clinical Features, Pathophysiology, and Treatment Rodger J. Elble Tremor is not understood completely, and pharmacotherapy for all tremor disorders is inadequate. Fortunately, deep brain stimulation is effective for
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the most common and disabling tremor disorders. Our understanding of pathologic tremors has increased at an accelerating pace during the past 30 years, and this will hopefully lead to improved pharmacotherapy in the near future.
Genetics and Treatment of Dystonia
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Cordelia S. Schwarz and Susan B. Bressman The torsion dystonias encompass a broad collection of etiologic subtypes, often divided into primary and secondary classes. Tremendous advances have been made in uncovering the genetic basis of dystonia, including discovery of a gene causing early onset primary torsion dystonia—a GAG deletion in exon 5 of the DYT1 gene that encodes torsinA. Although the exact function of torsinA remains elusive, evidence suggests aberrant localization and interaction of mutated protein; this may result in an abnormal response to stress or interference with cytoskeletal events and the development of neuronal brain pathways. Breakthroughs include the discovery of a genetic modifier that protects against clinical expression in DYT1 dystonia and the identification of the gene causing DYT6, THAP1. The authors review genetic etiologies and discuss phenotypes as well as counseling of patients regarding prognosis and progression of the disease. They also address pharmacologic and surgical treatment options for various forms of dystonia.
Huntington Disease and Other Choreas
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Francisco Cardoso Chorea is defined as a syndrome characterized by brief, abrupt involuntary movements resulting from a continuous flow of random muscle contractions. There are genetic and non-genetic causes of chorea. The most common genetic cause of chorea is Huntington’s disease (HD). Non-genetic forms of chorea include vascular choreas, auto-immune choreas, metabolic and toxic choreas, and drug-induced choreas. This chapter provides an overview of clinical features, pathogenesis and management of HD, other important genetic causes of chorea, Sydenham’s chorea, other autoimmune choreas and vascular choreas.
Tourette Syndrome Joohi Jimenez-Shahed Tourette syndrome (TS) is a neuro-developmental disorder of childhood that is often associated with various psychiatric morbidities. Timely diagnosis and appropriate management can significantly impact psychosocial functioning. Morbidities may be a major source of disability, and may determine ultimate prognosis, although most children will experience significant improvement or resolution of symptoms by adulthood. Additional management considerations must be made in those with TS symptoms persisting into adulthood. The mainstay of therapy remains dopamine receptor blocking drugs, but new therapies are emerging.
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Pathophysiology and Treatment of Myoclonus
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John N. Caviness Myoclonus is defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or inhibitions. Etiologic classification organizes the myoclonus disorders and provides major categories of clinical presentation. However, classifying myoclonus according to its source provides insight about its pathophysiology. The best strategy for symptomatic treatment is derived from defining the pathophysiology by way of source physiologic classification.
Restless Legs Syndrome
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William G. Ondo Restless legs syndrome (RLS) affects many people. General population prevalence surveys usually range from 1% to 12%, but most European ancestry studies suggest 10%. The development of validated rating scales and standardized diagnostic criteria have vastly improved the quality of RLS treatment trials. Although multiple medications have shown outstanding efficacy, all of them are felt to provide only symptomatic relief, rather than any ‘‘curative’’ effect. Dopamine agonists are clearly the best investigated and probably the most effective treatments for RLS.
Psychogenic Movement Disorders
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Elizabeth L. Peckham and Mark Hallett Psychogenic movement disorders (PMDs) represent a challenging dilemma for the treating neurologist. The terminology to classify this disorder is confusing and making the diagnosis is difficult. Once the diagnosis has been established, treatment options are limited, and the patient generally does not accept the diagnosis.
Peripherally Induced Movement Disorders
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Joseph Jankovic Peripherally induced movement disorders may be defined as involuntary or abnormal movements triggered by trauma to the cranial or peripheral nerves or roots. Although patients often recall some history of trauma before the onset of a movement disorder, determining the true relationship of the disorder to the earlier trauma is often difficult. The pathophysiology of these disorders is reviewed.
Index
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Movement Disorders
Preface
Joseph Jankovic, MD Guest Editor
Few neurologic disorders have attracted more attention from the scientific and lay communities than Parkinson disease and related neurodegenerative diseases. Advances in basic research into mechanisms of neuronal death, physiology of the basal ganglia, and biochemistry and pharmacology are now being translated into clinical practice. Despite extraordinary therapeutic advances during the recent past, Parkinson disease continues to be among the most common causes of disability, particularly among the elderly. In this issue of Neurologic Clinics, dedicated entirely to movement disorders, two articles, one by Dr. Schapira and another by Dr. Stacy, focus on the pathogenesis and medical treatment of Parkinson disease. Dr. Kluger and colleagues provide an update on surgical treatment, particularly deep brain stimulation, in Parkinson disease and other movement disorders. The clinical features, pathophysiology, and treatment of tremor, the most common movement disorder encountered in a movement disorders clinic, are reviewed by Dr. Elble. The remarkable progress in the understanding of the genetics of various dystonias and their treatment, including botulinum toxin, is reviewed by Drs. Schwarz and Bressman. Huntington disease, manifested by a combination of chorea, affective disorder, and cognitive decline, is reviewed by Dr. Cardoso. Although tetrabenazine has been used in the treatment of various hyperkinetic movement disorders for several decades, this monoamine depleter has recently become the first drug approved by the Food and Drug Administration for the treatment of chorea associated with Huntington disease. Tics and other features of Tourette syndrome, along with a review of possible pathophysiologic mechanisms and medical and surgical treatment, are discussed by Dr. JimenezShahed. In Dr. Caviness’s article, the pathophysiology and treatment of myoclonus are reviewed. Restless legs syndrome is one of the most common movement disorders in the general population; its pathogenesis and treatment are reviewed by Dr. Ondo. Some of the most challenging disorders, increasingly encountered in specialty clinics, are the psychogenic movement disorders, covered in some detail by Drs. Peckham and Hallett. In the last article, I review the clinical features and presumed pathophysiologic mechanisms of peripherally induced movement disorders, including hemifacial spasm,
Neurol Clin 27 (2009) ix–x doi:10.1016/j.ncl.2009.04.012 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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dystonia (with or without complex regional pain syndrome, previously referred to as reflex sympathetic dystrophy), tremor, and other disorders following peripheral injury. This comprehensive volume, written by a team of leading movement disorder neurologists, should be of interest not only to clinicians concerned with the care of those afflicted with Parkinson disease and other movement disorders, but also to clinical and basic investigators pursuing answers to some of the unanswered questions about the pathogenesis of this challenging group of disorders. The authors provide a broad and well-balanced review of the progress made in the understanding of this group of neurologic disorders. I would like to take this opportunity to thank Randolph Evans, MD, for his initial invitation and encouragements to edit this issue. I also thank Donald Mumford, Senior Developmental Editor and Editor of Neurologic Clinics at Elsevier, for his hard work, guidance, and professionalism. Finally, I wish to express my deep appreciation to all the authors who shared their knowledge and expertise by providing authoritative and comprehensive reviews of the assigned topics. Joseph Jankovic, MD Professor of Neurology Distinguished Chair in Movement Disorders Director Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, Texas 77030, USA E-mail address:
[email protected] (J. Jankovic)
Etiology and Patho genesis of Parkinson Dis eas e Anthony H.V. Schapira, MD, DSc, FRCP, FMedSci KEYWORDS Parkinson disease Alpha-synuclein Mitochondria Oxidative stress Proteosome Lewy body
Defining the epidemiology of Parkinson disease (PD) is confounded by several variables, which include the difficulty in diagnosis and the age dependence of the disease. Several studies have sought to define incidence. In the United States, the ageadjusted figure is 13.5 to 13.9 per 100,000 person years.1,2 The age-adjusted prevalence is approximately 115 per 100,000 and is estimated as 1.3 per 100,000 under age 45 years and 1192.9 per 100,000 in patients aged 75 to 85 years.1 A prevalence study in Holland found 3100 cases per 100,000 aged 75 to 85 years and 4300 per 100,000 for those older than 85 years.3 The geographic distribution of the disease appears similar across the United States and Japan, but failure to adjust population figures for age can lead to widely discrepant results, for example, prevalence of 10 per 100,000 in Nigeria.4 PD pathology is part of a multicentric neurodegenerative disease in which it is suggested that the appearance of morphologic abnormalities follows a specific sequence, beginning in the dorsal motor nucleus and in the olfactory bulbs and nucleus, followed by Lewy body formation in the locus ceruleus, and subsequently in the substantia nigra pars compacta (SNc).5 However, the relationship of the presence of the Lewy body to cell death is not yet defined. Neuronal cell loss in PD appears first in the dopaminergic cells of the SNc. This is associated with the appearance of the early motor features of PD and is the point at which a clinical diagnosis of PD becomes possible. It has been estimated that dopamine levels in the striatum are reduced to approximately 60% to 70% of normal values at the time of diagnosis. Imaging studies using positron emission tomography (PET) or single photon emission computerized tomography may demonstrate the asymmetric loss of posterior putaminal fluorodopa or dopamine transporter, respectively. Sequential imaging of PD patients suggests
University Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, UK E-mail address:
[email protected] Neurol Clin 27 (2009) 583–603 doi:10.1016/j.ncl.2009.04.004 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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that the preclinical period of cell loss is around 8 years, with the greatest rate of decline in the early stages of the disease.6 Thus, consideration of the etiology of PD must take into account the apparent latent period of the disease and the relative early selectivity of the pathology to the substantia nigra, the distribution of Lewy bodies not withstanding. Degeneration of nondopaminergic neurons also occurs in PD, but it usually occurs later in the course of the disease. The cholinergic nucleus basalis of Meynert, the serotoninergic neurons of the raphe nucleus, and the hypocretin-containing neurons of the hypothalamus suffer neuron loss with advanced disease. The noradrenergic dorsal vagal nucleus shows comparatively mild neuron loss despite marked deposition of alpha-synuclein. There is relatively mild cell loss in the amygdala, even at end-stage disease. The pattern and severity of cell loss in PD are thus not directly related to alpha-synuclein deposition, which has implications for understanding the contribution of this protein to pathology in different neurotransmitter pathways. The loss of nondopaminergic neurons contributes to the nonmotor features of PD.7 Inflammatory change has been identified as a common and important feature of PD pathology. Reactive microglia are found in the substantia nigra, particularly around pigmented neurons. Microglia have also been demonstrated in the putamen and cerebral cortex of PD. The extent of microglial activation in the substantia nigra correlates with the degree of alpha-synuclein deposition. Although the cause of PD is not known, both genetic and environmental factors are considered important.8 Several single gene mutations have now been identified in familial PD, other loci await characterization, and a number of putative association loci that might influence the development of PD have been described. A consistent pathogenetic profile is beginning to emerge from the study of familial and sporadic PD.9 Gene mutations are present in proteins involved in protein handling, oxidative stress, and mitochondrial function. These processes are closely interlinked. Environmental toxins used to model PD in animals inhibit mitochondrial function, increase free radical formation, and, in some cases, cause protein aggregation.
GENETIC FACTORS
Several recent case control studies have confirmed that PD is more common in relatives of PD cases compared with matched controls.10–13 Overall, the relative risk in first-degree relatives of PD cases has increased approximately 2 to 3-fold.14 A large PD twin study showed no significant concordance for PD among monozygotic twins, suggesting no significant genetic contribution to PD.15 However, for those with onset before age 50 years, the concordance rate was significant, implying that young-onset PD is more likely genetically determined. Another albeit smaller twin study using fluorodopa PET to image dopaminergic function in both affected and unaffected mono- and dizygotic twin pairs demonstrated an increased concordance for PD among identical twins, supporting a role for genetics in etiology.16 All of the twins were environmentally concordant in early life. At follow-up, the combined concordance levels for subclinical dopaminergic dysfunction and clinical PD were 75% in the 12 monozygotic twins and 22% in the 9 dizygotic twins evaluated twice. There have been numerous reports of familial aggregations of PD where inheritance has followed autosomal dominant or recessive inheritance. Several gene mutations and chromosomal loci have now been identified (Table 1).
Etiology and Pathogenesis of Parkinson Disease
Table 1 Causes of familial Parkinson disease Inheritance
Chromosomal locus
PARK 114
AuD
Protein Alpha-synuclein
Chr 4q
PARK 2
AuR
Parkin
Chr 6q
PARK 6
AuR
PINK1
Chr 1p
PARK 7
AuR
DJ1
Chr 1p
PARK 8
AuD
LRRK2
Chr 12q
PARK 9
AuR
ATP13A2
Chr 1p
Others UCHL1 Omi/HtrA2 Nurr1 mtDNA polymerase gamma Glucocerebrosidase Abbreviations: AuD, autosomal dominant; AuR, autosomal recessive.
Alpha-synuclein (Park 1)
The first familial cause of PD described involved mutations in the alpha-synuclein gene (PARK 1).17,18 More recently, multiplications of the wild-type alpha-synuclein gene have been described. A triplication of the gene was identified in a large autosomaldominant kindred with PD and tremor.19 Duplication of the gene was found in 1 of 42 familial probands of early onset PD.20 A third alpha-synuclein point mutation (E46K) has been reported in an autosomal-dominant family with parkinsonism and Lewy body dementia.21 The clinical spectrum associated with these mutations includes classical late-onset PD without prominent cognitive features, for example, the family carrying the A30P mutation, and early onset disease with dementia and rapid progression, for example, the A53T mutation. In the E46K family, there were features of early dementia and prominent autonomic dysfunction reminiscent of dementia with Lewy bodies, rather than typical PD. The discovery that multiplications of the normal (wild-type [WT]) gene cause autosomal-dominant parkinsonism with extensive LB inclusions is a potentially more important and relevant discovery than alpha-synuclein point mutations as a cause of PD. Not only are multiplications more common than point mutations of alpha-synuclein, but the fact that overexpression of WT alpha-synuclein protein is toxic to dopaminergic neurons and can reproduce the clinical and pathologic features of typical PD is of major importance to sporadic PD. A triplication of the alpha-synuclein gene was first identified in the so-called ‘‘Iowa-kindred,’’ a family with early onset parkinsonism, dementia, and prominent autonomic dysfunction.22,23 Postmortem examination of brains showed wide-spread aggregates of different shapes, with severe neuritic abnormalities and vacuolar changes in the temporal cortex.24 Duplications have been described in apparently sporadic patients with late-onset disease.25 There appears to be a gene dose effect in terms of age of onset: the greater the alpha-synuclein expression, the earlier the age of onset of PD.26 Polymorphisms of the promoter region of the alpha-synuclein gene have also been associated with increased protein production and enhanced risk for PD,27–29 although not all studies have been able to replicate these observations.30,31 The allele-specific
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binding of the transcriptional regulator poly-(ADP-ribose) transferase/polymerase-1 has been suggested as important.32 Although regulation of alpha-synuclein transcription and translation is likely to be complex, the emerging consensus that factors that upregulate this protein’s production contribute to PD risk provides a direct link between inherited and sporadic PD. Several models of abnormal alpha-synuclein expression have been developed over the past few years. Knockout of the gene in mice resulted in no detectable abnormality other than an alteration of dopamine release in response to rapid stimulation, although this has no clear functional correlate.33 Overexpression of WT human alpha-synuclein in mice resulted in loss of dopaminergic terminals; intranuclear and cytoplasmic ubiquitin-rich nonfibrillar a-synuclein inclusions in the substantia nigra, hippocampus, and cortex; and a rotor-rod motor deficit at 1 year.34 Overexpression of human WT and mutant a-synuclein in flies caused a loss of dopaminergic neurons, Lewy body-like inclusions with fibrillar a-synuclein, and a motor deficit with no significant difference between WT and mutant a-synuclein.35 Additional mouse models of a-synuclein expression have demonstrated inclusion formation and spinal cord pathology but no dopaminergic cell loss or motor deficit at late stage.36 Viral-mediated overexpression of alpha-synuclein induces nigral degeneration in rodents.37 The long-term expression of WT and mutant alpha-synuclein using recombinant adeno-associated viral vectors delivered to the ventral midbrain of marmosets induced parkinsonism with motor incoordination. Pathologic examination demonstrated the accumulation of pathologically phosphorylated alpha-synuclein, ubiquitinated aggregates, and dopamine cell degeneration.38 The A53T alpha-synuclein mutation enhances protofibrillar and fibrillar protein formation, which is considered the more toxic form of the protein.39 Catecholamines, including dopamine, and levodopa, inhibit fibril formation in vitro, and this is reversed by antioxidants, that is, catechol oxidation promotes protofibril formation.40 This observation would support a protective role for Lewy bodies in PD. An important observation revealing a potential toxic mechanism for alpha-synuclein is that the mutant form increases toxicity to dopamine, increasing cell death and free radical–mediated damage.41 The authors proposed that the mutation impaired vesicular uptake of dopamine, resulting in higher cytoplasmic or extravesicular synaptic concentrations of dopamine, which would in turn cause free radical–mediated damage. Phosphorylation at the Ser129 residue is required to mediate the toxicity of alpha-synuclein and increases the formation of inclusions in SHSY-5Y cells.42 This phosphorylated form of alpha-synuclein is present in Lewy bodies.43 Prevention of this phosphorylation by substitution of an alanine residue reduced inclusion formation in the SHSY-5Y model, and in the Drosophila model, this same mutation at 129, which prevents phosphorylation, protected against dopaminergic neuronal loss.44 Parkin (Park 2)
PARK2 gene mutations were first identified in autosomal recessive juvenile onset parkinsonism (ARJPD).45 ARJPD has been most commonly seen in the Japanese population and is characterized by onset before age 40 years, symptomatic improvement following sleep, mild dystonia, and a good response to levodopa.46 Resting tremor is seen less frequently than it is in idiopathic PD, and patients may have brisk tendon reflexes but no other pyramidal features. Progression is generally slower than that in sporadic PD. However, a broader clinical phenotype is also recognized with later onset and tremor, which more closely resembles sporadic PD. Pathologic changes include dopaminergic cell loss in the SNc and
Etiology and Pathogenesis of Parkinson Disease
locus ceruleus but no Lewy body deposition.47 The gene responsible for ARJPD was mapped to 6q25.2-q27,48 and in 1998, the gene was discovered and named parkin.45 Affected patients carry deletions or point mutations in various parts of the parkin gene.49,50 The relationship of parkin mutations to idiopathic PD has been highlighted by the identification of parkin mutations in apparently sporadic cases of PD. The role of single parkin gene mutations in determining the risk for PD remains controversial but of considerable interest. Parkin is ubiquitously transcribed, and intracellular localization studies have described association of the parkin protein with the endoplasmic reticulum, Golgi apparatus, synaptic vesicles, and mitochondria.51–53 The function of parkin is not known, but the protein contains a number of different domains for protein-protein interactions and E3 ligase activity. The latter involves a function within the ubiquitin proteasomal pathway, and several substrates for parkin ubiquitin ligase activity have been identified, including a 22 kD glycosylated form of alpha-synuclein, parkin-associated endothelin receptor-like receptor (Pael-R), and CDCrel-1. Overexpression of Pael-R causes it to become ubiquinated, insoluble, and unfolded and leads to endoplasmic reticulum stress and cell death.54 It has been demonstrated to accumulate in its insoluble form in the brains of patients with parkin mutations, suggesting a possible toxic mechanism. CDCrel-1 is a protein involved in cytokinesis and may influence synaptic vesicle function.55,56 Parkin is constitutively phosphorylated, and this can be modulated by proteasomal dysfunction and endocytoplasmic reticulum stress.57 The ability of parkin to ubiquinate proteins may be impaired by S-nitrosylation, which in turn may be a consequence of excitotoxic-mediated damage.58 Parkin has been reported to have an intramitochondrial localization in dividing cells.59 Parkin protein was released into the cytosol when cells were exposed to uncouplers or inhibitors of respiratory chain activity, including rotenone. Cell cycle blockers induced a similar redistribution of parkin. In contrast to undifferentiated, dividing SHSY-5Y cells, differentiation was associated with only a cytosolic distribution of parkin. The transfer of parkin from mitochondria to cytosol appeared to involve the mitochondrial permeability transition pore. Parkin protein could be imported into mitochondria and, interestingly, mutant forms less so than WT. The overexpression of parkin in SHSY-5Y cells induced increased transcription and translation of mitochondrial DNA (mtDNA) in dividing cells, which was mediated via an interaction with mtDNA transcription factor A. A parkin knockout mouse showed an increase in striatal extracellular dopamine, a reduction in synaptic excitability, and a mild nonprogressive motor deficit at 2 to 4 months.60 There was no loss of dopaminergic neurons and no inclusion formation. These mice had decreased striatal mitochondrial respiratory chain function and reductions in specific respiratory chain and antioxidant proteins.61 Parkin knockout flies developed muscle pathology, mitochondrial abnormalities, and apoptotic cell death.62 Overexpression of parkin in PC12 cells indicated that it is associated with the mitochondrial outer membrane.63 Parkin-positive patients have decreased lymphocyte complex I activity.64 The ability of parkin to ubiquinate proteins may be impaired by S-nitrosylation, which in turn may be a consequence of excitotoxic-mediated damage.58 UCH-L1 (Park 5)
A missense mutation in the gene encoding ubiquitin carboxyhydrolase L1 has been described in 2 siblings with typical PD.65 UCH-LI is an enzyme that hydrolyzes the C-terminus of ubiquitin to generate ubiquitin monomers that can be recycled to clear
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other proteins. The mutant form of UCH-L1 was shown to have reduced enzyme activity, resulting in impaired protein clearance through the ubiquitin-proteasome pathway. However, no other mutations in this gene have been identified in other families, suggesting that it is a rare cause of PD.66,67 PINK1 (Park 6)
Recessive mutations in PTEN-induced kinase 1 (PINK1) were found to be responsible for a familial form of early onset parkinsonism, previously mapped to chromosome 1p36.68 Several homozygous mutations have been described in familial PD patients, indicating that loss of function is the cause of disease pathogenesis. The majority of PINK1 mutation-positive patients have onset of parkinsonism below age 40 years, with relatively typical features of PD, good response to levodopa, slow progression, but early motor complications. Postmortem examination of brains of carriers with PINK1 mutations showed nigrostriatal cell loss and Lewy body formation.69 PINK1 protein has been observed in a small proportion (5%–10%) of Lewy bodies in PD brains and also localizes to the aggrosome under conditions of proteasomal inhibition, when there is also increased cleavage of the protein.70 Mutant PINK1 shows a similar distribution to Lewy bodies and aggrosomes under the same conditions. PINK1 mutations are relatively rare, and sequence variations are not considered an important factor influencing common forms of sporadic PD.71,72 In one European study, 2 of 100 young-onset PD patients had causative mutations, 1 homozygous and the other compound heterozygous.73 An additional 5 patients had 1 PINK1 mutation, that is, they were heterozygous compared with 2 of 200 controls. The heterozygote PINK1 carriers had mean age of onset of 44 years (range, 37–47 years), but the cohort only comprised PD cases with onset before age 50 years and so does not indicate the mean age of onset of carriers in the general PD population. These PINK1 carrier patients had features relatively typical of young-onset PD. In a study of 80 early onset (<55 years) PD patients, PINK1 mutations were found in 2 homozygous patients and 1 heterozygous carrier in an Asian population.74 PINK1 mutations were found to be enriched (1.2% vs 0.4%) in a PD population compared with controls, and these were associated with a reduction in mitochondrial membrane potential.75 Whether rare sequence variants or single PINK1 mutations predispose to PD remains a controversial area. In a meta-analysis, PINK1 heterozygotes were more frequent among patients than in controls (1.7% vs 1.0%), with an odds ratio (OR) of 1.62 (95% confidence interval [CI] 0.88–2.99) that did not reach statistical significance (P5.121).76 It is of interest that 18-fluorodopa PET is reduced in the PINK1 heterozygotes compared with that in controls.77 However, there is significant phenotypic variability among the PINK1 heterozygotes, suggesting that other genetic or environmental factors may play a role in penetrance. The PINK1 gene is ubiquitously transcribed and encodes a mitochondrial kinase, although there is evidence for extramitochondrial localization as well.68,78 Studies in cell culture have indicated that PINK1 may play a role in protecting cells against stress conditions that affect mitochondrial membrane potential. PINK1 mutations have recently been shown to reduce mtDNA levels.79 Recent studies on PINK1 knockdown neurons indicate an abnormality of mitochondrial calcium metabolism that is associated with abnormal bioenergetics and an increased risk for degeneration.80 As the majority of the reported mutations fall into the kinase domain of PINK1,68,73,81–82 altered phosphorylation of target proteins probably represents a key pathogenic mechanism, leading to abnormal stress response and neurodegeneration. The phosphorylation of mitochondrial proteins is considered pivotal to the regulation of respiratory activity in
Etiology and Pathogenesis of Parkinson Disease
the cell and to signaling pathways leading to apoptosis. The mitochondrial chaperone tumor necrosis factor (TNF) receptor associated protein 1 (TRAP1), also known as heat shock protein 75 is a substrate for PINK1.83 The TRAP1 may be involved in mediating events in apoptosis. TRAP1 is phosphorylated by PINK1 and can protect against cytochrome c release and apoptotic cell death. PD-associated PINK1 missense mutations G309D and L347P significantly reduced the ability of PINK1 to phosphorylate TRAP1 both in vitro and in vivo.83 PINK1 has been shown to regulate HtrA2 phosphorylation and represents another potentially important target for mediating the effects of PINK1.84 PINK1 knockout flies demonstrated viability but sterility or hypofertility, a motor deficit, and shorter life span. The flight muscle was abnormal with impaired function, disorganized mitochondrial morphology, reduced mitochondrial mass, and decreased ATP levels. There was a small reduction in the number of dopaminergic neurons.85,86 The flies showed increased sensitivity to paraquat and rotenone, implying that PINK1 participates in the defense against oxidative stress. This phenotype was similar to that expressed by parkin knockout flies, and it is therefore of interest that the PINK1related abnormalities were rescued by overexpression of parkin, but not vice versa. Furthermore, knockout of both genes did not exacerbate the phenotype. These data therefore suggest that parkin and PINK1 participate in the same pathogenetic pathway, that the pathway is linear, and that PINK1 is upstream of parkin. Given that PINK1 is a kinase and that data suggest that both proteins can be located within mitochondria, one explanation of this pathway might be that PINK1 activates parkin through phosphorylation either directly or indirectly. In one mouse model, the suppression of PINK1 expression in embryonic mouse tissues failed to produce any significant motor or behavior abnormalities and did not result in nigral dopaminergic neuronal loss at 6 months.87 In a knockout mouse homozygous for a large deletion of the kinase domain and a nonsense mutation in exon 8, mice showed no obvious abnormalities up to 9 months.88 However, there was evidence for a reduction in evoked dopamine release and specific impairments of corticostriatal long-term potentiation and long-term depression, which could be reversed by dopaminergic agents. DJ1 (Park 7)
DJ1 is a 23 kDa protein and is expressed throughout the brain, including the striatum, SNc, and reticulata, in both neurons and glia.89 Intracellular distribution studies demonstrated that DJ1 protein is located in several areas including the mitochondrion, where it is present in the intermembranous space and matrix. The protein appears to have several functions, including as an oncogene, in modulating androgen receptordependent transcription, and as an oxidative stress sensor.90–92 Oxidative stress and PD-associated mutations did not increase the mitochondrial localization, although others have shown that DJ1 may translocate to the mitochondrial outer membrane with oxidative stress.92–94 Deletion or silencing of DJ1 sensitizes cells to oxidative stress and overexpression protects, implying a protective role for the protein.95 DJ1 forms a nuclear complex with RNA- and DNA-binding proteins that regulate gene transcription and can prevent apoptotic cell death induced by alpha-synuclein or oxidative stress. Patients with DJ1 mutations are generally of young onset, progress slowly, respond well to levodopa, and may exhibit dystonia.96 Mutations of DJ1 that cause familial PD show protein instability or decreased nuclear localization, transcriptional activation, and protection against apoptosis.97 The L166P mutation is also associated with
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increased mitochondrial localization.96 DJ1 may also serve to reduce the aggregation of alpha-synuclein.98 DJ1 knockout mice exhibit motor abnormalities, although there is no change in nigral neuron number or morphology.99 Nigral neurons from these mice demonstrate enhanced sensitivity to blockade of Na/K ATPase and energy-dependent metabolism,100 and the mice show increased sensitivity to 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) and oxidative stress.101 LRRK2 (Park 8)
LRRK2 mutations are a common cause of PD. The G2019S mutation in the kinase domain is the most common and accounts for approximately 1% of sporadic and 4% of familial PD.102 The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation is 28% at age 59 years, 51% at 69 years, and 74% at 79 years. This mutation probably has a common founder within Europe and North Africa and may have arisen in the thirteenth century.103 Although a common cause of PD in European and North American populations, it appears to be even more common in North Africa, where the frequency among PD families was 41%104 and 30% among sporadic cases.105 Two studies have addressed the issue of whether common genetic variation within LRRK2 influences the risk for sporadic, idiopathic PD. Analysis of PD patients in Germany found no association,106 but a haplotype in the Chinese population significantly increased risk (OR, 5.5; 95% CI, 2.1–14.0) when present in 2 copies.107,108 The clinical features of patients with LRRK2 mutations do not differ significantly from those with sporadic PD, but the disease is generally more benign with fewer nonmotor features. 18Fluorodopa PET was typical of that seen in sporadic PD.109 Although all LRRK2 mutant brains examined to date demonstrate loss of dopaminergic neurons in the SNc, one of the morphologic hallmarks of idiopathic PD, additional pathology may also be seen. Pure nigral neuronal degeneration was found in the first family linked to this locus;110 neurofibrillary tangles, abnormal tau deposits, and widespread Lewy body synucleinopathy have been described in others, including 1 family with anterior horn cell loss.111,112 Three brains of ‘‘sporadic’’ PD with G2019S LRRK2 mutations have had pathologic examination and all have demonstrated nigral neuronal loss and Lewy body formation typical of PD.113 All of these subjects had PD based on clinical criteria. The LRRK2 gene encodes a 286-kDa cytoplasmic protein that is widely expressed in the brain.114 LRRK2 is a member of the ROCO protein family and appears to have multiple functions, at least by virtue of its predicted structure. The protein includes a leucine-rich motif that may have numerous functions, including protein-protein interactions and substrate binding for ubiquitination. The LRRK2 kinase domain belongs to the mitogen-activated protein kinase kinase kinase family of kinases, with catalytic activity for both serine/threonine and tyrosine residues. The G2019S mutation changes a highly conserved glycine at the start of the kinase activation segment, and it has been postulated that this has an activating effect causing a ‘‘gain of function’’ compatible with its autosomal-dominant inheritance pattern.115 Northern blot analysis demonstrates a possible 9-kbp mRNA transcript of LRRK2, which appears to be ubiquitously expressed and has shown expression in dopamine-innervated areas but little or no expression in dopamine neurons.116 LRRK2 antibodies have confirmed a wide distribution of the protein throughout the brain and peripheral tissues.117 LRRK2 is a predominantly cytoplasmic membrane-associated rather than membrane-bound protein and is present in microsomal and outer mitochondrial membrane fractions, approximately 10% of the protein being associated with the latter.118–120
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Mutations of the LRRK2 gene causing PD have now been described in all main protein domains. There is no distinction at present between the site of a mutation and any specific clinical phenotype. WT LRRK2 protein undergoes autophosphorylation, the kinase domain mutation I2020T significantly increased this activity by approximately 40%,120 and a similar effect was seen with the G2019S and, less so, with the R1441C mutations.118 LRRK2 autophosphorylation may represent a mechanism to regulate the parent protein. Mutations of the ROC, COR, or kinase domains do not appear to modify intracellular distribution in overexpression lines. Glucocerebrosidase Mutations
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency of the lysosomal enzyme glucocerebrosidase A (GBA). Diverse mutations within the gene that encodes GBA result in mutant enzymes with reduced activity. GD is characterized by widespread accumulation of substrate-loaded cells in many organs. The disease has 3 major forms—the commonest is type 1 (non-neuronopathic, adult) in which the metabolic defect is most prominent within the reticuloendothelial system. The central nervous system (CNS) is affected in type 2 (childhood, acute neuronopathic) and type 3 (young adults, chronic neuronopathic) GD. It is increasingly recognized that these forms of the disease are not discrete entities but form a continuum; the presence of CNS and peripheral nerve abnormalities in type 1 GD is increasingly recognized. GBA mutation carriers have a partial reduction in enzyme activity. There is now a clearly recognized link between PD and GD in that mutations in GBA constitute numerically the most important risk factors for apparently sporadic PD. The 2 most common GBA mutations (N370S and L444P) were found in 2.9% of 721 PD patients compared with 0.4% of 554 controls—a 7-fold increase.121 In a study of 395 PD patients and 483 controls from Italy, the frequency of these same mutations was 2.8% versus 0.2% (P<.002)—a 14-fold increase.122 In almost 100 Ashkenazi Jewish patients from Israel with PD who were tested for the 6 most common mutations known to cause GD, 31.3% were reported to have at least 1 mutation in the GBA gene.123 A smaller study found GBA mutations in 5 of 88 PD patients and 1 of 122 controls.124 GBA mutations were identified in 4.3% of 92 Chinese PD patients and 1.1% of matched controls.125 Analysis of 57 pathologically confirmed PD brains reported GBA mutations in 15% (ignoring possible polymorphisms).126 Alpha-synuclein–positive Lewy bodies have been identified in the brains of patients who died with GD and parkinsonism.127 These studies and others have confirmed the GBA mutation carrier status, that is, 1 mutated allele is a significant risk factor for PD and that the risk crosses ethnicity.128 Most of the PD cases described had no family history of PD, and the clinical phenotype of PD patients with GBA mutations was indistinguishable from idiopathic sporadic PD. The biochemical consequences of GBA deficiency have not been explored in the context of PD pathogenesis. POLG1 Mutations
mtDNA polymerase gamma 1 (POLG1) is essential for mtDNA synthesis, replication, and repair. It is encoded by nuclear DNA, imported into mitochondria, and located within the inner mitochondrial membrane. Mutations of the POLG1 gene have been described in a wide range of clinical phenotypes, including mtDNA depletion syndromes with liver failure129 and patients with autosomal dominant or recessive progressive external ophthalmoplegia (PEO) and parkinsonism.130 Patients first develop PEO with age of onset ranging from 10 to 54 years and then an asymmetric,
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levodopa-responsive, bradykinetic rigid syndrome together with resting tremor some years later. Additional features include variable limb, pharyngeal, or facial weakness, cataracts, ataxia, peripheral neuropathy, and premature ovarian failure.131 Muscle biopsy shows changes typical of mitochondrial disease with ragged, red, cytochrome oxidase negative fibers and multiple mtDNA deletions on Southern blotting. Mutations in various regions of the POLG1 gene have been associated with parkinsonism and result in multiple mtDNA deletions and depletion.131,132 The human POLG gene includes a trinucleotide microsatellite CAG repeat that encodes a polyglutamine tract in the amino-terminal region of the POLG protein, downstream of the presumed mitochondrial targeting sequence. No changes were seen in the CAG repeat in a series of PD patients.133 Similarly, no POLG1 mutations were found in 140 sporadic PD patients.134 Thus, the parkinsonian phenotype associated with POLG mutations is seen with either myopathy or neuropathy and morphologic changes in skeletal muscle. HtrA2/Omi
This nuclearly encoded mitochondrial protein is located in the intermembranous space and inactivates inhibitors of apoptosis, that is, it is proapoptotic. One HtrA2/Omi mutation (G399S) was found in 4 late-onset sporadic PD patients, and a polymorphism (A141S) was thought to represent a risk factor for PD.135 Expression of both the G399S and A141S mutations in SHSY-5Y cells lowered mitochondrial membrane potential and increased the sensitivity to apoptosis induced by staurosporin. To date, HtrA2/Omi mutations have not been described in additional PD cases. ENVIRONMENTAL FACTORS
The traditional view has been that the environment must play a significant role in the etiology of PD. This has been supported over the years with the description of cases of parkinsonism in response to certain dopaminergic nigral toxins such as MPTP. The role of the environment was reenforced by the failure of twin studies to unequivocally demonstrate significant concordance, particularly in late-onset cases. However, the discovery of single gene mutations as causes of familial PD has led to a reevaluation of the contribution of the environment to PD. It is true that single gene mutations appear to account for only a small minority of PD patients (w10%), but the recent experience of the LRRK2 mutation and its high prevalence may indicate a much higher proportion of genetically determined cases. However, there remains the potential for the environment to influence gene expression and penetration, although once again, there has been no evidence for this in PD so far. Nevertheless, several environmental associations may increase or decrease the risk for PD. A rural residency appears to increase the risk of the development of PD and in particular young-onset PD.136–138 However, this finding has not been confirmed in all studies.139–142 In addition, a further lifestyle study showed increased herbicide exposure in patients with PD.143 Some studies have found that the significant association of PD with farming as an occupation cannot be accounted for by pesticide exposure alone.141 Another rural factor that has been linked to PD is the consumption of well water,144 although this may simply be further evidence in support of herbicides or pesticides as etiological factors for PD. Two environmental factors are recognized to lower the risk for PD, cigarette smoking145 and coffee drinking.146 The mechanisms through which they can reduce risk are not known. Coffee drinking appears more protective for men, and so it is possible that there may be an interaction with endocrine factors. A study in PD has
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also shown that use of a nonsteroidal anti-inflammatory drug 2 or more times per week can produce a 45% lower risk for PD.147 High uric acid levels may be associated with a reduced risk for PD.148 Significant head injury increases the risk for PD in later life.149,150 The effects of physical activity, estrogen status (despite the male preponderance for PD), and diet on PD risk remain uncertain. There are, in addition, references in the literature to a range of occupational and environmental exposures that have variably been associated with a modest increased risk for PD, but their relevance to the majority of PD patients remains uncertain. These include exposure to heavy metals, which may, for instance, in the case of copper cause mitochondrial dysfunction and Wilson’s disease,151 an important differential diagnosis of PD. PATHOGENESIS OF PARKINSON DISEASE
Even before the discovery of the first gene mutation for PD, biochemical analyses of postmortem brains had established mitochondrial dysfunction and oxidative stress as major participants in the pathogenesis of PD. Their role has only been reinforced by the discovery of several genetic causes for PD and an understanding of their mechanism of action. Defects of the mitochondrial respiratory chain and, in particular, complex I deficiency were traditionally associated with mitochondrial myopathies.152,153 The first link between mitochondria and PD came with the identification of the deficiency of mitochondrial respiratory chain protein complex I activity in substantia nigra from patients with PD.154–156 This defect appears specific for the PD substantia nigra.157 Deficiencies of respiratory chain proteins were subsequently identified in platelets and skeletal muscle from PD patients, although these findings were not always consistent (see Schapira158 for review). The role of mitochondria in the pathogenesis of PD has been enhanced by the subsequent identification of mutations in genes encoding mitochondrial proteins, for example, PINK1, DJ1, and parkin, as causes of autosomal recessive PD. It is notable that environmental agents can influence mitochondrial function.159,160 There is evidence of free radical–mediated damage to proteins, lipids, and DNA in PD substantia nigra.161 The relationship of oxidative stress to the complex I defect is probably reciprocal and self-perpetuating. Mitochondrial dysfunction causes oxidative stress and vice versa.162,163 The recent finding that adult nigral dopaminergic neurons are particularly reliant on voltage-dependent calcium channels is of relevance to the interaction between mitochondria and free radicals.164 Increased intracellular calcium would lead to an increase in mitochondrial-derived free radicals, particularly in the dendrites, and could underlie, at lease in part, a predisposition to a ‘‘dyingback’’ neuronal degeneration. The third and most recent member of the PD pathogenetic triumvirate is proteasomal inhibition. Decreased activity and a reduction in protein subunits on immunoblotting in substantia nigra indicate an abnormality within the ubiquitin proteasomal system in PD.165 Systemic administration of a proteasomal inhibitor to rodents has been reported to induce loss of nigral dopaminergic neurons,166–168 although not all investigators have been able to reproduce these observations.169,170 Proteasomal degradation of proteins is achieved by a series of ATP-dependent peptidases.171 A defect of mitochondrial respiratory chain activity results in impaired oxidative phosphorylation and an increase in free radical generation and thus will affect UPS function by both limiting activity and increasing the substrate load of oxidized protein.172 Likewise, a source of free radicals independent of mitochondria will impair respiratory chain function and increase substrate
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load upon the proteasome. Any cause of proteasomal dysfunction will lead to accumulation of damaged proteins, with a potentially deleterious effect on cell function and survival. AUTOPHAGY
Intracellular protein degradation is achieved through a combination of the UPS and autophagic pathways. However, the role of the UPS in alpha-synuclein metabolism remains unclear. Attention has recently focused on the potential contribution of autophagy to the pathogenesis of neurodegenerative diseases.173–175 Autophagy comprises 3 separate pathways: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA). MA involves the formation of double-membraned autophagosomes, which fuse with lysosomes to deliver cytoplasmic contents, including misfolded or aggregated proteins for digestion and recycling of amino acids. Microautophagy involves lysosomal pinocytosis of cytoplasmic contents and is involved in the turnover of long half-life cytosolic proteins. CMA is dependent on the protein chaperone hsc70 and its binding to LAMP-2A, a lysosomal surface receptor. A highly specific subset of cytosolic proteins with a KFREQ motif are recognized by the hsc70 chaperone and internalized for degradation by LAMP-2A lysosomal membrane receptors.176 Alpha-synuclein has a pentapeptide (95VKKDQ99) sequence consistent with LAMP2A binding.177 Using isolated lysosomal preparations, WT alpha-synuclein has been shown to be degraded following binding to the CMA LAMP-2A receptor.178 However, in this system, mutant alpha-synuclein bound to this lysosomal receptor with high affinity but was not translocated across the membrane and appeared to block these receptors, thereby inhibiting the CMA pathway. This has led to the suggestion that decreased CMA may prevent the clearance of alpha-synucleins and contribute to oligomer and aggresome formation and the pathogenesis of PD. The increase in autophagic vacuoles in the substantia nigra of PD brains and toxin and transgenic models of PD179,180 support the notion that autophagy pathways are important in PD. SUMMARY
The last few years have witnessed important advances in our understanding of the etiology and pathogenesis of PD. Several features have become self-evident. The first is that there are multiple causes of the clinical phenotype that we currently recognize as PD, and these same causes can result in a spectrum of phenotypes. Thus, there is some disconnect between genotype and phenotype. Secondly, there is variation in the pathology that may be induced by the specific gene mutations, a further extension of the genotype-phenotype disconnect. However, the clinical features that enable a diagnosis of PD continue to serve us well, if correctly applied. The characterization of the single gene mutations causing familial PD has provided valuable insights into the pathogenetic mechanisms that result in cell damage and death. These have focused attention on the mitochondrion, free radical–mediated damage, and proteasomal dysfunction. The value of these insights is that they provide the basis for developing a program to identify drugs that might modify the course of PD.181,182 REFERENCES
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82. Rohe CF, Montagna P, Breedveld G, et al. Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism. Ann Neurol 2004;56(3):427–31. 83. Pridgeon JW, Olzmann JA, Chin LS, et al. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 2007; 5(7):e172 [Epub ahead of print]. 84. Plun-Favreau H, Klupsch K, Moisoi N, et al. The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol 2007; 9(11):1243–52. 85. Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006;441(7097):1157–61. 86. Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006;441(7097): 1162–6. 87. Zhou H, Falkenburger BH, Schulz JB, et al. Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci 2007;3(4):242–50. 88. Kitada T, Pisani A, Porter DR, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A 2007;104(27):11441–6. 89. Zhang L, Shimoji M, Thomas B, et al. Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 2005;14(14):2063–73. 90. Nagakubo D, Taira T, Kitaura H, et al. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 1997;231(2):509–13. 91. Takahashi K, Taira T, Niki T, et al. DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem 2001; 276(40):37556–63. 92. Taira T, Saito Y, Niki T, et al. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 2004;5(2):213–8. 93. Canet-Aviles RM, Wilson MA, Miller DW, et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A 2004;101(24):9103–8. 94. Bandopadhyay R, Kingsbury AE, Cookson MR, et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 2004;127(Pt 2):420–30. 95. Yokota T, Sugawara K, Ito K, et al. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 2003;312(4):1342–8. 96. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299(5604): 256–9. 97. Xu J, Zhong N, Wang H, et al. The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum Mol Genet 2005;14(9):1231–41. 98. Shendelman S, Jonason A, Martinat C, et al. DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2004;2(11):e362. Epub 2004 Oct 5. 99. Goldberg MS, Pisani A, Haburcak M, et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 2005;45(4):489–96.
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100. Pisani A, Martella G, Tscherter A, et al. Enhanced sensitivity of DJ-1-deficient dopaminergic neurons to energy metabolism impairment: role of Na1/K1 ATPase. Neurobiol Dis 2006;23(1):54–60. 101. Kim RH, Smith PD, Aleyasin H, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) and oxidative stress. Proc Natl Acad Sci U S A 2005;102(14):5215–20. 102. Healy DG, Falchi M, O’Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7(7):583–90. 103. Lesage S, Leutenegger AL, Ibanez P, et al. LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet 2005;77(2): 330–2. 104. Lesage S, Ibanez P, Lohmann E, et al. G2019S LRRK2 mutation in French and North African families with Parkinson’s disease. Ann Neurol 2005;58:784–7. 105. Hulihan MM, Ishihara-Paul L, Kachergus J, et al. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol 2008;7(7):591–4. 106. Biskup S, Mueller JC, Sharma M, et al. Common variants of LRRK2 are not associated with sporadic Parkinson’s disease. Ann Neurol 2005;58(6):905–8. 107. Skipper L, Li Y, Bonnard C, et al. Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson’s disease. Hum Mol Genet 2005;14(23):3549–56. 108. Tan EK, Schapira AH. Uniting Chinese across Asia: the LRRK2 Gly2385Arg risk variant. Eur J Neurol 2008;15(3):203–4. 109. Khan NL, Jain S, Lynch JM, et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005;128(Pt 12): 2786–96. 110. Funayama M, Hasegawa K, Kowa H, et al. A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002;51(3):296–301. 111. Wszolek ZK, Pfeiffer RF, Tsuboi Y, et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004;62(9): 1619–22. 112. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology. Neuron 2004;44(4): 601–7. 113. Gilks WP, bou-Sleiman PM, Gandhi S, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005;365(9457):415–6. 114. Ross OA, Farrer MJ. Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson’s disease. Biochem Soc Trans 2005;33(Pt 4):586–90. 115. Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005;76(4):672–80. 116. Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004;44(4):595–600. 117. Giasson BI, Covy JP, Bonini NM, et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006;59(2):315–22. 118. West AB, Moore DJ, Biskup S, et al. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005;102(46):16842–7.
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119. Smith WW, Pei Z, Jiang H, et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A 2005;102(51):18676–81. 120. Gloeckner CJ, Kinkl N, Schumacher A, et al. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 2006;15(2):223–32. 121. Mata IF, Samii A, Schneer SH, et al. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 2008;65(3):379–82. 122. De Marco EV, Annesi G, Tarantino P, et al. Glucocerebrosidase gene mutations are associated with Parkinson’s disease in southern Italy. Mov Disord 2008; 23(3):460–3. 123. haron-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2004;351(19):1972–7. 124. Sato C, Morgan A, Lang AE, et al. Analysis of the glucocerebrosidase gene in Parkinson’s disease. Mov Disord 2005;20(3):367–70. 125. Ziegler SG, Eblan MJ, Gutti U, et al. Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol Genet Metab 2007; 91(2):195–200. 126. Lwin A, Orvisky E, Goker-Alpan O, et al. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004;81(1):70–3. 127. Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82(3):192–207. 128. Goker-Alpan O, Schiffmann R, LaMarca ME, et al. Parkinsonism among Gaucher disease carriers. J Med Genet 2004;41(12):937–40. 129. Morris AA, Taanman JW, Blake J, et al. Liver failure associated with mitochondrial DNA depletion. J Hepatol 1998;28(4):556–63. 130. Schapira AH. Mitochondrial disease. Lancet 2006;368(9529):70–82. 131. Luoma P, Melberg A, Rinne JO, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004;364(9437):875–82. 132. Mancuso M, Filosto M, Oh SJ, et al. A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol 2004;61(11):1777–9. 133. Taanman JW, Schapira AH. Analysis of the trinucleotide CAG repeat from the DNA polymerase gamma gene (POLG) in patients with Parkinson’s disease. Neurosci Lett 2005;376(1):56–9. 134. Hudson G, Schaefer AM, Taylor RW, et al. Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Arch Neurol 2007;64(4):553–7. 135. Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 2005;14(15): 2099–111. 136. Rajput AH, Uitti RJ, Stern W, et al. Early onset Parkinson’s disease in Saskatchewan—environmental considerations for etiology. Can J Neurol Sci 1986;13(4): 312–6. 137. Rajput AH, Uitti RJ, Rajput AH. Neurological disorders and services in Saskatchewan—a report based on provincial health care records. Neuroepidemiology 1988;7(3):145–51. 138. Behari M, Srivastava AK, Das RR, et al. Risk factors of Parkinson’s disease in Indian patients. J Neurol Sci 2001;190(1–2):49–55.
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139. Semchuk KM, Love EJ, Lee RG. Parkinson’s disease and exposure to rural environmental factors: a population based case-control study. Can J Neurol Sci 1991;18(3):279–86. 140. Barbeau A, Roy M, Bernier G, et al. Ecogenetics of Parkinson’s disease: prevalence and environmental aspects in rural areas. Can J Neurol Sci 1987;14(1): 36–41. 141. Gorrell JM, DiMonte D, Graham D. The role of the environment in Parkinson’s disease. Environ Health Perspect 1996;104(6):652–4. 142. Fall PA, Fredrikson M, Axelson O, et al. Nutritional and occupational factors influencing the risk of Parkinson’s disease: a case-control study in southeastern Sweden. Mov Disord 1999;14(1):28–37. 143. Semchuk KM, Love EJ, Lee RG. Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 1992;42(7):1328–35. 144. Tanner CM, Goldman SM. Epidemiology of Parkinson’s disease. Neurol Clin 1996;14(2):317–35. 145. Baron JA. Cigarette smoking and Parkinson’s disease. Neurology 1986;36(11): 1490–6. 146. Ascherio A, Zhang SM, Hernan MA, et al. Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol 2001;50(1):56–63. 147. Chen H, Zhang SM, Hernan MA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 2003;60(8):1059–64. 148. Weisskopf MG, O’Reilly E, Chen H, et al. Plasma urate and risk of Parkinson’s disease. Am J Epidemiol 2007;166(5):561–7. 149. Goldman SM, Tanner CM, Oakes D, et al. Head injury and Parkinson’s disease risk in twins. Ann Neurol 2006;60(1):65–72. 150. Bower JH, Maraganore DM, Peterson BJ, et al. Head trauma preceding PD: a case-control study. Neurology 2003;60(10):1610–5. 151. Gu M, Cooper JM, Butler P, et al. Oxidative-phosphorylation defects in liver of patients with Wilson’s disease. Lancet 2000;356(9228):469–74. 152. Morgan-Hughes JA, Sweeney MG, Cooper JM, et al. Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype. Biochim Biophys Acta 1995;1271(1):135–40. 153. Schapira AH, Cooper JM, Morgan-Hughes JA, et al. Molecular basis of mitochondrial myopathies: polypeptide analysis in complex-I deficiency. Lancet 1988;1(8584):500–3. 154. Schapira AHV, Cooper JM, Dexter D. Mitochondrial complex I deficiency in Parkinson’s disease. Ann Neurol 1989;26:122–3. 155. Schapira AH, Cooper JM, Dexter D, et al. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1989;1(8649):1269. 156. Mann VM, Cooper JM, Daniel SE, et al. Complex I, iron, and ferritin in Parkinson’s disease substantia nigra. Ann Neurol 1994;36(6):876–81. 157. Schapira AH, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 1990;55(6):2142–5. 158. Schapira AH. Evidence for mitochondrial dysfunction in Parkinson’s disease—a critical appraisal. Mov Disord 1994;9(2):125–38. 159. Owen AD, Schapira AH, Jenner P, et al. Oxidative stress and Parkinson’s disease. Ann N Y Acad Sci 1996;786:217–23. 160. Smith PR, Cooper JM, Govan GG, et al. Smoking and mitochondrial function: a model for environmental toxins. Q J Med 1993;86(10):657–60.
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161. Gu M, Owen AD, Toffa SE, et al. Mitochondrial function, GSH and iron in neurodegeneration and Lewy body diseases. J Neurol Sci 1998;158(1):24–9. 162. Thomas PK, Cooper JM, King RH, et al. Myopathy in vitamin E deficient rats: muscle fibre necrosis associated with disturbances of mitochondrial function. J Anat 1993;183(Pt 3):451–61. 163. Schapira AH. Oxidative stress in Parkinson’s disease. Neuropathol Appl Neurobiol 1995;21(1):3–9. 164. Chan CS, Guzman JN, Ilijic E, et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 2007;447(7148):1081–6. 165. McNaught KS, Belizaire R, Isacson O, et al. Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 2003;179(1):38–46. 166. McNaught KS, Perl DP, Brownell AL, et al. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 2004;56(1):149–62. 167. Schapira AH, Cleeter MW, Muddle JR, et al. Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons. Ann Neurol 2006;60(2):253–5. 168. Zeng BY, Bukhatwa S, Hikima A, et al. Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats. Ann Neurol 2006;60(2): 248–52. 169. Manning-Bog AB, Reaney SH, Chou VP, et al. Lack of nigrostriatal pathology in a rat model of proteasome inhibition. Ann Neurol 2006;60(2):256–60. 170. Bove J, Zhou C, Jackson-Lewis V, et al. Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol 2006;60(2):260–4. 171. Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 1999;68:1015–68. 172. Hoglinger GU, Carrard G, Michel PP, et al. Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease. J Neurochem 2003;86(5):1297–307. 173. Martinez-Vicente M, Cuervo AM. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007;6(4):352–61. 174. Pan T, Kondo S, Le W, et al. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 2008;131(Pt 8): 1969–78. 175. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006;443(7113):780–6. 176. Majeski AE, Dice JF. Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol 2004;36(12):2435–44. 177. Dice JF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 1990;15(8):305–9. 178. Cuervo AM, Stefanis L, Fredenburg R, et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004;305(5688): 1292–5. 179. Anglade P, Vyas S, Hirsch EC, et al. Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol Histopathol 1997;12(3): 603–10. ¨ z tap E, Topal A. A cell protective mechanism in a murine model of Parkinson’s 180. O disease. Turk J Med Sci 2003;33:295–9. 181. Schapira AH, Bezard E, Brotchie J, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov 2006;5(10):845–54. 182. Schapira AH. Science, medicine, and the future: Parkinson’s disease. BMJ 1999;318(7179):311–4.
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Me dic al Treatment of Parkinson Dis eas e Mark Stacy, MD KEYWORDS Punding REM-behavior disorder Post-synaptic Hallucination Dyskinesia Pre-synaptic
The cardinal characteristics of Parkinson disease (PD) include resting tremor, rigidity, and bradykinesia.1 Besides these motor symptoms, patients may also develop autonomic dysfunction, cognitive changes, psychiatric symptoms, sensory complaints, and sleep disturbances. More than 1.5 million people in the United States are believed to have PD, and 70,000 new cases are diagnosed each year.2 The annual economic burden of PD in the United States alone is estimated to be $23 billion. Most of this cost is attributed to lost productivity and uncompensated care delivered by family and household members.3 The motor symptoms associated with PD are believed to arise from dopamine deficiency, although the pathophysiology of parkinsonian symptoms and signs is not yet fully understood.4 As dopamine replacement therapy, levodopa has become the standard of care for patients with PD.5 Although levodopa clearly improves motor symptoms, allowing many patients to better perform activities of daily living and continue working, this agent is also associated with motor fluctuations, for example, ‘‘wearing off’’ and dyskinesias.6–11 Because of these complications, many specialists advocate the early use of dopamine agonists in patients with motor disability. These drugs by class are less potent than levodopa, but are not associated with dyskinesias. This manuscript addresses the treatment of motor and nonmotor symptoms of Parkinson disease. THE NIGROSTRIATAL SYNAPSE
The medical management of PD is based on compensating for catecholamine depletion due to a loss of dopamine-producing cells in the substantia nigra through delivery of additional dopamine or directly stimulating the postsynaptic striatal neurons.12 Dopamine (DA) is synthesized from the amino acid levodopa, and exogenous replacement of levodopa is highly effective in treating motor symptoms. Although levodopa initially produces a robust and predictable response, with disease progression and nigrostriatal neuronal death motor fluctuations and dyskinesias may occur. For this
Division of Neurology, Department of Medicine, 932 Morreene Road, MS 3333, Duke University Medical Center, Durham, NC 27705, USA E-mail address:
[email protected] Neurol Clin 27 (2009) 605–631 doi:10.1016/j.ncl.2009.04.009 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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reason, DA agonists, medications that bypass the presynaptic neuron and directly stimulate striatal DA receptors, are often used (Table 1). MONOAMINE OXIDASE TYPE B INHIBITORS
The monoamine oxidase type B (MAO-B) inhibitors may be used as a first line treatment or as adjunctive therapy to levodopa in patients with PD. Blockade of MAO-B delays dopamine metabolism, thereby increasing neurotransmitter concentration in the striatum.13–15 Inhibitors that selectively block MAO-B avoid the potentially dangerous pressor effect associated with inhibition of MAO-A.14 The MAO-A enzyme is involved in the metabolism of dietary amines such as tyramine, which is found in cheese.14 Elevated tyramine levels are associated with dangerously high blood pressure. Studies performed with the specific MAO-B inhibitor selegiline and rasagiline found no pressor effect if the drug is given with tyramine and phenylethylamine.14,16 Rasagiline
Rasagiline was approved in 2006 by the US Food and Drug Administration (FDA) as an initial monotherapy and adjunct therapy in patients with PD taking levodopa.17,18 The safety and efficacy of this agent was evaluated in early PD in the TEMPO (Rasagiline Mesylate [TVP-1012] in Early Monotherapy for Parkinson’s Disease Outpatients) study.17 This multicenter, 26-week, parallel-group, double-blind, placebo-controlled clinical trial randomized 404 subjects to rasagiline mesylate at dosages of 1 or 2 mg/d or matching placebo. In this monotherapy study, Unified Parkinson’s Disease Rating Scale (UPDRS) changes were statistically different between the 1-mg dose of rasagiline versus placebo ( 4.20 units [95% confidence interval, 5.66 to 2.73 units; P<.001]) and the 2-mg dose and placebo ( 3.56 units [95% confidence interval, 5.04 to 2.08 units; P<.001]). There were no differences in the frequency of adverse events or premature withdrawals among the treatment groups. In a continued observation phase of this study, in which subjects initially treated with placebo were converted to rasagiline 1 mg daily, it was found that subjects initially started on active therapy continued to demonstrate benefit compared with the group who started on placebo. Because these findings suggested a possible disease modification effect, an additional trial, Attenuation of Disease progression with Azilect GIven Once-daily (ADAGIO), of more than 1100 subjects has been initiated. Data from this study are not fully available.19 Clinical trials demonstrate the safety and efficacy of adjunctive therapy with rasagiline in levodopa-treated patients.18,20 The Parkinson Rasagiline: Efficacy and Safety in the Treatment of ‘‘Off’’ (PRESTO) trial found that levodopa-treated patients taking rasagiline 0.5 or 1.0 mg/d showed improvements in motor fluctuations.18 This multicenter, randomized, placebo-controlled, double-blind study enrolled 472 subjects experiencing motor fluctuations while receiving levodopa. Reduction in mean adjusted total daily off time was 1.85 hours (29%) with rasagiline 1.0 mg/d, 1.41 hours (23%) with rasagiline 0.5 mg/d, and 0.91 hours (15%) with placebo (P % .02 versus placebo). Analysis of secondary efficacy outcome measures revealed significant improvements in the UPDRS Activities of Daily Living score and Motor score during off periods. Time without troublesome dyskinesias increased from baseline by 0.51 hours (P 5 .050 versus placebo) in the lower-dose rasagiline group and by 0.78 hours (P 5 .004 versus placebo) in the group taking 1 mg/d. Weight loss, vomiting, anorexia, and difficulty balancing were significantly more common with rasagiline than with placebo.21 Rasagiline and entacapone were compared with placebo in the Lasting Effect in Adjunct Therapy with Rasagiline Given Once Daily (LARGO) study.20,21 Patients
Medical Treatment of Parkinson Disease
were randomized to receive rasagiline 1 mg/d, entacapone 200 mg with each levodopa dose, or placebo as adjunctive therapy with levodopa. Results showed that decreases in daily off time with rasagiline (1.18 hours) and entacapone (1.20 hours) were significantly superior to the decrease with placebo (0.4 hour; P % .0001). The amount of on time with dyskinesia did not differ between groups. Active treatment allowed significant reductions in levodopa dose, whereas the placebo group required an increase. There were no significant increases in UPDRS Dyskinesia scores in either the rasagiline or the placebo group. The frequency of dopamine-related adverse events was similar with rasagiline and placebo.20 The use of rasagiline at any dose may be associated with hypertensive crisis (‘‘cheese reaction’’) if consumed with tyramine-rich foods and beverages, such as sausage, salami, pickled herring, sauerkraut, aged cheeses (cheddar, blue cheese) and nonpasteurized beer.22 In a recent report of tyramine challenges performed in rasagiline-treated patients at the end of 2 double-blind, placebo-controlled trials, 3 of 22 subjects receiving 0.5 mg/d developed self-limiting systolic blood pressure elevation of 30 mmHg or more on 3 measurements. None of the 12 patients receiving the 1-mg dose experienced this degree of blood pressure elevation in this study.16 Rasagiline is contraindicated for coadministration with meperidine, tramadol, methadone, propoxyphene, dextromethorphan, St. John’s wort, mirtazapine, cyclobenzapine, sympathomimetic amines, and other MOA inhibitors. The prescribing information for rasagiline also warns against coadministration with ciprofloxacin, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs).22 Selegiline
Selegiline is also approved as monotherapy or adjunctive therapy in patients with PD. This agent undergoes extensive first-pass metabolism with only 10% bioavailability and significant levels of desmethylselegiline, L-amphetamine, and L-methamphetamine metabolites; it is associated with a variable pharmacokinetic profile.14,23 Long-term treatment with oral selegiline in PD patients is associated with slower motor decline in the initial and extension phases of the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial.24,25 DATATOP randomized 800 treatment-naive patients with early PD to selegiline 10 mg/d, tocopherol 2000 IU/d, both agents, or placebo to assess whether these medications could delay the need for levodopa.24 This was followed by selegiline 10 mg/d for 5 years, after which a group of 368 patients who had progressed to requiring levodopa were randomized again to continue selegiline or switch to placebo for an additional 2 years.25 Patients who remained on selegiline reported more dyskinesias (34% versus 19%; P 5 .006), but were less likely to have on-off motor fluctuations or freezing of gait compared with placebo. The selegiline group also demonstrated a slower reduction in motor performance on UPDRS scores, the number of daily off periods, an increase in on periods, a reduction in the levodopa dosage, and an increase in the mean levodopa interdose interval. Selegiline was associated with orthostatic hypotension in the DATATOP trial and other studies.24–28 Withdrawal of selegiline improved blood pressure stability but also led to a decline in motor function.28 Selegiline Orally Disintegrating Tablets
Selegiline orally disintegrating tablets (ODT), approved in 2006 by the FDA as an adjunct therapy in patients with PD taking levodopa, is a rapidly dissolving oral mucosal drug delivery system.29,30 This mode of delivery bypasses the gastrointestinal system and first-pass metabolism in the liver.30 The rapid dissolution on the
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Table 1 Adjunctive agents used to treat Parkinson disease Drug
Mechanism of Action
Dose and Frequency
Adverse Effects
Rasagiline
Decrease breakdown of DA by way of MAO-B blockade
1 mg every day
Weight loss, vomiting, anorexia, balance difficulty
Oral selegiline
Decrease breakdown of DA by way of MAO-B blockade
5–10 mg twice a day
Nausea, dizziness, sleep disorder, impaired cognition, orthostatic hypotension
Selegiline ODT
Decrease breakdown of DA by way of MAO-B blockade
1.25–2.5 mg every day
Dizziness, dyskinesias, hallucinations, headache, dyspepsia
MAO-B inhibitors
Ergoline dopamine agonists Bromocriptine
Direct stimulation of DA receptors
15–30 mg 3–4 times a day
Nausea, hypotension, hallucinations, psychosis, peripheral edema, pulmonary fibrosis, sudden onset of sleep
Pergolide
Direct stimulation of DA receptors
1.5–5.0 mg three times a day
Nausea, hypotension, hallucinations, psychosis, peripheral edema, pulmonary fibrosis, sudden onset of sleep, restrictive valvular heart disease
Cabergoline
Direct stimulation of DA receptors
2–6 mg every day
Nausea, hypotension, hallucinations, psychosis, peripheral edema, pulmonary fibrosis, sudden onset of sleep, dyskinesia
Lisuride
Direct stimulation of DA receptors
0.6–2.0 mg 3–4 times a day with levodopa
Nausea, headaches, tiredness, dizziness, drowsiness, sweating, dry mouth, vomiting, sudden decreases in BP, nightmares, hallucinations, paranoid reactions, states of confusion, weight gain, sleep disorders
Nonergoline dopamine agonists Pramipexole
Direct stimulation of DA receptors
1.5–6.0 mg three times a day
Nausea, hypotension, hallucinations, psychosis, peripheral edema, sudden onset of sleep
Ropinirole
Direct stimulation of DA receptors
6–24 mg/d
Nausea, hypotension, hallucinations, psychosis, peripheral edema, sudden onset of sleep
Tolcapone
Increase levodopa half-life by blocking COMT pathway important in the catabolism of levodopa
100–200 mg three times a day
Diarrhea, dyskinesia, liver toxicity (monitoring required)
Entacapone
Increase levodopa half-life by blocking COMT pathway important in the catabolism of levodopa
200 mg with each dose of levodopa to 1600 mg/d
Exacerbation of levodopa side effects, diarrhea, discolored urine
Promotes DA release through blockade of NMDA and acetylcholine receptors
50–200 mg twice a day, with special considerations for elderly patients or those with renal insufficiency
Cognitive dysfunction, hallucinations, peripheral edema, skin rash, anticholinergic effects
COMT inhibitors
NMDA antagonist Amantadine
Medical Treatment of Parkinson Disease
Abbreviations: BP, blood pressure; COMT, catechol-O-methyltransferase; DA, dopamine; MAO-B, monoamine oxidase type B; ODT, orally disintegrating tablets. Data from Jankovic J, Stacy M. Medical management of levodopa-associated motor complications in patients with Parkinson’s disease. CNS Drugs 2007;21(8):681.
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tongue without the need for water may be useful in patients with dysphagia.31 The use of selegiline ODT does not require dietary tyramine restriction up to the highest approved dose of 2.5 mg/d.32 The ODT formulation of selegiline provides high bioavailability of the parent compound. Pharmacokinetic and pharmacodynamic studies performed on 156 healthy volunteers found 5 times higher area-under-the-curve values for selegiline after administration of selegiline ODT compared with an equivalent dose of conventional oral selegiline.33 In addition, the plasma concentrations of the 3 major selegiline metabolites were significantly lower after selegiline ODT administration. Selegiline ODT was evaluated as adjunctive therapy in a 3-month, randomized, placebo-controlled study in 140 patients with PD who experienced motor fluctuations while receiving levodopa.13 The reduction in daily off time was 2.2 hours in the selegiline ODT group compared with 0.6 hour in the placebo group (P 5 .001). In addition, selegiline ODT was associated with an additional 1.8 dyskinesia-free on hours daily compared with placebo (P 5 .006). Adverse events were generally similar between the selegiline ODT and placebo groups.13 The most common drug-related adverse events observed in the selegiline ODT group were dizziness, dyskinesias, hallucinations, headache, and dyspepsia. CATECHOL-O-METHYL TRANSFERASE INHIBITORS
Catechol-O-methyl transferase (COMT) is a key enzyme in the peripheral catabolism of levodopa. Inhibiting COMT increases levodopa plasma levels by about 26%.34–36 Two COMT inhibitors are available: tolcapone and entacapone. Tolcapone
Tolcapone is a potent and clinically effective agent, but its use has been limited by concerns about potential liver toxicity.37 Tolcapone has a rapid onset of action, showing therapeutic benefit approximately 2 weeks after treatment initiation. If given as adjunctive therapy in patients on levodopa, tolcapone improves wearing off effects, decreases off time, increases on time, decreases levodopa dosage by 30%, and reduces the number of levodopa doses needed during the day.38,39 In addition, after 6 weeks of treatment with tolcapone in a randomized, double-blind, placebocontrolled trial, patients exhibited an increase in on time of more than 2 hours.40 Potential adverse effects associated with COMT inhibitors are diarrhea, dyskinesia, and liver toxicity. For tolcapone, the unknown potential for fatal hepatotoxicity prompted the FDA to require monitoring of liver function.37 Initial recommendations called for testing of alanine aminotransferase and aspartate aminotransferase at baseline, every 2 weeks during the first year of treatment, every 4 weeks over the ensuing 6 months, and every 8 weeks subsequently. More recently, the FDA has recommended that alanine aminotransferase and aspartate aminotransferase be tested at baseline and then every 2 to 4 weeks for the first 6 months of therapy, then periodically at intervals deemed clinically relevant.41 Entacapone
The COMT inhibitor entacapone has not been associated with liver toxicity.37 Entacapone also has a shorter half-life and is given with levodopa.42 When administered in 200-mg doses with levodopa, entacapone was associated with a decrease in off time of 2.1 hours per day.43 A 6-month, randomized, double-blind, placebo-controlled study revealed that entacapone therapy significantly increased mean on time, reduced off time, and permitted a decrease of an average of 102 mg/d of levodopa.44 These
Medical Treatment of Parkinson Disease
benefits of entacapone therapy persisted through the 3-year open-label extension of the initial 6-month trial. A new formulation containing 200 mg of entacapone plus levodopa and carbidopa (Stalevo) in a single tablet is also available for the treatment of patients with PD and simple motor fluctuations. Whereas the entacapone dosage remains 200 mg per tablet in all formulations, the carbidopa/levodopa doses are calculated at a 1:4 ratio with levodopa dosages of 50, 75, 100, 125, 150 and 200 mg per tablet. Trials comparing entacapone and tolcapone are insufficient. In a double-blind trial of patients treated with entacapone for at least 15 days, 150 subjects were randomized to continue entacapone or switch to tolcapone. There were no differences in Investigator Global Assessment, UPDRS subscales II and III, off time or on time in the per protocol population. In addition, during this 3-week assessment period, 27 subjects (36%) withdrew from the study.45 LEVODOPA
Symptoms of PD result from the loss of dopaminergic neurons in the substantia nigra. These neurons normally synthesize dopamine from the essential amino acid, tyrosine. The conversion of tyrosine to levodopa is facilitated by the rate-limiting enzyme, tyrosine hydroxylase. Levodopa, whether it is derived from cellular metabolism of tyrosine or from oral supplementation, is converted to dopamine by the enzyme dopa-decarboxylase. Levodopa is competitively absorbed by way of a large neutral amino acid (LNAA) transporter protein in the small intestine. A similar saturable carrier is believed to be present at the blood–brain barrier.46 Erratic or delayed gastric emptying may cause individual doses of levodopa to fail or to have a slow onset of effect.47 In addition, levodopa dosing during a high protein meal, through competition for sites on the duodenal and blood–brain barrier transport molecules, may reduce levodopa transfer to the blood stream and brain.46 As a result of peripheral dopa-decarboxylase, less than 1% of the levodopa administered is actually converted into dopamine in the brain, leading to activation of the area postrema, and may cause nausea, vomiting, and, rarely, cardiac arrhythmia. By adding a dopa-decarboxylase inhibitor (DCI) that does not cross the blood–brain barrier, such as carbidopa or benserizide, sufficient concentration of levodopa reaches the central nervous system. In most patients 75 to 100 mg of a DCI are needed per day to effectively block blood stream conversion to DA. However, patients with early nausea from carbidopa/levodopa therapy often benefit from additional carbidopa (Lodosyn).48 Levodopa has been used in the treatment of PD for almost 40 years, and remains the subject of much debate. During the late 1980s and 1990s concerns regarding the potential for hastening disease progression were put forward in the setting of increased emphasis on dopamine agonists. However, the ‘‘neurotoxic’’ concerns raised regarding this amino acid remain completely unproven, and every effort should be made to educate patients that the potential for motor complications associated with levodopa does not translate to hastening disease progression. In a carefully designed trial to assess the disease modifying effects of levodopa, Fahn and colleagues49 conducted a randomized, double-blind, placebo-controlled trial in 361 subjects with early PD. Subjects received levodopa doses of 150 mg, 300 mg, and 600 mg daily or a matching placebo for a period of 40 weeks, followed by a 2-week washout period. The severity of parkinsonism increased more in the placebo group than in all groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo
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group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and 1.4 in those receiving 600 mg daily (P<.001), suggesting that levodopa may have a disease-modifying effect. Nonetheless, the subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo. AMANTADINE
Amantadine is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that has shown potential for reducing dyskinesias in patients with PD.50 A study of amantadine as an adjunct to levodopa in 11 patients with advanced PD demonstrated a 52% reduction in severity of dyskinesia compared with no change with placebo.50 In a larger, placebo-controlled, double-blind study involving 24 PD patients with levodopa-induced dyskinesias, amantadine was associated with a 24% decline in total dyskinesia score without affecting on time.51 In another study, 18 patients with advanced PD, motor fluctuations, and dyskinesias received amantadine or placebo in addition to levodopa.52 Dyskinesia scores were reduced by 60% in the amantadine-treated patients compared with the placebo-treated patients. In addition, motor fluctuations were also reduced in the amantadine-treated patients.53 In a separate report, these same investigators described reductions in dyskinesia scores unrelated to increases in parkinsonian symptoms.53 DOPAMINE AGONISTS
Dopamine agonists may be used as initial and adjunctive therapy in patients with PD, and reduce off time in levodopa-treated patients by 20% to 40% or an average of 2 hours per day.54 The mechanism of action of these agents involves direct stimulation of dopamine receptors. Currently available dopamine agonists have an ergoline or a nonergoline structure. Ergoline Dopamine Agonists
Bromocriptine is the oldest agent in this class approved for therapy in patients with PD.55 It is now rarely used in treating symptoms of PD. Pergolide is an ergoline dopamine agonist that is rapidly absorbed, reaching a peak concentration within 2 to 3 hours of administration.55 The drug has a long half-life of approximately 21 hours. In a study of 12 advanced PD patients experiencing motor fluctuations while receiving levodopa, pergolide plus levodopa significantly increased the duration of on time compared with either levodopa alone (P<.001) or bromocriptine plus levodopa (P 5 .05). The duration of therapeutic benefit was greater with pergolide than with bromocriptine (P 5 .02).56 However, the use of pergolide is now highly restricted after reports of restrictive valvular heart disease and pulmonary fibrosis.57 Cabergoline is also an ergoline dopamine agonist that has a long elimination half-life of 65 to 110 hours, and is also restricted for valvulopathy concerns. Comparison of cabergoline and pergolide in a single-blind, crossover study of 48 patients with advanced PD found similar improvements in on and off time with either medication.56 Lisuride has been evaluated as an adjunct to levodopa in a 1-year double-blind and 4-year open-label study design.57 During the first year of the study, patients were randomized to receive levodopa plus lisuride or levodopa alone. At the end of the year, oral selegiline 10 mg/d was added to both regimens. Motor improvements on UPDRS scores were significantly better in the combination therapy group, and motor complications were rare, and equivalent between the groups.
Medical Treatment of Parkinson Disease
Apomorphine is a soluble dopamine agonist administered subcutaneously by way of a specially designed syringe or catheter system and is an effective rescue treatment for patients with off periods by way of intermittent injections or as a continuous infusion for patients motor complications that are with difficult to manage. This drug is associated with nausea, orthostatic hypotension, yawning, and drowsiness.58 In a pivotal trial in the United States, 20 subjects were randomized to receive active drug and 9 to receive placebo. Results showed marked reductions in UPDRS scores (P<.001) at dosages ranging from 2.0 to 10.0 mg per injection in the active group, with a mean effective dose of 5.4 mg. Off-state events were arrested in 95% 2.4% of outpatient injections in the apomorphine group versus 23% 13.0% in the placebo group (P<.001).59 Nonergoline Dopamine Agonists
Pramipexole is a second-generation, nonergoline dopamine agonist with a half-life of 8 to 12 hours.60 Pramipexole and levodopa have been compared in a double-blind, randomized study (n 5 301) of initial treatment of early PD in the Comparison of the Agonist pramipexole with Levodopa on Motor complications of Parkinson’s Disease (CALM-PD) study.61 Eligible subjects were randomized to receive pramipexole or levodopa. A 10-week dose-escalation period was followed by a 21-month maintenance phase, during which open-label carbidopa/levodopa was available to all patients to treat emerging disability. The mean improvement in total UPDRS score from baseline to 23.5 months was greater in the levodopa group than in the pramipexole group (9.2 versus 4.5 points; P<.001), despite supplementation with open-label levodopa in both groups. However, initial pramipexole treatment resulted in significantly less wearing off, dyskinesia, or ‘‘on-off’’ motor fluctuations (28%) compared with levodopa (51%) (hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.30, 0.66; P<.001). Analysis after 4 years also found that the mean improvement in the total UPDRS score from baseline to 48 months remained higher in the levodopa group than in the pramipexole group. A significantly greater proportion of patients in the pramipexole group (72%) required levodopa supplementation compared with those in the levodopa group (59%; HR 1.64; 95% CI 1.22, 2.21; P 5 .001), however, a significantly smaller proportion of patients in the pramipexole group reached the primary end point of developing dyskinesia, wearing off or ‘‘on-off’’ fluctuations than those receiving levodopa (52% and 74%, respectively; HR 0.48; 95% CI 0.35, 0.66; P<.001). Most of the dopaminergic complications in the pramipexole group occurred after the initiation of supplementary levodopa, whereas in the levodopa group most complications occurred before the initiation of supplementary levodopa. This agent is also well studied as adjunctive therapy to levodopa. A randomized, double-blind, placebo-controlled study compared pramipexole and bromocriptine with placebo in 247 patients with advanced PD and levodopa-associated motor fluctuations showed that pramipexole decreased motor disability compared with placebo. Pramipexole was associated with improvements of 26.7% in the UPDRS Activities of Daily Living score versus 4.8% for placebo (P 5 .0002), and of 34.0% in the UPDRS Motor score versus 5.7% for placebo (P 5 .0006). The average percentage of awake hours off time was reduced by 15% in the pramipexole group (P 5 .007 versus placebo) but not to a significant extent in the bromocriptine group (P 5 .2 versus placebo).62 In a pivotal trial of pramipexole as adjunctive therapy, the average improvement in percentage of off time was 31% for pramipexole versus 7% for placebo (P 5 .0006).63 In this study, pramipexole use was also accompanied by an average 27% decrease in levodopa dosage versus 5% for placebo (P % .0001).
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Ropinirole is a nonergoline dopamine agonist with a half-life of approximately 6 hours.64 The drug is rapidly absorbed after oral administration. In a prospective, randomized, double-blind study (the Requip 056 Study), Rascol and colleagues65 compared the dopamine D2 receptor agonist ropinirole (n 5 179) with levodopa (n 5 89) over a period of 5 years in 268 patients with early PD. Eighty-five subjects in the ropinirole group (47%) and 45 subjects in the levodopa group (51%) completed the study. In the ropinirole group, 29 of the 85 patients (34%) received no levodopa supplementation. Time to dyskinesia showed a significant difference in favor of ropinirole (HR for remaining free of dyskinesia 2.82; 95% CI 1.78, 4.44; P<.001) with 20% in the ropinirole group and 45% in the levodopa group; however, motor subscores showed a significantly greater reduction in the ropinirole arm than in the levodopa arm (P 5 .008). The mean daily doses given by the end of the study were 16.5 mg of ropinirole, with an average dose of levodopa supplementation of 427 mg/d. The subjects randomized to levodopa received an average of 753 mg/d. A subset of subjects participated in a parallel neuroimaging arm with [18F]dopa positron emission tomography as an indirect marker of dopamine neuron loss.66 The 2-year study demonstrated that those originally assigned to ropinirole (n 5 68) had a 14.1% decrease of fluorodopa uptake in the putamen, compared with 22.9% decrease in those originally on levodopa (n 5 59). The interpretation of these data remains controversial. Most recently, 10-year follow-up data have been published demonstrating continued clinical benefit of ropinirole.67 In the pivotal study of adjunctive ropinirole therapy in patients with advanced PD, a greater number of patients taking ropinirole had a 20% or greater reduction in levodopa dose and off time compared with placebo (35% versus 13%; P 5 .003).68 The reduction in the average percentage of daily off time was 11.7% with ropinirole versus 5.1% for placebo (P 5 .039). Twenty-four hour ropinirole has been compared with placebo in advanced PD in a 24-week study in subjects with suboptimal control with levodopa.68 At week 24, the mean daily dose was 18.8 mg. Mean reduction in off time was 2.1 hours with ropinirole compared with 0.3 with placebo. Quality of life indicators, depression and sleep scales were also improved. A direct comparison with immediate-release ropinirole found the odds of having a 20% reduction in off time were significantly higher for the 24-hour compound compared with the immediate release compound (64% versus 51%). However, subjects in the ropinirole 24-hour arm were titrated to higher total daily doses, 18.6 mg versus 10.4 mg. Levodopa reductions were 162 mg/d versus 113 mg/d. Twenty-four hour ropinirole has a similar adverse event profile as immediate-release ropinirole. As adjunctive therapy, the most common side effects were dyskinesia (13%), nausea (11%), dizziness (8%), and somnolence (7%).68,69 Safety and Tolerability Concerns with Dopamine Agonists
Older ergoline dopamine agonists may cause vasoconstriction, painful reddish discoloration of the skin (erythromelalgia), peptic ulcer disease, and serosal fibrosis.48 Of more critical concern is the associated valvulopathy increasingly associated with the use of the ergoline agents, particularly pergolide and cabergoline. Ergoline and nonergoline dopamine agonists have been associated with confusion, hallucination, dyskinesia, sleep disorders, leg edema, and postural hypotension, which may limit the usefulness of these medications.48 Recent reports in the literature have linked dopamine agonist therapy with impulsive behaviors, such as pathologic gambling, compulsive eating, and hypersexuality.70–72 The effect seems to be dose dependent and reversible when the dose is reduced or the drug is discontinued. Somnolence
Medical Treatment of Parkinson Disease
and episodes of irresistible sleepiness seem to be a class effect of dopamine agonists.48,73 MOTOR COMPLICATIONS OF ANTI-PARKINSON THERAPY
Motor fluctuations in PD associated with levodopa are well recognized. Wearing off, defined as a generally predictable recurrence of motor and nonmotor symptoms preceding scheduled doses of antiparkinsonian medication, is related to declining dopamine storage capacity.74,75 Wearing off can develop gradually or suddenly and may be predictable or random (‘‘on-off’’ effect). Factors associated with motor complications include age at disease onset or at initiation of therapy, total daily levodopa dose, duration of treatment, and disease progression. Other off symptoms, believed to be related to low plasma levodopa levels include delayed (‘‘delayed on’’) or no response (‘‘no on’’ or ‘‘dose failure’’).8,9 In contrast to the re-emergence of off symptoms at low plasma levodopa concentrations, high plasma levels are associated with writhing or twisting involuntary movements, termed ‘‘dyskinesias.’’ Most commonly ‘‘peak-dose dyskinesias’’ are seen, and are classified as an ‘‘improvement-dyskinesia-improvement’’ (IDI) pattern. Another form, the ‘‘dyskinesia-improvement-dyskinesia’’ (DID) pattern, involves involuntary movements such as chorea or dystonia that correspond to rising and declining blood and brain levels of levodopa, and may be related to postsynaptic receptor changes.9 In patients with motor fluctuations it is useful to consider treatment of PD in terms of ‘‘presynaptic’’ (levodopa related) and ‘‘postsynaptic’’(DA agonist) therapies. Given 80% of patients are expected to have motor fluctuations after 5 years of levodopa therapy, using a ‘‘balanced’’ approach may minimize the side effects associated with a monotherapeutic emphasis (Fig. 1).48 Presynaptic treatment strategies in PD involve theoretical maintenance of physiologic synaptic concentrations of dopamine by keeping plasma levodopa levels within a therapeutic window. Initially, this is accomplished by exogenous replacement with levodopa combined with a DCI. The addition of a COMT inhibitor, such as entacapone or tolcapone, will further increase levodopa delivery. Striatal dopamine concentrations may also be increased by adding rasagiline or selegiline, MAO-B inhibitors that inhibit the metabolism of dopamine.48 Postsynaptic strategies act directly on the striatal outflow neuron, and emphasize the use of DA agonists. Because agonists are not dependent on the transport and metabolic pathways of levodopa, they are less dependent on nigrostriatal function. Amantadine may also be considered as a postsynaptic agent.48 Wearing Off
The essential concept in treating symptoms of wearing off is to optimize motor function by maintaining steady-state concentrations of medications in what is termed a therapeutic window. This is accomplished easily in early PD, but with disease progression, the therapeutic range narrows, and wearing off is seen at low drug plasma levels. In this event, increasing dosage per dosing interval, changing to a longer-acting formulation, addition of other medications, or decreasing the dosing interval are all reliable strategies. Dyskinesia
Dyskinesias have not been reported in patients without previous exposure to levodopa. For this reason, treatment of this motor symptom generally requires
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Substantia Nigra
MAO-B inhibitors Selegiline Rasagiline Zydis-selegiline
Levodopa
BBB Carbidopa Benserazide COMT inhibitors Tolcapone Entacapone
Dopamine agonists Pramipexole Ropinirole Rotigotine Apomorphine sc
GABAA
DA
A
AC h
Striatum
Amantadine Trihexiphenidyl
Fig. 1. Presynaptic and postsynaptic therapy in PD. This diagrammatic representation of the substantia nigra and the striatum demonstrates sites of action for medications used in the treatment of PD. Levodopa, metabolized to dopamine, increases the concentration of this neurotransmitter in the brain, and is taken up by the nigrostriatal neuron. Amantadine enhances the release of dopamine in the striatum, and has some anticholinergic effects. MAO-B inhibitors indirectly increase dopamine concentration in the synapse by reducing the rate of dopamine metabolism in glial and neuronal cells. COMT inhibitors and carbidopa cross the blood–brain barrier, but increase the concentration of levodopa in the central nervous system. Dopamine agonists improve dopaminergic tone by acting at the postsynaptic membrane.
postsynaptic therapeutic intervention, initially with DA and presynaptic therapy reduction, and, if still not effective, the addition of amantadine. To manage the symptoms of dyskinesia, the dose of levodopa (with or without the addition of a dopamine agonist) may be reduced, the frequency of levodopa administration increased, or otherwise modulated. Splitting the levodopa dose regimen into more frequent lower doses is sometimes used to manage peak-dose dyskinesia; however, this often provides only modest and temporary relief. A small reduction in levodopa dose may be effective, but as the disease progresses, many patients experience a reduction in the therapeutic window for eliciting a motor response to medication without also causing a dyskinetic response. For most patients this is not acceptable, and they choose to endure the dyskinesia rather than be immobile. A study by Cristina and colleagues76 has shown that partial substitution of levodopa with high doses of dopamine agonists (if tolerability allows) reduces the severity of dyskinesia without the unacceptable ‘‘off’’ period that accompanies the isolated reduction in levodopa dose. In this study, the ropinirole dose was increased stepwise from 18.4 3.5 mg to 34.7 5.5 mg, and the daily levodopa dose was decreased from 734.1 254.8 mg to 502.8 228.4 mg. After 12 months 25/36 patients were still on high doses of ropinirole. Daily doses of levodopa and ropinirole were 489 243 mg and 34.6 4.6 mg, respectively. There was a significant reduction in dyskinesia during ‘‘on’’ periods and a reduction in dystonias during ‘‘off’’ periods (P<.001), and the intensity and duration of ‘‘off’’ periods were reduced significantly (P<.001). The high-dose dopamine agonist strategy was deemed to be safe, and larger studies are needed to assess this strategy further. For patients with severe or medical-refractory dyskinesias and sudden off periods, continuous subcutaneous infusion of apomorphine has been shown to be beneficial.77–80 A small study has shown that replacement of oral levodopa with a continuous
Medical Treatment of Parkinson Disease
waking-day subcutaneous infusion of apomorphine reduced the severity of dyskinesia by 65%, and its frequency and duration by 85%.81 However, subcutaneous infusion is impractical for many patients as shown by low compliance rates in reported studies. More than 50% of patients experience side effects in the form of injection-site nodules or paniculitis.82 Continuous infusion of carbidopa/levodopa into the duodenum by way of a percutaneous catheter has been shown to be more effective than optimized oral therapy at controlling motor fluctuations in advanced PD.83 A gel formulation of carbidopa/levodopa (Duodopa) has been approved for use in Canada and European Union countries.84 Duodopa has gained fast track status from the US Food and Drug Administration (FDA) and may soon provide patients with late-stage PD in the United States with another effective treatment option.85 Clozapine, an atypical neuroleptic, has been shown to be effective in the treatment of levodopa-induced dyskinesia in patients with severe PD, in a placebo-controlled study in 50 patients.86 A reduction in severity of dyskinesia and in the duration of ‘‘on’’ periods with dyskinesia was seen to favor the clozapine group (P<.05 and P 5 .003; respectively). However, 3 patients in the clozapine group (12%) developed eosinophilia, although this resolved rapidly after withdrawal of the drug. Clozapine can induce other serious adverse events such as neutropenia and agranulocytosis in patients with PD, and blood monitoring for the management of these effects is necessary.87,88 These associations, together with risks of myocarditis, dilated myocardiopathy, and malignant neuroleptic syndrome, require careful follow-up.89 Finally, patients experiencing severe and disabling dyskinesia as a result of antiparkinsonian therapy may be considered for surgical treatment. Ablation of brain areas that are involved in PD can reduce Parkinsonian symptoms and permit a reduction in the required dose of levodopa, and also directly affect the expression of motor complications. Deep brain stimulation (DBS) is now the favored method of antiparkinsonian surgery as it mimics the effects of ablative procedures but does not create a brain lesion. Thalamic, subthalamic nucleus, and pallidal DBS have been shown to reduce motor complications in PD patients.90 Deuschl and colleagues91 demonstrated a significant improvement in overall quality of life in patients treated with bilateral subthalamic DBS compared with matched controls who received only best medical therapy.91 This outcome took into account motor efficacy and reduction of dyskinesia. Continuous subthalamic stimulation with DBS at earlier stages of the disease to reduce the required levodopa dose and therefore prolong time to development of dyskinesia has recently shown promise in a randomized trial by Schupbach and colleagues92 The perioperative surgical risks, however, are not trivial and need to be assessed for each individual.93 NONMOTOR SYMPTOMS IN PARKINSON DISEASE
Nonmotor symptoms in PD are increasingly recognized as significant cause of disability, and may involve almost any aspect of the nervous system. Autonomic nervous system dysfunction includes gastrointestinal disturbances, urogenital dysfunction, orthostatic hypotension, and thermoregulatory difficulties. Higher cortical dysfunction results in cognitive changes, whereas basal ganglia disturbances may result in impulsive or compulsive behaviors. Brainstem involvement may result in fatigue, bulbar, respiratory, and sleep dysfunction. Cognitive Disorders
Dementia is reported in approximately 20% of PD patients, and in more than 35% of patients beyond 70 years of age.94–96 A long-term follow-up study of 233 subjects
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found features of dementia were present in 60.1% of subjects by 12 years, and others report significant cognitive symptoms in more than 80% of end-stage patients.97 Symptoms of dementia may be subdivided into subcortical and cortical presentations.98 Subcortical dementia affects information processing (visuospatial, attentional, and executive functions). Cortical dementia is seen in Alzheimer disease (AD) and diffuse Lewy body (DLB) disease, and interferes with storage processing (memory and language).99 Cholinesterase inhibitors have been shown to improve cognitive impairment and other behavioral problems associated with PD, but may aggravate parkinsonian symptoms.100,101 A double-blind, randomized, placebo-controlled, 10-week study of 14 patients on donepezil (5 or 10 mg/d) was associated with a 2.1 point increase in the mean Mini Mental State Evaluation (MMSE) score compared with 0.3 point increase on placebo, without worsening of parkinsonism.102 A study of 541 PD patients with symptoms of dementia randomized to rivastigmine or placebo demonstrated significant benefit in the mean Alzheimer Disease Assessment Scale-Cognitive Component (ADAS-cog) score (2.1 points in the active group versus 0.7 in the placebo group [P<.001]) and the MMSE (0.8 in the active group versus 0.2 in the placebo group [P 5 .03]).103 Nausea, vomiting, dizziness, and tremor were significantly more frequent in the rivastigmine group. It should be noted that 55.5% of the active subjects were receiving 9 to 12 mg, a dose substantially lower than the suggested dose of 24 mg/d. A follow-up report demonstrated sustained benefit in a 48-week extension study.104 Another rivastigmine report of 487 subjects reports significant improvements in attention.105 A 12-week study comparing donepezil and rivastigmine found similar improvements in cognition, but that donepezil was better tolerated.106 Memantine is reported to improve symptoms in moderate cases of AD and PD, but is also known to trigger psychosis in some PD patients. Because the memantine potencies at NMDA receptors and dopamine D2 receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors.107 Psychiatric Disorders
Psychosis in PD is linked to cognitive decline and mortality, and the criteria for psychosis in PD were recently reviewed by a National Institutes of Health working group.108 A review of PD patients with psychosis found that after 2 years, hallucinations were linked to dementia (68%), nursing home placement (42%), or death (25%).109,110 Psychosis in PD typically begins 10 years after diagnosis, and early onset psychosis suggests the diagnoses of DLB disease, AD, or a pre-existing psychiatric diagnosis. Autopsy series report high concentrations of Lewy bodies in the parahippocampus, amygdala, and frontal, temporal, and parietal lobes. Symptoms of psychosis include hallucinations and delusional thought. Presence or passing (vague images in the peripheral vision) hallucinations and visual illusions are early symptoms. Persistent images are superimposed on the normal environment.108 Visual hallucinations are by far the most common type of hallucinations, and are usually well-formed people or animals, or inanimate objects.108 Caregivers report that alerting stimuli will usually improve symptoms. Delusions are paranoid, usually spousal infidelity or abandonment. Grandiose, somatic and religious delusions are infrequent.111 Delirium is common in PD patients due to their comorbid medical problems and multiple medications. Distinguishing delirium from drug-induced psychosis may be difficult, especially in a patient with dementia.112 Fluctuating levels of consciousness, marked declines in cognitive performance, increased confusion, and disorientation
Medical Treatment of Parkinson Disease
from baseline are the hallmark signs. In psychotic patients, baseline memory, orientation, and cognition are unimpaired. Two trials compared low-dose clozapine versus placebo with a significantly better outcome for clozapine regarding efficacy and motor functioning.113,114 More recently, 27 subjects with PD and recent-onset psychosis were randomly allocated to 2 arms of 22 weeks treatment with quetiapine or clozapine. Both drugs were equally effective. Clozapine had an advantage over quetiapine in controlling the frequency of hallucinations (P 5 .097) and had a significant advantage in reducing delusions (P 5 .011).115,116 In 2 further placebo controlled trials, olanzapine did not improve psychotic symptoms and significantly caused more extrapyramidal side effects.117,118 Fourteen patients meeting entry criteria were started on aripiprazole 1 mg/d and titrated up to a maximum dose of 5 mg as needed. Although some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms.119 Depression
Depression is reported in 30% to 90% of patients with PD.120,121 A recent metaanalysis suggests that the average prevalence of major depressive disorder is 17%, with dysthymia occurring in 13% and minor depression in 22% of PD patients.122 If depression is suspected, inquiry concerning early morning awakening, low mood with diurnal variation, apathy, crying, withdrawal, and suicidal tendencies are helpful. Unique features attributed to depression in the Parkinson population include increased dysphoria, irritability, sadness, anxiety, brooding, cognitive deficits, pessimism, and suicidal ideation without action.123 In addition, PD patients seem to have less guilt and self-blame than other populations.112 Two large surveys have found that 16 to 20% of patients with PD were taking antidepressant medications.124,125 The tricyclic antidepressants, such as amitriptyline or nortriptyline, may be helpful in the treatment of depression, and in addition may improve sialorrhea because of their anticholinergic side effects. These drugs must be used cautiously in patients with cognitive compromise. SSRIs are also helpful in the treatment of depression in patients with PD and seem to be well tolerated.126 Of the SSRIs, sertraline has low selectivity for serotonin relative to dopamine reuptake and has been suggested to have the most favorable profile; compared with tricyclics it improves quality of life, particularly in activities of daily living, mobility, and stigma, and may even improve motor symptoms.127 Anxiety Syndromes and Panic Attacks
Up to 40% of patients experience clinically significant anxiety, including panic disorder, generalized anxiety, and phobic disorders.128 Symptoms difficult to differentiate from PD include tremor, numbness, tingling sensations; somatic symptoms include breathlessness, sweating, chest discomfort, gastralgia, restlessness, and dizziness.129 A more unique, yet rare, group of symptoms attributed to this population are a fear of institutionalization, of going insane, or of dying. Treatment of off-period symptoms should be addressed by adjusting dopaminergic therapy; generalized anxiety may require anxiolytic or antidepressant therapies.112 Impulse Control Disorders
Behavioral disturbances in PD associated with dopaminergic therapy have been recognized for more than 30 years. Hyperlibidinous behavior is emphasized in the early literature on levodopa, but more recently pathologic gambling, compulsive shopping, and binge eating have been recognized.130 In addition, some PD patients will
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develop compulsive motor behaviors, termed punding, such as endless fumbling through a bag, rearranging collectable objects, or journalling.131 Dopamine dysregulation syndrome describes patients taking high, and often inappropriate, doses of dopamine replacement therapy, who exhibit severe dyskinesias, cyclical mood disorder with hypomania or manic psychosis, and impairment of social and occupational functioning.132 Impulse control disorder (ICD) syndrome comprises several maladaptive behaviors that emerge with PD progression and increasing antiparkinson medications. These include disruptive behaviors or punding, destructive behaviors (compulsive spending or gambling, binge eating, or hypersexuality), and addictive behaviors regarding antiparkinson medications.133 Symptoms of ICD most often respond to reduction or withdrawal of dopaminergic therapy, particularly dopamine agonists. Others reports include SSRIs, quetiapine, valproic acid, naltrexone, topiramate, donezepil, and clozapine.134 Acamprosate was approved for the treatment of alcohol dependence in 2004. Because acamprosate is a mGluR5 antagonist and seems to modify D2 receptor density in the nucleus acumbans, it may modify impulsive behavior without significant adverse motor effects.135,136 There are also reports of improvement after deep brain stimulation surgery, in the context of dopaminergic therapy reduction. However, some also report worsening or emergence of ICD behaviors after surgery.134 Sleep Disorders
Sleep difficulties are estimated to occur in 60% to 98% of patients, and nighttime awakenings are 3 times more frequent in PD patients than in healthy age-matched controls (38.9% versus 12%).137 Polysomnography found that PD patients not taking medication had less total sleep time, less sleep efficiency, more frequent awakenings, and greater overall waking time compared with controls.138 Excessive daytime sleepiness (EDS) is associated with advancing disease, increasing dopaminergic therapy, longer duration of disease and male gender.139,140 Contributing factors include intrinsic abnormalities in PD, concurrent medical illness, sedating medication, and the effects of nocturnal sleep disturbance. With the exception of selegeline, all anti-PD medications have some potential to induce excessive daytime sleepiness. Circadian rhythm disruption is common in advancing PD, and patients often nap frequently during the day with resulting nighttime wakefulness. The advanced sleep phase syndrome in which the patent retires early in the evening is also common in PD. Environmental factors such as noise, frequent awakenings by a bed partner, and nocturia are common causes of insomnia in the normal and PD population.137 In rapid eye movement (REM) sleep behavior disorder there is failure of the normal suppression of EMG activity during REM sleep and an absence of atonia. Affected individuals physically act out their dreams, sometimes causing injury to themselves, their bed partners, or caregivers. One study showed that 50% of PD patients undergoing screening polysomnography as part of a research protocol were found to have REM sleep behavior disorder, suggesting a 38% increase in risk of developing PD in patients diagnosed with REM sleep behavior disorder followed for a mean of 13 years.141,142 Sleep attack is a clinical phenomenon of an unavoidable and abrupt transition from wakefulness to sleep. Similar case histories for apomorphine, bromocriptine, cabergoline, pergolide, and lisuride are reported.143 Hauser and colleagues144 retrospectively reviewed reports of daytime somnolence in 22 of 45 subjects participating in 3 double-blind, randomized, placebo-controlled pramipexole clinical trials. Although no differences between active and placebo groups were seen in the double-blind
Medical Treatment of Parkinson Disease
phase, 21 of 37 subjects reported somnolence in the open-label extension studies, and 14 subjects had moderate to severe difficulties with EDS. REM behavior disorder, often the initial manifestation of parkinsonism, may respond to nighttime clonazepam or melatonin (Table 1). Modafinil 200 to 400 mg/d is effective in reversing EDS and the sedative effects of anti-PD medications.145 Despite the subjective improvement in daytime drowsiness reported by a substantial percentage of PD patients, no objective benefit on Multiple Sleep Latency Test, Epworth Sleepiness Scale (ESS), Fatigue Severity Scale, or Hamilton Depression Scale could be demonstrated in a double-blind placebo-controlled study.146 Nocturnal administration of sodium oxybate has been found in an open-label polysomnographic study involving 38 subjects to improve excessive daytime sleepiness and fatigue in patients with PD.147 Constipation
Prolonged gastrointestinal transit time is seen in more than 80% of PD patients, and constipation is described in 60% of patients.148 Mean colonic transit time is more than double the normal population. Paralytic ileus affects 7.1% of PD patients; symptoms often include abdominal bloating, pain, nausea, vomiting, and abdominal distension.149 Anismus, or an inability to relax the external anal sphincter for defecation, is seen in off periods.150 Effective treatments for constipation include increasing fluid intake, psyllium, polyethylene glycol, bisacodyl, and magnesium sulfate.151 Lubiprostone activates intestinal ClC-2 chloride channels and increases intestinal fluid secretion without altering serum electrolyte levels.152 Tegaserod maleate, a novel selective serotonin receptor type 4 (5-HT(4)), is a partial agonist that stimulates upper gastrointestinal motility.153 Another agent, macrogol, an isosomotic electrolyte, has been found to significantly increase the frequency of bowel movements and improve stool consistency.154 Prucalopride at 4 mg/d, a selective, high-affinity 5-hydroxytryptamine receptor agonist, increased bowel frequency in about 50% of patients with severe chronic constipation, but this agent has not been specifically tested in patients with PD.155 Other strategies include neostigmine, symbiotic yogurt containing components such as Bifidobacterium and fructoligosaccharide, sphincteric botulinum toxin injections, and sacral nerve stimulation.156 Urological Dysfunction
Lower urinary tract symptoms occur in 38% to 71% of patients with PD, and are attributed to loss of the dopaminergic inhibitory effect on micturation.157 Detrusor overactivity (DO) causes urgency, frequency, and incontinence. Bladder contraction is mediated through the cholinergic, parasympathetic (muscarinic) pelvic nerve, whereas relaxation results from noradrenergic sympathetic receptors at the hypogastric nerve.158 Urethral contraction is linked to noradrenergic, sympathetic hypogastric nerve and cholinergic (nicotinic), somatic pudendal nerve activity. Sexual dysfunction occurs in 12% to 60% of men with PD.159 A review of sexual functioning of 32 women found difficulties with arousal (87.5%), reaching orgasm (75.0%), and sexual dissatisfaction (37.5%). In the same survey, 43 men reported erectile dysfunction (68.4%), sexual dissatisfaction (65.1%), premature ejaculation (40.6%), and difficulties reaching orgasm (39.5%). Associated illnesses, use of medications, motor difficulties, depression, anxiety, and advanced stage of PD contributed to sexual dysfunction.160 Increased urinary frequency due to overactive bladder often improves not only with levodopa treatment161 but also with antimuscarinic oxybutynin (5 mg 3–4 times daily),
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oxybutynin transdermal patch (1 patch twice a week), tolterodine (2 mg 3 times daily), solifenacin (5–10 mg/d), or darifenacin (7.5–15 mg/d).162 More recently, botulinum toxin injections into the bladder wall have been reported to be beneficial.163,164 Sildenafil citrate has been found to be safe and effective in the treatment of erectile dysfunction associated with PD, but may unmask orthostatic hypotension.165 Orthostatic Hypotension
Orthostatic hypotension is reported in 10% to 20% of patients, and increases with age and severity of PD; if unrecognized, it may lead to unnecessary evaluations for dizziness and syncope. Symptoms include light—headedness, initial dizziness on standing, fatigue, and pain across the back of the shoulders and neck. Frequent monitoring of standing and sitting blood pressure are helpful in following this problem, and may often be done by caregivers.112,166 Orthostatic hypotension can be treated with salt, fludrocortisones, and midodrine.167,168 In 2007, the FDA approved DOPS (Droxidopa, Chelsea Therapeutics) for the treatment of orthostatic hypotension.169 Droxidopa (L-threo-3,4-dihydroxyphenylserine or L-DOPS) is a synthetic amino acid precursor of norepinephrine that has been marketed in Japan since 1989 for the treatment of orthostatic hypotension. Salivary Disturbances
Sialorrhea has been reported in as many as 78% of patients with PD.170 Although the exact mechanism of sialorrhea remains poorly understood, it is usually a function of excessive saliva production or difficulties in clearing saliva from the mouth. In the PD population, this symptom is most likely from the combination of infrequent and impaired swallowing. Three major pairs of salivary glands (parotid, submandibular, and sublingual) produce more than 90% of saliva. Drooling is a highly embarrassing PD symptom, and is often easily treated with botulinum toxin injections.171,172 SUMMARY
Treatment of symptoms of PD should be subclassified into motor and nonmotor categories. In the patient at the early stages of PD, motor symptoms should always be emphasized, but with time and disease progression nonmotor problems are increasingly important. At the early stages of PD, decisions to initiate therapy are based on the patient’s perceptions of disability, and appropriate therapies may include MAO-B inhibition, dopamine agonists, and levodopa. In the event of motor complications, a balanced approach with dopamine agonists and levodopa is recommended. Severe dyskinesias and unpredictable wearing off periods often require deep brain stimulation, but in the future less cumbersome and less costly continuous infusion therapies may be available. Eventually, nonmotor symptoms will become the primary focus of care, and a careful review of the array of these symptoms may lead to interventions that greatly improve the patient’s quality of life. REFERENCES
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61. Holloway RG, Shoulson I, Fahn S, the Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004;61(7):1044–53. 62. Guttman M, the International Pramipexole-Bromocriptine Study Group. Doubleblind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson’s disease. Neurology 1997;49(4):1060–5. 63. Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 1997;49(1):162–8. 64. Shill HA, Stacy M. Update on ropinirole in the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat 2009;5:33–6. 65. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342(20): 1484–91. 66. Whone AL, Watts RL, Stoessl AJ, et al, REAL-PET Study Group. Slower progression in early Parkinson’s disease treated with ropinirole compared with l-dopa: the REAL-PET study. Ann Neurol 2003;54(1):93–101. 67. Hauser RA, Rascol O, Korczyn AD, et al. Ten-year follow-up of Parkinson’s disease patients randomized to initial therapy with ropinirole or levodopa. Mov Disord 2007;22:2409–17. 68. Lieberman A, Olanow CW, Sethi K, et al. A multicenter trial of ropinirole as adjunct treatment for Parkinson’s disease. Ropinirole Study Group. Neurology 1998;51(4):1057–62. 69. Pahwa R, Stacy MA, Factor SA, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007;68:1108–15. 70. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61(3):422–3. 71. Nirenberg MJ, Waters C. Compulsive eating and weight gain related to dopamine agonist use. Mov Disord 2006;21(4):524–9. 72. Prescrire Editorial Staff. Hypersexuality due to dopaminergic drugs. Prescrire Int 2005;14(80):224. 73. Etminan M, Gill S, Samii A. Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease: a meta-analysis. Drug Saf 2003;26(6):439–44. 74. Stacy M, Hauser R, Oertel W, et al. End of dose wearing-off in Parkinson’s disease: a 9-question survey assessment. Clin Neuropharmacol 2006;29: 312–21. 75. Stacy M, Bowron A, Guttman M, et al. Identification of motor and nonmotor wearing off in Parkinson’s disease: comparison of a patient questionnaire versus a clinician assessment. Mov Disord 2005;20(6):726–33. 76. Cristina S, Zangaglia R, Mancini F, et al. High-dose ropinirole in advanced Parkinson’s disease with severe dyskinesias. Clin Neuropharmacol 2003;26: 146–50. 77. Katzenschlager R, Hughes A, Evans A, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord 2005;20:151–7. 78. Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998;64:573–6.
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79. Kanovsky P, Kubova D, Bares M, et al. Levodopa-induced dyskinesias and continuous subcutaneous infusions of apomorphine: results of a two-year, prospective follow-up. Mov Disord 2002;17:188–91. 80. Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson’s disease: long-term follow-up study of 64 patients. Mov Disord 2002;17:1235–41. 81. Stocchi F, Olanow CW. Continuous dopaminergic stimulation in early and advanced Parkinson’s disease. Neurology 2004;62:S56–63. 82. Koller W, Stacy M. Other formulations and future considerations for apomorphine for subcutaneous injection therapy. Neurology 2004;62:S22–6. 83. Kurth MC, Tetrud JW, Tanner CM, et al. Double-blind, placebo-controlled, crossover study of duodenal infusion of levodopa/carbidopa in Parkinson’s disease patients with ‘on-off’ fluctuations. Neurology 1993;43:1698–703. 84. Solvay Pharmaceuticals. Available at: http://www.solvaypharmaceuticals.com/ products/group/product/0,30641-2-0,00.htm. Accessed June 20, 2008. 85. Solvay’s Duodopa intestinal gel gets FDA fast track status for Parkinson’s. AFX News Limited; Feb 19, 2008. Available at: http://www.forbes.com/markets/ feeds/afx/2008/02/19/afx4667956.html. Accessed June 30, 2008. 86. Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology 2004;62:381–8. 87. Ellis T, Cudkowicz ME, Sexton PM, et al. Clozapine and risperidone treatment of psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2000;12: 364–9. 88. Rudolf J, Grond M, Neveling M, et al. Clozapine-induced agranulocytosis and thrombopenia in a patient with dopaminergic psychosis. J Neural Transm 1997;104:1305–11. 89. Ziegenbein M, Steinbrecher A, Garlipp P. Clozapine-induced aplastic anemia in a patient with Parkinson’s disease. Can J Psychiatry 2003;48:352. 90. Metman LV, O’Leary ST. Role of surgery in the treatment of motor complications. Mov Disord 2005;20(Suppl 11):S45–56. 91. Dueschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006;355:896–908. 92. Schu¨pbach WMM, Malteˆte D, Houeto JL, et al. Neurosurgery at an earlier stage of Parkinson disease. Neurology 2007;68:267–71. 93. Ferreira JJ, Rascol O. Prevention and therapeutic strategies for levodopainduced dyskinesias in Parkinson’s disease. Curr Opin Neurol 2000;13:431–6. 94. Biggins CA, Boyd JL, Harrop FA, et al. A controlled, longitudinal study of dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992;55: 566–72. 95. Buter TC, van den Hout A, Matthews FE, et al. Dementia and survival in Parkinson disease: a 12-year population study. Neurology 2008;70:1017–22. 96. Hely MA, Reid WGJ, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008;23: 837–44. 97. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord 2007;22:2314–24. 98. Tro¨ster AI. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease with dementia: differentiation, early detection, and implications for ‘‘mild cognitive impairment’’ and biomarkers. Neuropsychol Rev 2008;18:103–19.
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99. Halliday G, Hely M, Reid W, et al. The progression of pathology in longitudinally followed patients with Parkinson’s disease. Acta Neuropathol 2008;115:409–15. 100. Leroi I, Brandt J, Reich SG, et al. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson’s disease. Int J Geriatr Psychiatry 2004;19:1–8. 101. Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson’s disease: a randomised, double blind, placebo controlled, crossover study. J Neurol Neurosurg Psychiatry 2005;76:934–9. 102. Aarsland D, Laake K, Larsen JP, et al. Donepezil for cognitive impairment in Parkinson’s disease: a randomized controlled study. J Neurol Neurosurg Psychiatry 2002;72:708–12. 103. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004;351:2509–18. 104. Poewe W, Wolters E, Emre M, et al, EXPRESS Investigators. Long-term benefits of rivastigmine in dementia associated with Parkinson’s disease: an active treatment extension study. Mov Disord 2006;21:456–61. 105. Wesnes KA, McKeith I, Edgar C, et al. Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 2005;65:1654–6. 106. Wilkinson DG, Passmore AP, Bullock R, et al. A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. Int J Clin Pract 2002;56:441–6. 107. Seeman P, Caruso C, Lasaga M. Memantine agonist action at dopamine D2High receptors. Synapse 2008;62(2):149–53. 108. Ravina B, Marder K, Fernandez H, et al. Diagnostic criteria for psychosis in Parkinson’s disease: report of an NINDS/NIMH work group. Mov Disord 2007;22: 1061–8. 109. Goetz CG, Stebbins GT. Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology 1993;43:2227–9. 110. Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology 1995;45:669–71. nelon G. Psychosis in Parkinson’s disease: phenomenology, frequency, risk 111. Fe factors, and current understanding of pathophysiologic mechanisms. CNS Spectr 2008;13(3 Suppl 4):18–25. 112. Stacy M. Managing late complications of Parkinson’s disease. Med Clin North Am 1999;83:469–81. 113. Parkinson Study Group. Low-dose clozapine for the treatment of drug induced psychosis in Parkinson’s disease. N Engl J Med 1999;340:757–63. 114. The French Clozapine Parkinson Study Group. Clozapine in drug-induced psychosis in Parkinson’s disease. Lancet 1999;353(9169):2041–2. 115. Rabey JM, Prokhorov T, Miniovitz A, et al. Effect of quetiapine in psychotic Parkinson’s disease patients: a double-blind labeled study of 3 months’ duration. Mov Disord 2007;22:313–8. 116. Merims D, Balas M, Peretz C, et al. Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson’s disease psychosis. Clin Neuropharmacol 2006;29:331–7. 117. Kurlan R, Cummings J, Raman R, et al, Alzheimer’s Disease Cooperative Study Group. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology 2007;68(17):1356–63. 118. Klein C, Prokhorov T, Miniovich A, et al. Long-term follow-up (24 months) of quetiapine treatment in drug-induced Parkinson disease psychosis. Clin Neuropharmacol 2006;29(4):215–9.
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119. Friedman JH, Berman RM, Goetz CG, et al. Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson’s disease. Mov Disord 2006;21:2078–81. 120. Ravina B, Camicioli R, Como PG, et al. The impact of depressive symptoms in early Parkinson’s disease. Neurology 2007;69:342–7. 121. Dooneief G, Mirabello E, Bell K, et al. An estimate of the incidence of depression in idiopathic Parkinson’s disease. Arch Neurol 1992;49:305–7. 122. Tandberg E, Larsen JP, Aarsland D, et al. The occurrence of depression in Parkinson’s disease: a community—based survey. Arch Neurol 1996;53:175–9. 123. Borek LL, Amick MM, Friedman JH. Non-motor aspects of Parkinson’s disease. CNS Spectr 2006;11:541–54. 124. Brandt-Christensen M, Kvist K, Nilsson FM, et al. Treatment with antiparkinson and antidepressant drugs: a register-based, pharmaco-epidemiological study. Mov Disord 2007;22:2037–42. 125. Antonini A, Colosimo C, Marconi R, et al, PRIAMO study group. The PRIAMO study: background, methods and recruitment. Neurol Sci 2008;29(2):61–5. 126. Dell’Angnello G, Ceravalo R, Nuti A, et al. SSRIs do not worsen Parkinson’s disease: evidence from an open-label, prospective study. Clin Neuropharmacol 2001;24:221–7. 127. Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, et al. Motor changes during sertraline treatment in depressed patients with Parkinson’s disease. Eur J Neurol 2008;15:953–9. 128. Seimers ER, Shekhar A, Quaid K, et al. Anxiety and motor performance in Parkinson’s disease. Mov Disord 1993;8:501–6. 129. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology 2002;59(3):408–13. 130. Ferrara JM, Stacy M. Impulse control disorders and Parkinson’s disease. CNS Spectr 2008;13:690–8. 131. Fernandez HH, Friedman JH. Punding on L-dopa. Mov Disord 1999;14:836–8. 132. Evans AH, Katzenschlager R, Paviour D, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19: 397–405. 133. Stacy M. Impulse control disorder in Parkinson’s disease: criteria for diagnosis. Mov Disord 2008;23(Suppl 9):1349–51. 134. Galpern WR, Stacy M. Management of impulse control disorders in Parkinson’s disease. Curr Treat Options Neurol 2007;9:189–97. 135. De Witte P, Littleton J, Parot P, et al. Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 2005; 19:517–37. 136. Cowen MS, Adams C, Kraehenbuehl T, et al. The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine system. Addict Biol 2005;10:233–42. 137. Stacy M. Sleep disorders in Parkinson’s disease: epidemiology and management. Drugs Aging 2002;19:733–9. 138. Van Hilten B, Hoff JI, Huub AM. Sleep disruption in Parkinson’s disease. Arch Neurol 1995;51:922–8. 139. Verban D, van Rooden SM, Visser M, et al. Nighttime sleep problems and daytime sleepiness in Parkinson’s disease. Mov Disord 2008;23:35–41. 140. Tandberg E, Larsen JP, Karlsen K. Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study. Mov Dis 1999;14: 922–7.
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141. Comella CL, Tanner CM, Ristanovic RL. Polysomnographic sleep measures in Parkinson’s disease patients with treatment induced hallucinations. Ann Neurol 1993;34:710–4. 142. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a Parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996;46:388–93. 143. Frucht S, Rogers JD, Greene PE, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999;52: 1908–10. 144. Hauser RA, Gauger L, Anderson WM, et al. Pramipexole induced somnolence and sleep episodes of daytime sleep. Mov Disord 2000;15:658–63. 145. Adler CH, Caviness JN, Hentz JG, et al. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 2003;18:287–93. 146. Ondo WG, Fayle R, Atassi F, et al. Modafinil for daytime somnolence in Parkinson’s disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005;76:1636–9. 147. Ondo WG, Perkins T, Swick T, et al. Sodium oxybate for excessive daytime sleepiness in Parkinson disease: an open-label polysomnographic study. Arch Neurol 2008;65:1337–40. 148. Wullner U, Schmitz-Hubsch T, Antony G, et al. Autonomic dysfunction in 3414 Parkinson’s disease patients enrolled in the German Network on Parkinson’s disease: the effect of aging. Eur J Neurol 2007;14:1405–8. 149. Verbaan D, Marinus J, Visser M, et al. Patient-reported autonomic symptoms in Parkinson disease. Neurology 2007;69:333–41. 150. Mathers SE, Kempster PA, Law PJ, et al. Anal sphincter dysfunction in Parkinson’s disease. Arch Neurol 1989;46:1061–4. 151. Eichhorn TE, Oertel WH. Macrogol 3350/electrolyte improves constipation in Parkinson’s disease and multiple system atrophy. Mov Disord 2001;16:1176–7. 152. Degen L, Petrig C, Studer D, et al. Effect of tegaserod on gut transit in male and female subjects. Neurogastroenterol Motil 2005;17:821–6. 153. Sullivan KL, Staffetti JF, Hauser RA, et al. Tegaserod (Zelnorm) for the treatment of constipation in Parkinson’s disease. Mov Disord 2006;21:115–6. 154. Zangaglia R, Martignoni E, Glorioso M, et al. Macrogol for the treatment of constipation in Parkinson’s disease. A randomized placebo-controlled study. Mov Disord 2007;22:1239–44. 155. Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008;358(22):2344–54. 156. Kapoor S. Management of constipation in the elderly: emerging therapeutic strategies. World J Gastroenterol 2008;14(33):5226–7. 157. Fitzmaurice H, Fowler CJ, Rickards D, et al. Micturition disturbance in Parkinson’s disease. Br J Urol 1985;57:652–6. 158. Ransmayr GN, Holliger S, Schletterer K, et al. Lower urinary tract symptoms in dementia with Lewy bodies, Parkinson’s disease and Alzheimer disease. Neurology 2008;70:299–303. 159. Brown RG, Jahanshahi M, Quinn N, et al. Sexual function in patients with Parkinson’s disease and their partners. J Neurol Neurosurg Psychiatry 1990;53:480–6. 160. Bronner G, Royter V, Korczyn AD, et al. Sexual dysfunction in Parkinson’s disease. J Sex Marital Ther 2004;30:95–105. 161. Brusa L, Petta F, Pisani A, et al. Acute vs chronic effects of l-dopa on bladder function in patients with mild Parkinson disease. Neurology 2007;68:1455–9.
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162. Brunton S, Kuritzky L. Recent developments in the management of overactive bladder: focus on the efficacy and tolerability of once daily solifenacin succinate 5 mg. Curr Med Res Opin 2005;21:71–80. 163. Ouslander JG. Management of overactive bladder. N Engl J Med 2004;350: 786–99. 164. Sahai A, Khan MS, Arya M, et al. The overactive bladder: review of current pharmacotherapy in adults. Part 2: treatment options in cases refractory to anticholinergics. Expert Opin Pharmacother 2006;7:529–38. 165. Hussain IF, Brady CM, Swinn MJ, et al. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001;71:371–4. 166. Hillen ME, Wagner ML, Sage JI. ‘‘Subclinical’’ orthostatic hypotension is associated with dizziness in elderly patients with Parkinson’s disease. Arch Phys Med Rehabil 1996;77:710–2. 167. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind placebo-controlled study with midodrine. Am J Med 1993;95: 38–48. 168. Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. JAMA 1997;277:1046–51. 169. Kaufmann H. The discovery of the pressor effect of DOPS and its blunting by decarboxylase inhibitors. J Neural Transm Suppl 2006;70:477–84. 170. Chou KL, Evatt M, Hinson V, et al. Sialorrhea in Parkinson’s disease: a review. Mov Disord 2007;22:2306–13. 171. Sheffield JK, Jankovic J. Botulinum toxin in the treatment of tremors, dystonias, sialorrhea and other symptoms associated with Parkinson’s disease. Expert Rev Neurother 2007;7:637–47. 172. Capaccio P, Torretta S, Osio M, et al. Botulinum toxin therapy: a tempting tool in the management of salivary secretory disorders. Am J Otolaryngol 2008;29: 333–8.
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Surgical Treatment of Movement Disorders Benzi M. Kluger, MDa,*, Olga Klepitskaya, MDa, Michael S. Okun, MDb,c KEYWORDS Movement disorders Surgical treatment Deep brain stimulation Parkinson’s disease Dystonia Essential tremor
The past 2 to 3 decades have been marked by a resurgence in surgical approaches for the treatment of movement disorders, specifically the creation of neuroanatomical lesions and deep brain stimulation (DBS). This renewed interest has been spurred on by several factors including (1) improvements in our understanding of the neurophysiology and anatomy of movement disorders, (2) the refinement of DBS as a surgical approach, (3) improvements in neurosurgery and neuroimaging, which have enhanced our ability to localize brain structures, and (4) an increasing role for surgical interventions, especially in circumstances in which current pharmacologic treatments have reached their limits. Appropriate patient selection for surgery can result in a compelling treatment option for a variety of movement disorders, with the most common to date including Parkinson’s disease (PD), dystonia, and essential tremor. HISTORY
Surgical treatments for movement disorders can be traced to the late 1800s and early 1900s where applications included lesions placed in the motor cortex,1 the corticospinal tracts,2 and the cerebral peduncles.3 Early attempts at therapy were focused mainly on treating hyperkinetic movement disorders, including tremor. Not surprisingly, these early treatments had an unacceptable rate of side effects, particularly of motor weakness. With the introduction of the stereotactic head frame technology in
This work was supported by an American Academy of Neurology Foundation Clinical Research Training Fellowship (B.M.K.), and the National Parkinson Foundation Center of Excellence, Gainesville, FL. a University of Colorado Denver and Health Sciences Center, Academic Office 1 mailstop B185, PO Box 6511, Aurora, CO 80045, USA b Department of Neurology, University of Florida, 100 S. Newell Dr, Room L3-100, PO Box 100236, Gainesville, FL 32610, USA c University of Florida Movement Disorders Center, McKnight Brain Institute, 100 S. Newell Dr. Room L3-100, PO Box 100236, Gainesville, FL, USA * Corresponding author. E-mail address:
[email protected] (B.M. Kluger). Neurol Clin 27 (2009) 633–677 doi:10.1016/j.ncl.2009.04.006 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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the late 1940s by Spiegel and colleagues,4 targeting very small subcortical structures became a more realistic possibility. However, there was still a paucity of basic or clinical scientific evidence to know which nodes of this circuitry would be most appropriate for surgical interventions. A breakthrough in our understanding came in 1953, when Cooper accidentally ligated the anterior choroidal artery during a pedunculotomy, and this dramatically improved his patient’s tremor. The ligation interrupted the main blood supply to many structures in the basal ganglia, including the globus pallidus, a finding confirmed by pathologic examination of some of Cooper’s5 similar but later cases. Although this procedure was abandoned as a result of unacceptable side effects, and because of difficulty in reproducing Cooper’s success, it was followed by more refined surgical approaches that focused largely on many subcortical structures. In 1955, Hassler6 reported that thalamotomy was more effective than pallidotomy for tremor. Cooper subsequently endorsed this surgical approach, adding that results of thalamotomy were more consistent than those of pallidotomy. In 1960, Svennilson and colleagues7 reported that the clinical results of pallidotomy were location dependent, with posterior lesions demonstrating superior results to anterior lesions. Although this article demonstrated that posteroventral pallidotomy improved all the cardinal motor signs of PD, this research did not influence general clinical practice, which continued to favor the thalamotomy. In 1963, a few authors published results suggesting that subthalamotomy may obtain tremor improvement similar to that with thalamotomy.8 However, the fear of inducing hemiballism and subsequent reports showing clinical improvements in only a minority of patients with subthalamotomy led to thalamotomy being the procedure of choice.9 The introduction of levodopa in 1967 for the treatment of PD provided a remarkable therapeutic benefit, which initially threatened to make all surgical approaches to PD obsolete.10 The 1980s brought a renewed interest in surgical approaches for movement disorders, beginning with the use of thalamotomy for severe drug-resistant tremor.11 In 1992 Laitinen and colleagues12 replicated Leksell’s benefits for posteroventral pallidotomy in all cardinal PD motor signs, and in 1997, Gill and Heywood13 reported their results of bilateral subthalamotomy. This renewed interest in surgery was driven largely by an increased recognition of the limitations of long-term levodopa therapy. Equally important were advances made in our understanding of basal ganglia circuitry and physiology,14 including the emergence of animal models of basal ganglia disease.15 In 1987, Benabid and colleagues16 observed that high-frequency electrical stimulation to the ventral intermediate (VIM) nucleus of the thalamus, usually performed as part of neurosurgical localization, could be left in place and have dramatic chronic effects in improving tremor. This observation fueled the further development of DBS as a means of treating basal ganglia disorders. Although there are no adequately powered trials published to date comparing DBS to lesion therapy, DBS has virtually supplanted surgical lesions mainly due to its reversibility, flexibility in changing settings, and its improved tolerability in patients requiring bilateral surgical treatment (eg, avoiding speech and swallowing problems). We focus on DBS in this review, recognizing that the efficacy and general principles of lesion therapy are similar and that there may be cases in which ablative surgery may be advantageous.18 MECHANISMS OF ACTION
Ablative brain lesions seem to achieve their functional improvement through the disruption of aberrant network activity. The pioneering work of Delong14 and Albin and Young17 in describing the direct and indirect pathways as well as the parallel
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circuitry of the basal ganglia circuitry has laid the foundation for identifying potential regions where surgical interventions may improve symptoms. PD is known to result in increased firing rates and changes in the pattern of activity of both the globus pallidus interna (GPi) and subthalamic nucleus (STN).19 These patterns have been confirmed in humans by physiologic recordings from PD patients undergoing DBS or ablative surgery.20 Moreover, ablative lesions within the GPi and STN appear to somewhat normalize this abnormal physiologic activity and are associated with functional improvements.15 Although DBS appears to produce an informational lesion (a term coined by Grill) that may mimic many of the effects from ablative surgery, the physiologic mechanisms are thought to be more complex.21 In simple terms, DBS is thought to work by inhibiting cells close to the stimulating electrode and by exciting passing fiber tracts, but this simplistic model does not consider many of the complex changes that may contribute to DBS effects. There is currently evidence to support the existence of several potential sites of action including the following: 1. Inhibition of neuronal cell bodies in close proximity to the electrode. Evidence from primate recordings demonstrates a reduction in firing rates of cells adjacent to stimulation electrodes during therapeutic stimulation of both STN and GPi.22 This reduction in firing rate may be due to a depolarization block through alterations of potassium or sodium channels and/or alterations in the balance of presynaptic excitatory and inhibitory afferents.23 Depolarization blockade as a singular mechanism has fallen out of support of most experts in the field. 2. Stimulation of axons in close proximity to the electrode. In fact, studies have shown increased output from an inhibited nucleus, which is believed to be due to action potentials initiated via axonal stimulation.24 This activity is time locked to the stimulator frequency. Computer models have further suggested that the therapeutic efficacy of STN is strongly linked to axonal activation.25 3. Stimulation of fiber tracts passing through the field of stimulation. DBS currents sufficient for axonal activation may spread beyond the anatomic target to adjacent fiber tracts. Several tracts important to basal ganglia functioning pass in close proximity to the STN and have been hypothesized to contribute to the clinical effect of DBS, including cerebellothalamic fibers (tremor reduction), nigrostriatal tracts (increase striatal dopamine release), and the zona incerta (all cardinal motor symptoms).23 4. Alterations in neurotransmitter release and synthesis. As noted above, activation of the nigrostriatal tract may increase striatal dopamine release. Other microdialysis studies of STN DBS in rats have demonstrated modulatory effects on both glutamate and g-aminobutyric acid release within basal ganglia circuits.26 5. Alterations in network dynamics. DBS may interrupt pathologic neural output by providing stimulation greater than a neuron’s spontaneous activity and thus preempting intrinsic firing. This has been referred to as an ‘‘informational lesion,’’ because it replaces irregular pathologic activity with regular but ‘‘informationally’’ neutral output.21 Functional imaging studies have demonstrated changes in multiple nodes of the motor circuitry, including the motor cortex, supplementary motor area (SMA) and cerebellum with symptom improvement following DBS. 6. Chronic network changes. As discussed in the section on dystonia, many clinical improvements take days to weeks, suggesting that they are dependent on neuroplastic changes. Consistent with this concept, studies have demonstrated longterm changes in synaptic plasticity following DBS.27 There is also preliminary evidence to suggest that DBS may confer some neuroprotective effects.28
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These mechanisms are not mutually exclusive, and it appears likely that the therapeutic effects of DBS are the result of multiple mechanisms.26 Moreover, there is evidence that the mechanisms of DBS may not be identical across disease states,29 subcortical targets,30 or stimulation parameters.31 SELECTION OF SURGICAL CANDIDATES
The evolution of DBS therapy has resulted in the acceptance that selection of appropriate patients is critically important to the therapeutic benefit. In fact, only a small subset of patients (10%–20%) may be appropriate at any one time.32 Currently, patients with PD, dystonia, and essential tremor (ET) may be considered surgical candidates after they have failed medical management (DBS is Food and Drug Administration approved for these indications in the United States). Patients must be motivated and have the resources available to participate in the extensive follow-up required to program and monitor the DBS device. In addition, potential candidates must have an acceptable risk benefit ratio favoring surgery. All indications (PD, ET, and dystonia) for DBS carry risks, especially with comorbidities such as age, cognitive dysfunction, frailty, psychiatric disease, cerebral atrophy, blood thinners, and especially hypertension. Among dystonia patients, primary and/or tardive dystonia seems to have the best response, whereas patients with other forms of secondary dystonia, including structural changes or neurometabolic diseases, tend to have less-predictable responses to DBS.33 However, an increasing number of successes may be seen in these secondary dystonias with appropriate selection of target and stimulus parameters.34 In PD, patients and clinicians should be aware that DBS will potentially benefit only symptoms that are levodopa responsive.35 DBS can improve ‘‘on’’ time, reduce on-off fluctuations, and decrease dyskinesias but, with the exception of tremor, does not provide motor benefits that exceed the patient’s best ‘‘on’’ medication state (with the current available targets of STN or GPi). It is thus critical for potential PD DBS candidates to have the Unified Parkinson disease rating scale (UPDRS) completed in both the practically defined ‘‘on’’ and ‘‘off’’ states. In general, clinics should follow the Core Assessment Program for Surgical Intervention Therapies in PD criteria, which include a minimal disease duration of 5 years, a diagnosis of idiopathic PD, screening for depression and cognitive decline, and assessment for minimal motor improvement of 30% based on UPDRS scores.35 One exception to this 30% rule is medically refractory tremor in PD, which may occur in 20% or more patients. There is currently insufficient evidence to support the use of ‘‘early’’ DBS in any movement disorder, although considerations are being explored in research arenas, including effects on quality of life (QOL), decreased surgical mortality (vs delayed operations), cost savings, and the possibility that DBS may have a diseasemodifying effect.36 Caution is required in how we define ‘‘early’’ disease, particularly in patients without significant disability, patients who have not received adequate trials of standard medications, and in patients with short disease duration who may not have a definitive diagnosis. Although potential surgical candidates may be identified by general neurologists, the decision to proceed through surgery is in the best circumstances made by an experienced multidisciplinary/interdisciplinary team typically including a movement disorders neurologist, neurosurgeon, psychiatrist, neuropsychologist, and, in some circumstances, a social worker, speech therapist, occupational therapist, and/or physical therapists (Fig. 1).37 Each member of the multidisciplinary team should have a specific role in this evaluation and should contribute to a discussion by the team regarding the diagnosis, scale changes, expectations of benefit, risk, financial
Surgical Treatment of Movement Disorders
Fig. 1. Multidisciplinary team.
issues, QOL, target choice, staged versus simultaneous implantation if bilateral devices may be required, and the ability of the patient to meet the schedule of follow-up appointments. The neurologist must ensure that patients have been correctly diagnosed and that they present with symptoms likely to respond to DBS. They must have exhausted medical options and their symptoms carefully quantified with appropriate disease-specific scales (eg, on/off UPDRS for PD, tremor rating scale [TRS] for ET, and Burke-Fahn-Marsden dystonia rating scale [BFMDRS]). In the case of PD, it is recommended that the patient have at least 5 years of symptoms as it is frequently difficult to distinguish levodopa-responsive parkinsonian syndromes that may be manifesting in early stages. The Florida Surgical Questionnaire for Parkinson’s Disease (FLASQ-PD) was developed as a screening questionnaire to aid in the identification of surgical candidates with PD (Box 1).37 It is important that the neurologist appropriately educates the patient, because unrealistic expectations regarding the benefits and convenience of DBS are a frequent cause of patient’s perception of DBS failure. As discussed later, significant nonmotor complications, including mood, cognition, and speech, may occur following DBS and may be in part preventable through the appropriate screening of high-risk patients.38 There is some evidence that younger patients (younger than 70 years) may have less risk of cognitive complications; however, this is not an absolute rule, and many older patients have excellent outcomes following DBS. STIMULATOR PLACEMENT AND PROGRAMMING
The accurate localization of DBS targets requires a combination of high-quality neuroimaging, stereotactic localization (frameless or frame-based), and physiologic recordings. The superior resolution of subcortical structures evident on magnetic resonance imaging (MRI) has resulted in its use as the primary imaging modality at most centers. Many centers fuse computed tomography with MRI images to save time on the day of surgery (by performing the MRI the day before) and postoperatively to localize lead
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Box 1 FLASQ-PD A. Diagnosis of idiopathic Parkinson’s disease Diagnosis 1: Is Bradykinesia present? Yes/No (Please circle response) Diagnosis 2: (check if present): —Rigidity (Stiffness in arms, leg, or neck) —4–6 Hz resting tremor —Postural instability not caused by primary visual, vestibular, cerebellar, proprioceptive dysfunction Does your patient have at least 2 of the above? Yes/No (Please circle response) Diagnosis 3: (check if present): —Unilateral onset —Rest tremor —Progressive disorder —Persistent asymmetry affecting side of onset most —Excellent response (70%–100%) to levodopa —Severe levodopa-induced dyskinesia —Levodopa response for 5 y or more —Clinical course of 5 y or more Does your patient have at least 3 of the above? Yes/No (Please circle response) (‘‘Yes’’ answers to all 3 questions above suggest the diagnosis of idiopathic PD) B. Findings suggestive of Parkinsonism due to a process other than idiopathic PD Primitive reflexes 1- RED FLAG—presence of a grasp, snout, root, suck, or Myerson’s sign N/A—not done/unknown Presence of supranuclear gaze palsy 1- RED FLAG—supranuclear gaze palsy present N/A—not done/unknown Presence of ideomotor apraxia 1- RED FLAG—ideomotor apraxia present N/A—not done/unknown Presence of autonomic dysfunction 1- RED FLAG—presence of new severe orthostatic hypotension not due to medications, erectile dysfunction, or other autonomic disturbance within the first year or 2 of disease onset N/A—not done/unknown Presence of a wide-based gait 1- RED FLAG—wide-based gait present N/A—not done/unknown Presence of more than mild dementia
Surgical Treatment of Movement Disorders
1- RED FLAG—frequently disoriented or severe cognitive difficulties, severe memory problems, or anomia N/A—not done, not known Presence of severe psychosis 1- RED FLAG—presence of severe psychosis, refractory to medications N/A—not done, not known History of unresponsiveness to levodopa 1- RED FLAG—Parkinsonism is clearly not responsive to levodopa, patient is dopamine naı¨ve, or patient has not had a trial of levodopa N/A—not done, not known (Any of the ‘‘FLAGs’’ above may be contraindications to surgery)
positions. There is, however, even under the best circumstances, a chance for clinically significant errors from stereotactic targeting, frame shift, brain shift, or misinterpretation of microelectrode recordings (MER). Suboptimal lead placement by even a few millimeters may result in an unacceptable outcome. It should be noted that most DBS targets, including the thalamus (VIM), STN and GPi, have a somatotopic and functional organization that includes sensorimotor, cognitive (associative), and limbic regions. In fact, nonmotor regions have been estimated to make up roughly one-third of each target.39 To ensure the accurate placement of DBS leads (or lesions) into the sensorimotor region of the intended target structure, most institutions will perform clinical examinations in the conscious patient and MER to ensure that they are within the correct region of their target site. Macrostimulation, which follows MER, involves delivering test stimulation with the actual DBS electrode. Macrostimulation may identify target areas on the basis of acute symptom improvement, and it may also clarify mislocalization on the basis of common side effects usually seen with the stimulation of nearby structures. Examples may include reports of phosphenes with stimulation in the region of the optic tract or muscle twitches or pulling with stimulation of the internal capsule. Some centers rely primarily on macrostimulation and do not routinely perform MER. MER involves the passage of a small micrometer-size recording tip (usually platinum iridium or tungsten) into the target region. As the microelectrode passes through various brain structures, the neurologist or physiologist can identify the relevant brain structures, including white matter and deep brain nuclei, on the basis of their unique firing rates and patterns of activity. These data may be supplemented by passive and active movements of the limbs and facilitate the identification of inhibition or driving activity that may define sensorimotor territories. Oscillatory activity may also be identified and correlated to a patient’s tremor. Although MER and macrostimulation data may aid the accuracy of DBS placement, there also may be some risk to using multiple passes through cerebral structures to generate a 3-dimensional representation that guides localization.40,41 These risks may include a slightly higher rate of hemorrhage (especially in patients with uncontrolled hypertension) and cognitive or mood side effects, most prominently postoperative confusion, particularly when operations are performed in a simultaneous bilateral, as opposed to staged, procedure. Although there are 3 general techniques used for MER (target verification, multiple pass mapping, and Ben-Gunn),41 these techniques have not been compared with regard to their risks or efficacy. Similarly,
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Table 1 Deep brain stimulation complications Summary of Adverse Events Event
No. of Patients (%)
Intraoperative Vasovagal response
8 (2.5)
Syncope
4 (1.2)
Severe cough
3 (0.9)
IVH
2 (0.6)
ICH
2 (0.6)
Arrhythmia (junctional rhythm)
1 (0.3)
Confusion
1 (0.3)
Extreme anxiety
1 (0.3)
Laceration of soft palate
1 (0.3)
TIA
1 (0.3)
Perioperative (within 2 wk) Headache
48 (15.0)
Confusion
16 (5.0)
Hallucination
9 (2.8)
Nausea/vomiting
5 (1.6)
Seizure
4 (1.2)
Dysarthria
3 (0.9)
Dyskinesia
2 (0.6)
Hypertension
2 (0.6)
Paranoia
2 (0.6)
Paresthesia
2 (0.6)
Sore throat
2 (0.6)
TIA
2 (0.6)
Urinary retention
2 (0.6)
Angina
1 (0.3)
Arrhythmia (right bundle branch block)
1 (0.3)
Deep vein thrombosis
1 (0.3)
Depression
1 (0.3)
Dizziness
1 (0.3)
Insomnia
1 (0.3)
Pulmonary edema
1 (0.3)
SDH (evacuated)
1 (0.3)
Long-term (2 wk) Infection
14 (4.4)
Cognitive dysfunction
13 (4.0)
Dysarthria
13 (4.0)
Worsening gait
12 (3.8)
Agitation
5 (1.6)
Paresthesia
4 (1.2)
Depression
3 (0.9)
Headache
2 (0.6) (continued on next page)
Surgical Treatment of Movement Disorders
Table 1 (continued) Summary of Adverse Events Event
No. of Patients (%)
Psychogenic tremor
2 (0.6)
Urinary incontinence
2 (0.6)
Blepharospasm
1 (0.3)
Emotional lability
1 (0.3)
Insomnia
1 (0.3)
Metallic taste
1 (0.3)
Suicide
1 (0.3)
Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.
more research is needed to determine if staged or simultaneous procedures have distinct advantages and in which populations they should be applied. SURGICAL AND DBS COMPLICATIONS
DBS complications may be divided into risks associated with the surgical procedure and chronic complications of therapy that may or may not be device related. The most serious complications associated with DBS surgery are cerebrovascular accidents (including transient ischemic events) (0.9%), intracranial hemorrhage (1.2%), seizure (1.2%), device infection (4.4%), lead fracture (3.8%), and device movement or misplacement (3.2%),42 and the risks vary from study to study depending on many factors. Many centers do not prospectively assess adverse events, and this may lead to under-reporting.43 These risks may be somewhat attenuated by appropriate screening and treatment of comorbid conditions, including hypertension, which increases hemorrhage risk during MER; diabetes, which increases the risk of infection; psychiatric disease, which increases the risk of depression and suicide; cognitive deficits, which increase the risk of postoperative confusion; and obesity or other significant cardiopulmonary diseases, which may increase the general risk of surgery.44,45 Complications of DBS may also occur following the acute operative period. These complications may occur from problems in triage, screening, inadequate patient counseling/unreasonable patient expectations, operative procedure (including DBS misplacement), medication adjustments, or device programming difficulties. In a series of patients seeking further management after suboptimal DBS outcomes, the most common reasons for poor DBS outcome/DBS failure included inadequate screening (no movement disorder neurologist or documented neuropsychological testing) (66%), inappropriate or missed diagnosis (22%), suboptimally placed electrodes (46%), inadequate programming follow-up (17%) or suboptimal DBS parameters (37%), and suboptimal medication management (73%).38 Of the patients seen in this series, two-thirds had good outcomes (51%) or modest improvement (15%) after receiving appropriate interventions. Chronic side effects may occur in patients even when the device has been appropriately placed, and lead settings may be optimized for the greatest symptomatic benefit. Side effects may be stimulation related and may be reversible with a simple change in settings. However, some side effects may be due to microlesional effects of the DBS placement and thus not amenable to changes in
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Table 2 Summary of STN and GPi DBS outcomes for PD Author, Year
N
Type
Target
Duration (mo)
Krack et al., 1997101
27
Prosp NC
STN
1–12
NA
Ghika et al., 1998102
6
Prosp NC
GPi
24
Krack et al., 1998103
8
Retrosp NC
STN
5
UPDRS III Motor
LE
NA
22/17 22.7%
63/28 55.6%
N/A
N/A
20/8 60.0%
31/10 67.7%
38/28 26.3%
66/33 50.0%
1080/960 11.1%
3.5/2.5 28.6%
6
7.9/4.6 41.8%
33.3/9.1 72.7%
4.0/1.4 65.0%
6
13.6/ 10.6 22.0%
27.8/ 15.0 46.0
57.5/ 17.1 70.3% 53.6/ 32.5 39.4%
1156/681 41.1%
GPi
18.2/ 14.7 19.2% 23.2/ 26.5 14.0%
865/1110 28.3%
4.8/1.2 75.0%
N/A
26.0% 40.0%
N/A
27.0% 41.0%
Unchanged 30.0%
UPDRS II ADL
LID
Comments
Kumar et al., 1998104
8 6
Prosp NC Prosp NC
GPi STN
3 3
Kumar et al., 1998105
7
Prosp DB
STN
6
10.5/ 12.4 18.1%
28.1/ 19.7 29.9%
30.1/ 17.7 41.2%
55.7/ 19.4 65.2%
40.0%
1.8/0.3 83.3%
Limousin et al., 1998106
20
Prosp NC
STN
12
N/A
60.0%
10.0%
60.0%
1224/615 49.8%
11.0/7.7 30.0%
Decreased speech fluency; Dysarthria Improvement of executive function (marginal) Decreased off time from 40% to 10%
60.0% 41.0%
S&E off 29.0/73.2 ( 152.4%) Off time 2.2/0.6 (72.7%) FBA 39.6/37.4 (5.6%)
Volkmann et al., 1998107
9
Prosp NC
GPi
3
Ardouin et al., 1999108
26
Prosp
STN
3
Burchiel et al., 1999109
6
Prosp DBl
STN
12
N/A
78.0%
N/A
4
Prosp DBl
GPi
12
N/A
63.0%
Limousin et al., 1999110
73
Prosp NC
Th
12
N/A
Moro et al., 1999111
7
Prosp NC
STN
16
Pinter et al., 1999112
9
Prosp NC
STN
20.6/8.4 59.2%
33.9/ 19.4 42.8%
54.1/ 23.9 55.8%
767/675 12.0% NS
2.6/0.4 84.6%
Weight gain ADL improved Decrease in verbal fluency S&E off 52.2/83.9 ( 60.7%) Stable results in 6, 9 and 12 mo
44.0%
51.0%
N/A
N/A
39.0%
Unchanged
11.6/3.8 67.2% 9.5/5.0 47.4%
13.85/ 9.24 33.3%
N/A
37.0/ 25.7 30.5%
649/610 (LD)
2.0/1.5 25.0%
S&E 72.35/82.77 ( 14.4%)
15.3/ 14.3 6.5%
36.1/ 17.3 52.1%
29.3/ 30.7 -4.8%
67.6/ 39.3 41.9%
1507/521 65.4%
Reduced
Sleep improved Weight gain 13% Neuropsychological testing unchanged
3
11.6/9.1 21.6%
29.6/ 12.6 57.4%
24.1/ 18.8 22.0%
60.0/ 27.8 53.7%
527/133 74.8%
2.9/0.5 82.8%
STN
12
11.6/9.3 19.8%
29.6/ 12.8 56.8%
24.1/ 18.8 22.0%
60.0/ 27.1 53.8%
527/211 60.0%
S&E off 47.5/82.5 ( 73.7%) Off time decreased 8.8/ 1.0 (88.6%) S&E off 47.5/80.0 0. ( 68.4%)
55.4/ 19.8 64.3%
N/A
Bejjani et al., 2000113
12
Prosp NC
STN
6
N/A
N/A
78.0%
64.0%
70.0%
83.0%
Motor fluctuations 88.0%
Houeto et al., 2000114
23
Prosp NC
STN
6
11/2 81.8%
30/10 66.7%
N/A
N/A
1340/820 38.8%
7.0/1.6 77.1%
Fluctuation 4.5/1.0 (77.8%) (continued on next page)
Surgical Treatment of Movement Disorders
9
12.6/4.8 61.9%
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Table 2 (continued) Author, Year
N
Type
Target
Duration (mo)
Jahanshahi et al., 2000115
7
NC (on/off)
STN
2–26
6
UPDRS II ADL
UPDRS III Motor
LE
LID
Comments
62.7/25.1 60.0%
GPi
Improves some aspects of executive functioning
54.2/27.2 49.8%
Molinuevo et al., 2000116
15
Prosp NC
STN
6
N/A
26.7/7.5 71.9%
N/A
49.6/16.9 65.9%
1338/262 80.4%
Pillon, 2000117
48
NC
STN
12
N/A
N/A
N/A
55.4/18.1 67.3%
1110/348 68.6%
15
STN
6
N/A
N/A
N/A
8
GPi
12
N/A
N/A
N/A
5
GPi
6
N/A
N/A
N/A
56.1/19.4 65.4% 55.4/37.1 33.0% 41.6/27.0 35.1%
1063/465 56.3% 744/873 17.3% 850/735 13.5%
Alegret, 2001118
15
Prosp
STN
3
N/A
29.9/10.9 63.6%
N/A
53.6/23.2 56.7%
57.9%
Capus, 2001119
7
Prosp NC
STN
6
N/A
N/A
20.3%
50.6%
40.7%
80.6%
Off time 89.7% S&E 38.7/84 ( 117.1%) H&Y 3.8/1.9 (50.0%) Improved psychomotor speed and working memory
S&E 27.5/72.5 (-163.6%) H&Y 4.2/2.3 (45.2%) Moderate deterioration of verbal memory 73.5%
Motor fluctuations improvement 57.2% PDQ38 improvement 49.9%
DBS/PD study group, 2001120
Prosp DBl Crossover
STN
6
11.2/10.2 8.9%
28.4/16.0 43.7%
23.6/17.8 24.6%
54.0/25.7 52.4%
1218/764 37.3%
1.9/0.8 57.9%
38
Same
GPi
6
12.7/8.8 30.7%
17.9/17.9 0.0%
24.1/16.5 31.5%
50.8/33.9 33.3%
1090/1120 -2.8%
2.1/0.7 66.7%
9
Prosp NC
STN
3
Prosp NC
STN
12
31.55/13.78 56.3% 31.2/14.3 54.2%
22.44/13.44 40.1% 21.6/17.2 20.4%
62.9/32.6 48.2% 65.0/40.5 37.7%
NA
6
8.66/7.67 11.4% 9.2/7.5 18.5%
5.33/2.22 58.4% 4.33/0.5 88.5%
Slight impairment in executive function The same subjects as those in the previous group
Faist et al., 2001122
8
Prosp NC
STN
15
N/A
N/A
N/A
49.8/7.4 85.1%
N/A
N/A
Improves walking velocity Stride length S&E off 43.7/88.7 ( 103.0%)
Lopiano et al., 2001123
16
Prosp NC
STN
3
8.8/7.7 12.5%
28.3/9.1 67.8%
20.3/14.8 27.1%
59.8/25.9 56.7%
1162/321 72.4%
3.5/1.1 68.6%
Off time 2.0/0.3 (85%)
Lopiano et al., 2001124
20
Prosp NC
STN
12
N/A
N/A
19.8/16.8 5.0%
58/25.1 56.7%
954/228 76.1%
Volkmann et al., 2001125
16
Prosp NC
STN
12
GPi
12
28.8/12.6 56.3% 21.0/12.1 42.4%
15.1/16.4 -8.6% 30.2/16.7 44.7%
56.4/22.4 60.3% 52.5/16.7 68.2%
2.73%
11
13.7/11.0 19.7% 12.1/5.8 52.1%
2.0/0.4 80.0%
2.4/0.4 83.3% 836/605 27.6%
6
GPi
6
N/A
N/A
Unchanged
36%
N/A
60%
6 6 6
GPi GPi GPi
12 24 36
N/A N/A N/A
N/A N/A N/A
Unchanged Unchanged Unchanged
26% 38% 32%
N/A N/A 1415/1225 13.4%
30% 20% 40%
Dujardin et al., 2001121
Durif et al., 2002126
NA
Off time 49/19% (percentage of waking hours) Off time 37/24% (percentage of waking hours)
Neuropsychological assessment stable
Off time decreased by 50% 25% 40% 10% (continued on next page)
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Table 2 (continued) Author, Year
N
Type
Figueiras-Mendez 22 Prosp NC et al., 2002127
Duration Target (mo) STN
UPDRS II ADL
UPDRS III Motor
LE
LID
Comments
1–12
16/9 43.8%
30/16 46.7%
24/10 58.3%
2 13/18 91.6%
32.0%
NA
22/7 68.2%
23/12 47.8%
44/14 68.2%
N/A
28.1/0 100.0%
Off time 31/0% (percentage of waking hours) PDQ 39 38.4/22.3 (24.3%) Nonsurgical 41.3/42.7 ( 3.4%)
9.6/5.8 39.6%
BDI 10.5/8.5 (19.0%) PDQ 90.3/129 (42.9%)
Just and Ostergaard, 2002128
11 Prosp NC STN Nonsurgical
6
11/5 54.6%
Lagrange et al., 2002129
60 Prosp NC
STN
12
11.3/11.4 29.6/23.4 0.1% 21.0%
53.7/24.3 20.3/18.8 54.7% 7.4%
1010/522 48.3%
Loher et al., 2002130
10 Prosp NC
GPi
12
37.6/24.9 34.9/22.9 33.8% 34.4%
34.7/24.9 63.4/37.5 28.2% 40.8%
1235.5/1300.6 9.8/5.0 5.3% 48.9%
Martinez-Martin et al., 2002131
17 Prosp NC
STN
6
N/A
29.53/8.29 N/A 71.9%
Ostergaard et al., 2002132
26 Prosp NC
STN
12
9.3/6.8 26.9%
25.2/8.5 66.3%
23.5/10.7 51.3/18.3 54.5% 64.3%
1197/964 19.5%
Romito et al., 2002133
22 Prosp
STN
24–36
N/A
31.6/10 68.4%
N/A
1505.9/491.7 67.4%
55.7/20.76 1400/509 62.7% 63.6%
60.2/29.9 50.3%
S&E Off 28.8/45.0 ( 56.3%) On 51.0/60.0 (17.6%)
N/A
Off time 1.8/0.3 (83.3%) PDQL 40.89/20.18 (50.6%)
2.1/0.3 85.7%
Weight increase 75/8 kg S&E off 49/84 ( 71.4%) Off periods 1.8/0.3 (83.3%) Hypophonia Dysarthria Improved sleep S&E off med 24.5/80.0 ( 226.5%)
Simuni et al., 2002134
12 Prosp NC
STN
12
N/A
N/A
19.3/19.8 43.5/23.0 2.6% 47.1%
1946/875 55.0%
4.2/1.5 64.3%
Thobois et al., 2002135
18 Prosp NC
STN
6
STN
12
26.9/12.7 52.8% 26.9/10.7 60.2%
17.9/15.2 15.1% 17.9/13 27.4%
1045/360 35.5% same
76.0%
14 Prosp NC
5.3/8.1 52.8% 5.3/7.5 41.5%
Vesper et al., 2002136
38 Prosp NC
STN
12
N/A
N/A
27.7/17.4 48.3/24.9 37.2% 48.4%
900/580 35.5%
3.2/0.9 71.9%
Off time 14.5/6 (58.6%)
Vingerhoets et al., 2002137
20 Prosp NC
STN
21
N/A
21.0/13.3 37%
N/A
48.8/26.9 44.8%
1135/230 79.7%
4.8/0.4 92%
50% of patients discontinued medications
Voges et al., 2002138
15 Prosp NC
STN
6–12
N/A
NA
N/A
55.3/22.7 58.9%
909/374 58.9%
NA
S&E off 42/77 ( 83.3%)
Welter et al., 2002139
41 Prosp NC
STN
6
10.4/6.6 36.5%
29/11.1 61.7%
14.7/10.6 51.4/18.5 27.9% 64.0%
1459/480 67.1%
2.1/0.2 90.5%
Chen et al., 2003140
7
Prosp NC
STN
6
N/A
N/A
39.0/19.1 65.7/32.8 51.0% 50.0%
N/A
Improved S&E off 22.9/70.0 ( 205.7%)
Daniele et al., 2003141
20 Prosp NC
STN
12
9
STN
18
10.1/6.2 38.6% 12.4/5.4 56.5%
31.8/8.8 72.3% 33.1/7.4 77.6%
24.0/22.1 7.9% 25.0/17.3 30.8%
58.8/30.9 47.5% 60.8/27.0 55.6%
1395/500 64.2% 1185/535 54.8%
Funkiewiez et al., 50 Prosp NC 2003142
STN
12
N/A
N/A
N/A
N/A
N/A
12/4 67%
BDI 13.9/11.5 (17.3%) MDRS 136.8/136.7 (0.1%) FS 40.8/39.5 (3.2%)
Herzog et al., 2003143
48 Prosp NC
STN
6
N/A
STN
12
N/A
STN
24
N/A
44.2/21.7 50.9% 43.9/18.7 57.4% 44.9/19.2 57.2%
1425/730 48.8% 42.4%
20
18.7/14.7 21.4% 18.1/12.4 31.5% 19.3/12.4 35.8%
2.6/1.9 26.9% 2.5/0.3 87.0% 2.4/0.3 85.0%
Temporary psychiatric adverse events
32
22.6/10.7 52.6% 21.6/10.7 49.2% 23.4/13.2 43.2%
44.9/20.2 55.0% 44.9/17 62.1%
91.0%
PDQ 83.2/54.3 (34.7%) 87.7/49.7 (43.3%)
(continued on next page)
Surgical Treatment of Movement Disorders
67.8%
Off time 1.6/1.0 (37.5%) S&E off 39.6/77.5 ( 95.7%)
647
648
Kluger et al
Table 2 (continued) Author, Year
N
Type
Target
Duration (mo)
Kleiner-Fisman et al., 2003144
25
Prosp NC
STN
12
12.1/10.5 13.2%
Krack et al., 2003145
49
Prosp NC
STN
60 (5 y)
Pahwa et al., 2003146
33
Prosp NC
STN
19
UPDRS III Motor
LE
25.8/17.4 32.6%
22.8/19.4 14.9%
50.1/24.6 50.9%
38.0%
46.4%
7.3/14.0 91.8%
30.4/15.6 48.7%
14.3/21.1 47.6%
55.7/25.8 53.7%
1409/518 63.2%
4.0/1.4 65.0%
DRS 136/131 (3.7%) BDI 15.5/14.9 (3.9%) FBA 40.4/37.3 (7.7%)
12
N/A
21.1/14.3 32.2%
N/A
43.8/26.5 39.5%
10.4/5.8 44.2%
18/4%
STN
24
11.6/12.8 10.3%
21.1/15.3 27.5%
26.2/24.1 8.0%
41.3/29.8 27.8%
12.4/5.3 57.3%
19/11%
Off time 44/20% (percentage of waking hours) Off time 43/17% (percentage of waking hours)
UPDRS II ADL
LID
Comments
Varma et al., 2003147
7
Prosp NC
STN
6
15/14 6.7%
38/25
34.2%
61%
2067/1055 49.0%
44%
Volkmann et al., 2004148
9
Prosp NC
Gpi
36
11.3/7.1 37.2% 8.8/10.3 17.1%
20.9/15.5 25.8% 19.5/19.8 1.5%
30.8/13.9 54.9% 22.2/18.7 15.8%
52.8/26.8 49.2% 49.5/38.0 23.2%
870/897 3.1% 961/760 20.9%
1.9/0.6 68.4% 1.0/0.6 40.0%
12
10.0/9.4 6.0%
26.0/17.3 33.5%
17.6/19.7 11.9%
38.4/23.9 37.8%
1364/867 36.4%
2.9/0.7 75.9%
33
10.0/17.2 72.0%
26.0/22.3 14.2%
17.6/22.1 25.6%
38.4/26.5 31.0%
1364/1029 24.6%
2.9/0.9 69.0%
6 Liang et al., 2006149
27
60 Prosp NC
STN
MMSE 29/29
Off time 1.9/1.2 (36.8%) S&E off 47.2/72.1 (52.8%) Off time 1.9/1.1 (42.1%) S&E off 47.2/66.7 ( 41.3%)
Portman et al., 2006150
20
Prosp NC
STN
12
N/A
N/A
23/20 13.0% NS
46/33 28.3%
1242/751 39.5%
8.8/3.75 57.4%
Derost, 2007151
53
Prosp NC
STN
24
45.0%
24
18.0/15.6 13.3% 18.8/16.7 11.2%
N/A
STN
3.7/8.5 1.3% 5.6/11.1 98.0%
N/A
41.0%
1246/885 28.9% 1308/760 41.9%
3.4/0.7 79.4% 2.7/1.1 59.3%
STN
12
4.5/8.5 88.9% 4.5/12.5 177.8%
23.7/12.5 47.3% 23.7/13.9 41.4%
14.1/12.5 11.3% 14.1/12.5 11.3%
42.2/21.0 50.2% 42.2/19.3 54.3%
1228/470 61.7% 1228/631 48.6%
9.0/1.9 78.9% 9.0/31.1 245.6%
34 Gan et al., 2007152
36
Prosp NC
36
S&E off 52/72 ( 38.5%) Off time 10%
DRS 135.9/137.4 (NS) BDI 12.8/11.6 (NS) DRS 135.9/135.5 (NS) BDI 12.8/16.1 (NS)
11
Prosp NC
Gpi
7
N/A
N/A
12.5/10.4 16.8%
40.6/21.8 46.3%
1182/1216 2.9%
10.5/2.5 76.0%
Schu¨pbach et al., 2007154
10
Prosp NC Comp BMT
STN
18
2.3/5.1 121.7%
19.2/12.9 32.8%
NA
69.0%
57.0%
83.0%
DRS 140.5/140.5 (NS) FBA 48/47.5 (NS) MADRS 7/3 (improved)
Tir et al., 2007155
100
Prosp NC
STN
12
9.5/8 15.8%
27.5/19 30.9%
20/14.4 28.0%
50/29 42.0%
1222/721 41.0%
61.0%
Cognitive decline in 7.7% Depression 18%
Vesper et al., 2007156
73
Prosp NC
STN
24
N/A
N/A
30/26 13.3%
50/25 50.0%
45.0%
Witjas et al., 2007157
40
Prosp NC
STN
12
8.8/4.7 46.6%
23.7/13.3 43.9%
11.8/6.9 41.5%
38/12.4 67.4%
1091/460 57.8%
5.6/1.3 76.8%
S&E off 45.3/63.7 (40.6%) DRS 137.4/136 (-1.0%) BDI 8.1/6.4 (21.0%) (continued on next page)
Surgical Treatment of Movement Disorders
Rodriques et al., 2007153
649
650
Kluger et al
Table 2 (continued) Author, Year
N
Type
Target
Duration (mo)
Zibetti et al., 2007158
36
Prosp NC
STN
12
N/A
24
N/A
6
10.0/11.5 15.0% 10.0/12.8 28.0% 10.0/18.9 89.0%
Wider et al., 2008159
50
Prosp NC
STN
24 60
UPDRS II ADL 25.3/9.9 60.9% 25.3/10.3 59.3% N/A N/A N/A
UPDRS III Motor N/A N/A 24.3/26.7 9.9% 24.3/27.7 14.0% 24.3/30.6 25.9%
LE
LID
54.5/25.8 52.7% 54.5/24.1 55.8%
1023/405 60.4% 1023/417 59.2%
47.2/24.8 47.5% 47.2/24.9 47.3% 47.2/33.2 29.7%
1128/195 82.7% 1128/391 65.3% 1128/485 57.0%
Comments N/A N/A
Off time 1.55/0.11 (92.9%) Off time 1.55/0.03 (98.1%)
4.8/0.7 85.4% 4.8/0.8 83.3% 4.8/0.7 85.4%
Abbreviations: BDI, Beck’s Depression Inventory; BMT, Best medical treatment; DRS, Mattis Dementia rating scale; Dyskinesia, as measured by UPDRS IV-a (motor complication) or AIMS (abnormal involuntary movements scale); FBA, frontal battery assessment scale; GPi, Globus pallidus part interna; ICH, intracerebral hemorrage; IVH, intraventricular hemorrage; LD, Levodopa dose only; LE, Levodopa equivalent (the method of calculation was not standardized across the studies); LID, levodopa induced dyskinesias; MADRS, Montgomery and Asberg depression rating scale; MDRS, Mattis Dementia Rating Scale; MMSE, Folstein mini mental status Examination; NS, nonsignificant; Off and On, applies to the medication state; Off time, Hours per day spent in clinically defined off period (immobile); PDQ, Parkinson disease quality-of-life questionnaire, total score; Prosp., NC, prospective noncontrolled clinical trial; S&E, Schwab and England disability scale; SDH, subdural hemorrage; STN, Subthalamic nucleus; Th, Thalamus; TIA, transient ischemic attack; UPDRS II—ADL, activities of daily living, maximum 52; UPDRS III, motor subscore, maximum 108. Results are represented as Preoperative/Postoperative, with the percentage change calculated as: [(Preoperative Postoperative)/Preoperative] 100. Data from Kenney C, Simpson R, Hunter C, et al. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–5.
Surgical Treatment of Movement Disorders
settings. Common stimulation-related side effects may include paresthesias due to spread of current to lemniscal and sensory regions and muscle tightening due to spread of current to motor fibers (corticobulbar and corticospinal tracts). More significant side effects may include dysarthria, cognitive deficits (particularly declines in verbal fluency), and alterations in mood (including depression, anxiety, mania, and suicidality). The STN in particular may have a high risk for cognitive and mood side effects, including executive dysfunction, hypomania (up to 15% in some series), depression, anxiety and suicidality.46 However, randomized comparative studies to confirm these clinical findings remain to be published. Although DBS has been repeatedly demonstrated to improve QOL,47 there are often significant difficulties with social adjustment following DBS, particularly with marital and professional life.48 This finding stresses the importance of preoperative counseling and discussions regarding the patient’s expectations of surgery. See Table 1 for a summary of DBS complications.
SPECIFIC MOVEMENT DISORDERS AND TARGETS Parkinson’s Disease
Successful patient outcomes in PD have been obtained with DBS directed toward 1 of 3 intracranial targets, namely, STN, GPi, and VIM. There is currently no consensus on which targets may be preferable for which symptoms; however, some important insights have emerged from the literature. We anticipate that further data will demonstrate differences in particular symptom efficacy and side effect profiles (mood, motor, cognitive, and QOL) so that the choice of an appropriate DBS target can be tailored to an individual. There is currently good evidence to show that VIM DBS is effective in the treatment of arm tremor but does not ameliorate other PD symptoms or capture leg tremor in many cases.49 VIM DBS is generally not considered a first-line target in PD; however, elderly patients with symptoms mostly linked to medication refractory upper-extremity tremor who have impaired QOL or activities of daily living (ADLs) may obtain excellent results.50 STN or GPi DBS may address tremor, bradykinesia, and rigidity but have less impact on gait and postural instability, with much of the outcome related to whether specific symptoms responded preoperatively to levodopa. DBS also does not prevent disease progression into areas such as gait, speech, and cognition. Other DBS targets are currently under investigation in PD. Emerging evidence has suggested that gait in PD may be improved by DBS directed to the pedunculopontine nucleus.51 However, proper outcome studies and criteria to determine patient selection have not been performed. Zona incerta DBS is another potential target for tremor and other cardinal motor manifestations, and this remains under investigation.52 Although the first randomized, double-blinded trials of STN versus GPi are currently underway, there is preliminary evidence for the potential of differential responses and/ or side effects from the 2 targets based on clinical observation. In general, both procedures are well tolerated and considered generally safe in appropriately selected patients, with meta-analyses showing comparable motor efficacy.53 There is some evidence that STN DBS may be associated with a slightly greater motor/tremor benefit; however, there may also be a higher risk of cognitive, behavioral, and mood side effects.45 Although both STN and GPi improve dyskinesias and smooth on/off fluctuations, there may be reasons to favor a specific target site, as well as reasons to perform unilateral versus bilateral operations and to consider simultaneous versus staged bilateral procedures. These differences will potentially emerge as randomized studies are published. For example, STN DBS achieves dyskinesia reduction by reducing levodopa requirements, whereas GPi DBS has a direct antidyskinetic effect,
651
652
Kluger et al
Table 3 Summary of VIM thalamic DBS outcomes for ET Study
Sample Size
Study Type
Tremor Improvement
Nonmotor Outcomes
Pahwa et al., 2006160
26
Prosp NC
46% (unilateral) and 78% (bilateral) FTM TRS
35%–50% improvement on ADLs (from TRS), drawing and pouring
Lee and Kondziolka, 2005161
18
Case series
75% improvement FTM TRS
64% improvement in handwriting
Putzke et al., 2005162
22
Case series
81% improvement FTM TRS
N/A
Putzke et al., 2004163
52
Case series
45% improvement FTM TRS
70% improvement in ADLs
Kumar et al., 2003164
5
Case series
62% improvement in FTM TRS
Tolerance to DBS developed in 2 of 5 patients
Bryant et al., 2003
165
16
Case series
34% FTM TRS
45% improvement ADLs
Fields et al., 2003166
35
Case series
56% FTM TRS improvement
Significant improvements in mood, QOL, and several cognitive outcomes
Rehncrona et al., 2003167
19
Prosp NC
46% improvement FTM TRS
N/A
Hariz et al., 200259
27
Prosp NC
47% improvement FTM TRS
Significant improvements in mood, QOL, and ‘‘emotional constraints’’ domain of QOL
Koller et al., 2001168
49
Case series
78% improvement FTM TRS
24% of patients required at least 1 additional surgical procedure
Obwegeser et al., 2001169
31
Case series
6-point reduction in FTM TRS
N/A
Pahwa et al., 2001170
17
Case control (vs thalamotomy)
50% improvement FTM TRS
Equivalent benefit with less complications than thalamotomy
Krauss et al., 2001171
42
Case series
57% excellent outcome, 36% marked improvement
N/A
40
Prosp NC
51% reduction in FTM TRS
Significant improvements across multiple domains of QOL, anxiety, and cognitive function except verbal fluency.
Limousin et al., 1999110
37
Prosp NC
55% reduction in FTM TRS
Significant improvement in ADLs
9
Case series
57% improvement in FTM TRS
Significant improvement in ADLs
Kumar et al., 1999173
9
Case series
61% improvement FTM TRS
Significant improvement in ADLs and global disability
Koller et al., 1999174
38 (head tremor)
Case series
Head tremor improved in 75% of patients
N/A
Hariz et al., 1999175
36
Case series
48% improvement in FTM TRS
Significant improvement in ADLs
Lyons et al., 1998176
22
Case series
39% improvement in FTM TRS
57% improvement on tremor ADL scale
Ondo et al., 1998177
14
Case series
83% improvement in FTM TRS
>50% improvement in ADLs and disability scores
Koller et al., 1997178
29
Prosp NC
> 50% improvement in FTM TRS
Significant improvement in ADLs
Hubble et al., 1996179
10
Prosp NC
>50% improvement in both patient and clinician FTM TRS ratings
63% improvement in patient and clinician ratings of global disability
Blond et al., 1992180
4
Case series
Sustained improvement in 75% of patients
No change in MMSE, verbal fluency, or Wisconsin Card Sort
Pahwa et al., 1999
172
Abbreviations: ADLs, activities of daily living; FTM TRS, Fahn Tolosa Marin tremor rating scale; MMSE, Folstein mini mental status examination; QOL, Quality of life.
Surgical Treatment of Movement Disorders
Troster et al., 199957
653
654
Author
N
Type of Dystonia
Target
Follow-up Period (mos)
Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
Vercueil et al., 2001181
1
Primary generalized
GPi
12
BFMDRS (m/d)
N/A
N/A
67/81
Includes 12 patients with thalamic DBS alone and 3 with thalamic and GPi DBS.
1
GPi
6
BFMDRS (m/d)
N/A
N/A
70/50
1 1 1
Primary generalized Primary DYT11 Primary DYT1 Cranial-cervical
GPi GPi GPi
12 24 6
BFMDRS (m/d) BFMDRS (m/d) BFMDRS (m/d)
N/A N/A N/A
N/A N/A N/A
86/86 41/43 66/66
Bereznai et al., 2002182
3 1
Segmental Primary DYT11
GPi GPi
3–12 3–12
BFMDRS (m) Tsui scale
N/A N/A
N/A N/A
72.50 45
Krauss et al., 2002183
5
Cervical
GPi
20
TWSTRS (s/d/p)
20.5/40. 5/6
7.5/12.7/3
62/69/50
Cif et al., 2003184
15 Primary DYTI1 17 Primary DYT1
GPi GPi
24–36 24–36
BFMDRS (m/d) BFMDRS (m/d)
60.8/16.7 56.5/16.4
14.2/5.7 15.1/9.5
71/63 74/49
Katayama et al., 2003185
5
Primary
GPi
6
BFMDRS (m)
18–62
4–23
51–92
Krauss et al., 2003186
2
Primary DYT1
GPi
24
BFMDRS (m)
81
21.5
73
Kupsch et al., 2003187
1 3 1
Primary DYT11 Primary DYT1 Segmental
GPi GPi GPi
3–12 3–12 3–12
BFMDRS (m) BFMDRS (m) BFMDRS (m)
34.5 40 32
27 20 19
22 50% 41
Includes 1 patient with bilateral pallidotomy and 1 patient with unilateral pallidotomy
Kluger et al
Table 4 Summary of GPi DBS outcomes for dystonia
Yianni et al., 2003188
12
Generalized
GPi
4–184
BFMDRS (m)
79.7
45.3
46
Includes the same patients as the other study by Yianni and colleagues, 2003
Cervical
GPi
2–12
TWSTRS (t)
57.8
23
59
2 11 7
Primary DYT11 Primary DYT1 Cervical
GPi GPi GPi
12 12 12
BFMDRS (m) BFMDRS (m) TWSTRS (s/d/p)
N/A N/A 21.3/21.7/ 15.1
N/A N/A 10/14/8.3
85 46 50/38/43
Cif et al., 2004190
1
Myoclonusdystonia syndrome
GPi
20
UMRS
69
13
81
BFMDRS (m/d)
9.5/9
1.5/1
84/89
Coubes et al., 2004191
17 14
Primary DYT11 Primary DYT1
GPi GPi
24 24
BFMDRS (m) BFMDRS (m)
62.6 56.3
12.4 13.4
83 75
Detante et al., 2004192
13 3
Primary generalized Secondary PKAN
STN STN
3 3
N/A N/A
N/A N/A
N/A N/A
No improvement No improvement
Eltahawy et al., 200433
1
Primary DYT11
GPi
6
BFMDRS (m)
88
66
25
1 3
Primary DYT1 Cervical
GPi GPi
6 6
BFMDRS (m) TWSTRS (t)
48 37.7
16 16
21 57
Krause et al., 2004193
4 6 1
Primary DYT11 Primary DYT1 Cervical
GPi GPi GPi
12–66 12–66 12–66
BFMDRS (m) BFMDRS (m) BFMDRS (m)
72 73.9 6
34 50 6
53 32 0
Trottenberg et al., 2005194
5
Secondary tardive
GPi
6
BFMDRS (m/d)
32/8
N/A
87/96
Vayssiere et al., 2004195
19
Primary generalized
GPi
N/A
BFMDRS
N/A
N/A
>80
Study also includes pallidotomy patients
(continued on next page)
Surgical Treatment of Movement Disorders
7 Yianni et al., 2003189
655
656
Kluger et al
Table 4 (continued) Author
N
Type of Dystonia
Target
Follow-up Period (mos)
Scale
Preoperative Score
Postoperative Score
Improvement (%)
Comments
Bittar et al., 2005196
2
Primary DYT11
GPi
24
BFMDRS (t)
103.8
55.8
46
DYT11 and DYT1 analyzed together
4 6
Primary DYT1 Cervical
GPi GPi
24 24
TWSTRS (t)
57.8
23.7
59
Castelnau et al., 2005197
6
Secondary PKAN
GPi
21
BFMDRS (m/d)
75/20
20/9.6
74/53
Chou et al., 2005198
1
Cervical dystonia and ET
STN
6
TWSTRS (s/d)
14/20
3/0
79/100
Vidailhet, 200560
7 1
Primary DYT11 Primary DYT1
GPi GPi
12 12
BFMDRS (m/d) BFMDRS (m/d)
55.1/14.7 41.96/10.2
26.1/8.5 18.7/5.5
53/46 55.4/45
Zorzi et al., 2005199
1 8
Primary DYT11 Primary DYT1
GPi GPi
4 19
BFMDRS (m/d) BFMDRS (m/d)
47/11 68.9/17.9
14/6 46.5/12.6
70/45 32/37
Diamond et al., 2006200
5
Primary DYT11
GPi
5
UDRS
44.6
27.5
38
All groups analyzed together. 2 patients with pallidotomy
5 1
Primary DYT1 Hemidystonia
GPi GPi
5 3
6
Primary DYT11
GPi
6
BFMDRS (m/d)
36.4/10
20.2/5.9
45/41
All groups analyzed together
27 7
Primary DYT1 Primary
GPi GPi
6 6
Kupsch et al., 200663
Class 1 evidence
Starr et al., 2006201
6 3 1 1 1 1 4 2
Zhang et al., 2006202
GPi GPi GPi GPi GPi
13 22 9 12 33
BFMDRS BFMDRS BFMDRS BFMDRS BFMDRS
GPi
32
GPi
(m) (m) (m) (m) (m)
59.6 22.6 30 30 82
24.2 12 3 6 51
59 47 90 80 38
BFMDRS (m)
54
49.5
No improvement
20
BFMDRS (m)
46.5
24.6
47
11
BFMDRS (m)
83
72.8
12
Secondary tardive dystonia
STN
3
BFMDRS (m)
98.8
8
92
1
STN
3
BFMDRS (m)
26.5
2
91
STN
6
BFMDRS (m)
76
7
91
5
Secondary antiemetics Secondary neonatal anoxia Other secondary
STN
N/A
N/A
N/A
N/A
Did poorly
12
Primary DYT11
GPi
12
BFMDRS (m/d)
35/8
4/2
89/75
3
Primary DYT1
GPi
12
6 cases bilateral STN, 2 cases unilateral STN, 1 case left STN and right GPi
DYT1 1 and DYT1 analyzed together (continued on next page)
Surgical Treatment of Movement Disorders
GPi
1
2
Alterman, 2007203
Primary DYT11 Segmental Cranial-cervical (MS) Secondary PKAN Secondary cerebral palsy Secondary posttraumatic Secondary tardive Generalized
657
658
Follow-up Target Period (mos) Scale
Preoperative Score
Postoperative Score Improvement (%) Comments
10 Secondary tardive
GPi
6
ESRS
73.1
27.8
AIMS
25
31.1
Evidente et al., 2007205
1
X-linked dystonia Parkinsonism
GPi
12
UPDRS-III
21
8
62
–
BFMDRS (t)
32.5
9.5
72
–
Grips et al., 2007206
8
Segmental
GPi
N/A
UDRS
36.9
16.1
56
BFMDRS GDS
25.6 29.3
13.1 10.3
61 67
All patients previously reported – –
Author
N
Damier et al., 2007204
Type of Dystonia
GPi GPi
62
50% improvement with doubleblind evaluation
24
Hung et al., 200762
10 Cervical
GPi
12–67
TWSTRS (s/d/p) 21.9/18/11.7
9.9/7.4/5.8
55/52/51
–
Kiss et al., 2007207
10 Cervical
GPi
12
TWSTRS (s/d/p) 14.7/14.9/26.6 8.4/5.4/9.2
43/64/65
Class 1 evidence
Kleiner-Flisman et al., 2007208
1
Cervical
STN
12
1 1
Cervical Cervical
STN STN
12 12
1
Primary generalized
STN
12
BFMDRS (m/d) TWSTRS (s/d/p) TWSTRS (s/d/p) BFMDRS (m/d) TWSTRS (s/d/p) BFMDRS (m/d)
36.5/5 31/27/14 21/16/17 53/14 26/27/15.3 23/5
29/10 23/20/5.5 12/5/14.3 59/17 28/24/18.3 12/3
21/50 26/26/61 43/69/16 11/-21 8/11/ 20 72/40
1
Primary generalized
STN
29
BFMDRS (m/d)
N/A
N/A
23/42
Novak et al., 2007209
Kluger et al
Table 4 (continued)
Ostrem et al., 200767
6
Cranial-cervical
Sun et al., 200766
12 Primary generalized 2 Secondary tardive
Tisch et al., 2007210
7 8
Primary DYT1
GPi
6
Vidailhet et al., 2007211
7
Primary DYT11
GPi
36
Loher et al., 2008212
4 2
Primary DYT11
15 Primary DYT1
GPi GPi
6 6
BFMDRS (m/d) TWSTRS (t)
22/6 39
6.1/3.7 17
72/38 54
STN
6–42
BFMDRS
N/A
N/A
76–100
Groups reported together
STN
6–42
GPi
6
BFMDRS (m/d)
38.9/9.0
11.9/4.1
70/58
DYT1 1 and DYT1 analyzed together
BFMDRS (m/d)
46.3/11.6
19.3/6.3
58/46
DYT11 and DYT1 analyzed together
36 36 36
TWSTRS (s/d/p) 20.5/40.5/6 BFMDRS (m/d) 81/18.5
14.7/15.7/3.7 28.3/7.5
28/61/38 65/59
Magarinos-Ascone 10 Primary generalized GPi et al., 200864
12
BFMDRS (m/d)
57.8/18.1
20.0/8.6
65/52
Sako et al., 2008213
21
BFMDRS (m/d)
N/A
N/A
86/80
6
Secondary tardive
GPi
1 patient DYT11
This table is an expanded version of that published in the work of Ostrem, 2007, with full permission from Elsevier Ltd. Abbreviations: BFMDRS (m/d), Burke-Fahn-Marsden dystonia rating scale (motor subscore, maximum 120/disability subscore, maximum 30); BFMDRS (t), BurkeFahn-Marsden dystonia rating scale, total score; PKAN, pantothenate kinase associated neurodegeneration; TWSTRS (s/d/p), Toronto western spasmotic torticolis rating scale (severity, maximum 35/disability, maximum 30/pain, maximum 18); UDRS, Unified dystonia rating scale; UPDRS-III, Unified Parkinson disease rating scale, motor subscore (maximum 108); UMRS, Unified myoclonus rating scale; ESRS, Extrapyramidal symptoms rating scale; AIMS, Abnormal involuntary movements scale; GDS, Global dystonia scale; Primary generalized, Primary generalized dystonia of an unknown etiology; Primary DYT1 1, Primary generalized DYT1 gene positive dystonia; Primary DYT1 -, Primary; generalized DYT1 gene negative dystonia, Percentage of change was calculated as [(Preoperative–Postoperative)/Preoperative]x100. For generalized and cervical dystonia, only reports with 5 or more cases were included. For other types of dystonia all published reports were included.
Surgical Treatment of Movement Disorders
GPi
Cervical GPi Primary generalized GPi
659
660
Study
Sample Size
Study Type
Dx
Target
Motor Improvement
Nonmotor Outcomes
Welter et al., 2008214
3
Randomized, controlled, doubleblinded, crossover
TS
GPiCM-Pf
78% and 45% reductions in Yale tic severity scale with GPi and CM-pf respectively. No further improvement with both targets
No change in neuropsychological testing. Mild improvements in impulsivity and depression were noted with CM-pf only
Dehning et al., 200875
1
Case study
TS
GPi
88% improvement in YGTSS
No change in neuropsychological testing
Shields et al., 200876
1
Case study
TS
Anterior IC and CM-Pf
23% improvement in YGTSS with IC; 46% improvement with CM
Depression with AIC
Servello et al., 200874
18
Prosp NC
TS
CM-Pf
Improvements in YGTSS not quantified
Improvements reported in psychiatric comorbidities. Neuropsychology testing performed but results not reported
Bajwa et al., 2007215
1
Case study
TS
CM
66% improvement in YGTSS
OCD symptoms also improved
Kuhn et al., 200777
1
Case study
TS
NAc
41% improvement in YGTSS
OCD symptoms also improved
Shahed et al., 2007216
1
Case study
TS
GPi
84% improvement in YGTSS
Improved OCD symptoms and QOL. Neuropsychology tests stable or improved, except mild decrease in memory
Maciunas et al., 2007217
5
Randomized, controlled, doubleblind, crossover
TS
CM-Pf
44% improvement in YGTSS
Trend toward decreased neuropsychology and improved mood. QOL significantly improved
Kluger et al
Table 5 Summary of DBS outcomes for other movement disorders
2
Case study
TS
One patient GPi, other CM
85%–90% reduction in tics/minute both patients
Improved OCD symptoms
Flaherty et al., 2005219
1
Case study
TS
Anterior IC
25% improvement in YGTSS
Euthymic with optimal settings
Diederich et al., 2005220
1
Case study
TS
GPi
46% improvement in YGTSS
Depression and anxiety mildly improved. Neuropsychology stable
Houeto et al., 2005221
1
Case study
TS
CM-Pf and GPi
65% improvement in YGTSS with either or both sites
Neuropsychology stable or improved Mild improvements with depression and impulsivity with CM-Pf
VisserVandewalle et al., 2003222
3
Case series
TS
CM
82% reduction tics/minute
Mild decrease in 1 patient on timed neuropsychology tests
Vandewalle et al., 1999223
1
Case study
TS
CM
901% reduction tics/ minute
N/A
Fasano et al., 200897
1
Case study
HD
GPi
Complete resolution of chorea
Continued deterioration of cognition and gait
Hebb et al., 200698
1
Case study
HD
GPi
Significant improvement in total UPDRS and chorea
Noted weight gain and stable neuropsychology function over 12 mo
Moro et al., 2004224
1
Case study
HD
GPi
44% and 37% improvements in chorea and dystonia
Mild improvements in functional assessment and independence
Freund et al., 200799
1
Case study
SCA-2
VIM STN
Improved tremor
Improved speech and ADLs
Shimojima et al., 2005100
1
Case study
SCA (negative genetic testing)
VIM
45% improvement in FTM TRS
Improved ADLs
Foote and Okun, 200596
1
Case study
Traumatic Holmes tremor
VIM, VOA and VOP
40% improvement in FTM TRS
Significant improvement in disability
Surgical Treatment of Movement Disorders
Ackermans et al., 2006218
(continued on next page)
661
662
Sample Size
Study Type
Dx
Target
Motor Improvement
Nonmotor Outcomes
Nikkhah et al., 200469
2
Case series
Holmes tremor
VIM
Improved tremor and dystonia
Improved speech
Kudo et al., 2001225
1
Case study
Holmes tremor
VIM
Improved tremor
N/A
Plaha et al., 200892
13
Case series
PD, MS, ET, Holmes, dystonic tremor
Zona Incerta
60%–90% improvement in all tremors
N/A
Lim et al., 200779
2
Case studies
MS and stroke
VIM/VOA and GPi (stroke only)
40% improvement in MS with VIM/VOA, 7% in stroke with GPi only
Mild improvements in ADL ratings for both patients
Foote et al., 200685
4
Case series
MS 1 Trauma 3
VIM VOA/VOP
23%–66% improvement in TRS, trend toward more improvement with dual leads in 2 patients
N/A
Moringlane et al., 200490
1
Case study
MS
VL
Improved tremor
No change in neuropsychology function, improved ADLs
Wishart et al., 200395
4
Case series
MS
VIM
Improved tremor
Dysarthria in 1 patient
Schulder et al., 200393
9
Case series
MS
VIM
68% improvement in Bain-Finchley TRS
Stimulation-related fatigue in 1 patient
Bittar et al., 200583
10
Case series
MS
VOP/ZI
64% and 36% improvement of postural and intention tremor on 10-point scale
N/A
Berk et al., 200282
12
Case series
MS
VIM
Overall tremor reduction 63% on Fahn rating scale
Improved ADLs. No change in SF-36 QOL
Study
Kluger et al
Table 5 (continued)
9
Case series
MS
VIM
61% tremor reduction Bain-Finchley scale
Mild neuropsychology decline over 30 mo, possibly 2/2 disease progression
Hooper et al., 200287
10
Prospective
MS
Thalamic (targeted to tremor)
Significant reduction on Fahn-TRS
No change in neuropsychology Mild improvement in anxiety
Matsumoto et al., 200188
9
Case series
MS
VIM
Significant reduction in clinical TRS
No change in disability, mild decrease in QOL
Schuurman et al., 200094
5
Randomized (vs thalamotomy)
MS
VIM
Improvement on UPDRS tremor rating
N/A
Brice and McLellan, 198084
2
Case series
MS
Thalamus
Improved tremor
Dysarthria
Montgomery et al., 199989
15
Case series
MS
VIM
Improved clinical TRS
N/A
Benabid et al., 199681
4
Case series
MS
VIM
Tremor improved in 2 patients
N/A
Geny et al., 199686
13
Case series
MS
VIM
Significant decrease in tremor in 9 patients
Improvement in functional disability
Nguyen and Degos, 199391
4
Case series
MS, germinoma, TBI and mercury poisoning
VIM
Tremor improved from ‘‘severe’’ to mild or none in all subjects
Improved functional use of arm
Siegfried and Lippitz, 199480
11
Case series
MS (9), trauma, stroke
VIM
70%–100% of patients with tremor control (not reported by subgroup)
Tremor control limited in some patients by side effects, mainly dysarthria
Abbreviations: ADLs, activities of daily living; AIC, anterior internal capsule; CM-Pf, centromedian parafasicular, Dx, diagnosis; ET, essential tremor; FTM TRS, Fahn Tolosa Marin tremor rating scale; HD, Huntington’s disease; IC, Internal capsule; MS, multiple sclerosis; NAc, nucleus accumbens; OCD, obsessive compulsive disorder; PD, Parkinson’s disease; QOL, Quality of life; SCA, spinocerebellar ataxia; SF-36, 36-item short-form health survey; TBI, traumatic brain injury TS, Tourette syndrome; VL, ventral lateral; YGTSS, Yale Global Tic Severity Scale. Data from Ostrem J, Marks WJ, Volz M, et al. Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome). Mov Disord 2007;22(13):1885; with permission.
Surgical Treatment of Movement Disorders
Schulder et al., 200393
663
664
Kluger et al
and this may provide a rationale for target choice in an individual patient.54 A summary of published studies for DBS for PD is provided in Table 2. Essential Tremor
VIM thalamic DBS has proven to be a generally well-tolerated and efficacious treatment for ET.55 Candidates for ET DBS usually have postural and/or action tremors, which significantly interfere with ADLs and QOL and should be medication refractory, including maximally tolerated doses of primidone (and/or other anticonvulsants), propanolol (and/or other beta blockers), and a benzodiazepine (typically clonazepam). VIM DBS has been particularly efficacious for contralateral limb tremor, although it has some ipsilateral positive effects.56 VIM DBS may improve vocal or head tremor, but, in our experience, it is not a reliable benefit when looking across patients. Botulinum toxin injections may be synergistic with DBS for these tremors, particularly if there is a dystonic component. Potential chronic side effects of VIM DBS include speech abnormalities (dysarthria and decreased verbal fluency) and difficulty with gait, particularly with bilateral stimulator placement, and if there are premorbid issues such as cerebrovascular disease or ventricular enlargement. Possibly with the exception of verbal fluency, cognitive and mood outcomes do not seem to decline with VIM DBS in the ET population.57 However, given recent data of neuropsychological impairments in ET and reports of mood disturbances and suicides following VIM DBS, careful screening is still appropriate.58 In Table 3 we provide a complete review of the literature on VIM DBS outcomes for motor, mood, QOL, and cognitive outcomes.59 Dystonia
Bilateral GPi DBS has been recently demonstrated by several groups as safe and efficacious in the treatment of primary generalized dystonias,60 tardive dystonia,61 and in some cases of focal or segmental dystonia.62,63 There have also been several case reports of successful treatment of myoclonus-dystonia syndrome with bilateral GPi DBS64 and thalamic DBS.65 Although not commonly used, STN and thalamic DBS have shown efficacy in primary, tardive, and segmental dystonia.66 In patients with nontardive secondary hemidystonia, segmental, or focal dystonia, the appropriate target(s) are not clear at this time. Patient selection follows similar principles to PD. Patients should have a definitive diagnosis of dystonia by a movement disorder neurologist/neurologist experienced in dystonia and have significant effects on QOL or ADLs despite maximally tolerated medical treatments, including anticholinergics, benzodiazepines, muscle relaxants, and antiepileptics. In patients with focal or limited segmental dystonia, an adequate trial of botulinum toxin injections should also be attempted. Mobile dystonia has been found to be more responsive to DBS regardless of the underlying etiology, and fixed orthopedic deformities are unlikely to be improved by DBS. In Table 4 we provide a review of the literature on GPi dystonia DBS outcomes. The majority of studies of DBS in dystonia have been performed in primary generalized dystonia, where patients have generally shown a 40%–60% improvement in dystonia severity. Similar results have been obtained in cervical dystonia,62 Meige syndrome67 and tardive dystonia.61 Case reports of improvement in dystonia following GPi DBS have also been reported in dystonia secondary to trauma, stroke, and pantothenate kinase deficiency.68–70 DBS for dystonia is notably different from other disorders in that DBS typically has a delayed benefit possibly owing to cortical remodeling due to stimulation effects, although the exact cause of this finding is currently unknown.71 Similarly, following DBS, dystonic patients may experience lasting benefits after discontinuation of DBS therapy. Dystonia patients may also accumulate benefit over
Surgical Treatment of Movement Disorders
several months or even longer, suggesting that GPi DBS in dystonia may have both direct effects from stimulation and also induce longer-term neuroplastic changes or disease-modifying benefits.23 The potential chronic side effects of GPi DBS for dystonia are similar to those seen in PD. With regard to mood disturbances, a careful neuropsychiatric evaluation, particularly in patients with tardive dystonia, is strongly recommended.58 Patients with dystonia appear to have a lower risk of cognitive side effects after GPi DBS, possibly because they are younger and the underlying disease may be associated with less cognitive dysfunction and fewer comorbidities.72 However, suicides in patients, particularly those with premorbid depression, have been reported following GPi DBS for dystonia.73 Another side effect noted in a small case series of patients with Meige syndrome was the development of a subjective sense of clumsiness and slowness in previously unaffected body parts.67 Although these symptoms were often not evident on examination, they were persistent and present only when DBS was turned on. Side effects from field spread into pallidal and surrounding regions are similar to what is seen in GPi DBS for PD. OTHER MOVEMENT DISORDERS
There have been several case series demonstrating the potential for DBS in Tourette syndrome (TS). These case series have used multiple separate targets and combinations of targets, including the centromedian thalamus-parafascicular complex (including the ventralis oralis complex of the thalamus),74 GPi,75 the anterior limb of the internal capsule,76 and the nucleus accumbens.77 As a side benefit, many of these patients also noted improvements in comorbid psychiatric symptoms, including anxiety and obsessive-compulsive disorder. Principles of patient selection are similar to those in other movement disorders, namely, the use of a multidisciplinary team to carefully screen patients and failure to achieve adequate symptom control despite maximal medical management. The Tourette Syndrome Association has now published general guidelines for Tourette DBS.78 There are several small case series showing improvement in poststroke tremor,79,80 posttraumatic tremor,79,80 and multiple sclerosis (MS) tremor with DBS.79–95 These treatments typically target the VIM, although some authors have used multiple simultaneous thalamic or GPi and thalamic targets.79,85,96 VIM in complex tremors may not be the target of choice, and other areas of thalamus will need to be explored ventralis oralis anterior, ventralis oralis posterior and centromedian (Voa, Vop, CM). In these patients, one must be careful to determine how much disability is due to tremor, which may improve with DBS, versus ataxia or weakness, which will not improve with DBS. Three case reports suggest that chorea in Huntington’s disease (HD) may be reduced with bilateral GPi DBS.97,98 Case reports of efficacy in some of the spinal cerebellar ataxias have also been reported.99,100 In Table 5 we provide a review of the literature on DBS outcomes in other movement disorders for motor, mood, QOL, and cognitive outcomes. In studies of mixed populations, we included only studies where specific outcome information was available for each diagnosis. SUMMARY
DBS is an efficacious treatment option for appropriately selected patients with PD, ET, and dystonia. Indications and options for DBS continue to expand rapidly. There are important side effects and benefits that may influence target selection for individual patients. Advances in our understanding of the pathophysiology of movement disorders combined with technological advances in our ability to precisely target neuroanatomical structures continue to push improvements in the efficacy and safety of DBS
665
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for basal ganglia disorders. Basic science advances need to be combined with welldesigned clinical trials to define rational treatment algorithms to improve motor, mood, cognitive, and QOL outcomes. ACKNOWLEDGMENT
The authors would also like to acknowledge Leah Gaspari for her assistance in the preparation of this manuscript. REFERENCES
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194. Trottenberg T, Volkmann J, Deuschl G, et al. Treatment of severe tardive dystonia with pallidal deep brain stimulation. Neurology 2005;64(2):344–6. 195. Vayssiere N, Gaag NVd, Cif L, et al. Deep brain stimulation for dystonia confirming a somatotopic organization in the globus pallidus internus. J Neurosurg 2004;101(2):181–8. 196. Bittar R, Yianni J, Wang S, et al. Deep brain stimulation for generalised dystonia and spasmodic torticollis. J Clin Neurosci 2005;12(1):12–6. 197. Castelnau P, Cif L, Valente E, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol 2005;57(5):738–41. 198. Chou K, Hurtig H, Jaggi J, et al. Bilateral subthalamic nucleus deep brain stimulation in a patient with cervical dystonia and essential tremor. Mov Disord 2005; 20(3):377–80. 199. Zorzi G, Marras C, Nardocci N, et al. Stimulation of the globus pallidus internus for childhood-onset dystonia. Mov Disord 2005;20(9):1194–200. 200. Diamond A, Shahed J, Azher S, et al. Globus pallidus deep brain stimulation in dystonia. Mov Disord 2006;21(5):692–5. 201. Starr P, Turner R, Rau G, et al. Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. J Neurosurg 2006;104(4):488–501. 202. Zhang J, Zhang K, Wang Z, et al. Deep brain stimulation in the treatment of secondary dystonia. Chin Med J (Engl) 2006;119(24):2069–74. 203. Alterman R, Miravite J, Weisz D, et al. Sixty hertz pallidal deep brain stimulation for primary torsion dystonia. Neurology 2007;69(7):681–8. 204. Damier P, Thobois S, Witjas T, et al. Bilateral deep brain stimulation of the globus pallidus to treat tardive dyskinesia. Arch Gen Psychiatry 2007;64(2):170–6. 205. Evidente V, Lyons M, Wheeler M, et al. First case of X-linked dystonia-parkinsonism (‘‘Lubag’’) to demonstrate a response to bilateral pallidal stimulation. Mov Disord 2007;22(12):1790–3. 206. Grips E, Blahak C, Capelle H, et al. Patterns of reoccurrence of segmental dystonia after discontinuation of deep brain stimulation. J Neurol Neurosurg Psychiatry 2007;78(3):318–20. 207. Kiss Z, Doig-Beyaert K, Eliasziw M, et al. The Canadian multicentre study of deep brain stimulation for cervical dystonia. Brain 2007;130(Pt 11):2879–86. 208. Kleiner-Fisman G, Liang G, Moberg P, et al. Subthalamic nucleus deep brain stimulation for severe idiopathic dystonia: impact on severity, neuropsychological status, and quality of life. J Neurosurg 2007;107(1):29–36. 209. Novak K, Nenonene E, Bernstein L, et al. Successful bilateral subthalamic nucleus stimulation for segmental dystonia after unilateral pallidotomy. Stereotact Funct Neurosurg 2008;86(2):80–6. 210. Tisch S, Zrinzo L, Limousin P, et al. Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia. J Neurol Neurosurg Psychiatry 2007;78(12):1314–9. 211. Vidailhet M, Vercueil L, Houeto J, et al. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol 2007;6(3):223–9. 212. Loher T, Capelle H, Kaelin-Lang A, et al. Deep brain stimulation for dystonia: outcome at long-term follow-up. J Neurol 2008;255(6):881–4. 213. Sako W, Goto S, Shimazu H, et al. Bilateral deep brain stimulation of the globus pallidus internus in tardive dystonia. Mov Disord 2008;23(13):1929–31. 214. Welter M, Mallet L, Houeto J, et al. Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol 2008;65(7):952–7.
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215. Bajwa R, Lotbinie`re Ad, King R, et al. Deep brain stimulation in Tourette’s syndrome. Mov Disord 2007;22(9):1346–50. 216. Shahed J, Poysky J, Kenney C, et al. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities. Neurology 2007;68(2): 159–60. 217. Maciunas R, Maddux B, Riley D, et al. Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome. J Neurosurg 2007;107(5):1004–14. 218. Ackermans L, Temel Y, Cath D, et al. Deep brain stimulation in Tourette’s syndrome: two targets? Mov Disord 2006;21(5):709–13. 219. Flaherty A, Williams Z, Amirnovin R, et al. Deep brain stimulation of the anterior internal capsule for the treatment of Tourette syndrome: technical case report. Neurosurgery 2005;57(Suppl 4):E403. 220. Diederich N, Kalteis K, Stamenkovic M, et al. Efficient internal pallidal stimulation in Gilles de la Tourette syndrome: a case report. Mov Disord 2005;20(11): 1496–9. 221. Houeto J, Karachi C, Mallet L, et al. Tourette’s syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry 2005;76(7):992–5. 222. Visser-Vandewalle V, Temel Y, Boon P, et al. Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases. J Neurosurg 2003;99(6):1094–100. 223. Vandewalle V, Linden Cvd, Groenewegen H, et al. Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet 1999;353(9154):724. 224. Moro E, Lang A, Strafella A, et al. Bilateral globus pallidus stimulation for Huntington’s disease. Ann Neurol 2004;56(2):290–4. 225. Kudo M, Goto S, Nishikawa S. Bilateral thalamic stimulation for Holmes’ tremor caused by unilateral brainstem lesion. Mov Disord 2001;16(1):170–4.
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Tremor : Clinic al Features, Pathophysiolo gy, a nd Treatment Rodger J. Elble, MD, PhD KEYWORDS
Essential tremor Parkinson disease Holmes tremor Orthostatic tremor Palatal tremor Rhythmic cortical myoclonus Cerebellar intention tremor Psychogenic tremor
Tremor is an approximately rhythmic, roughly sinusoidal involuntary movement. Here we review the phenomenology, pathophysiology, and treatment of tremor disorders.
PHYSIOLOGIC TREMOR
Physiologic tremor is barely visible to the unaided eye and is symptomatic only during activities that require extreme precision. Physiologic tremor consists of 2 distinct oscillations, mechanical reflex and 8- to 12-Hz, which are superimposed upon a background of irregular fluctuations in muscle force and limb displacement.1,2 The mechanical-reflex component is a passive mechanical oscillation. The limbs and other body parts have underdamped inertial, viscous, and elastic properties, such that oscillation occurs in response to irregularities in subtetanic motor unit contraction and cardioballistic vibrations produced by the ejection of blood at cardiac systole.2,3 Participation of the stretch reflex is evident only when physiologic tremor is enhanced by fatigue, anxiety, hyperthyroidism, or tremorogenic drugs (enhanced physiologic tremor).4,5 The 8- to 12-Hz component of physiologic tremor is produced by rhythmic bursts of motor unit activity at 8 to 12 Hz.1,6 The 8- to 12-Hz tremor is believed to originate from oscillation in olivocerebellothalamocortical pathways7,8 and therefore is also called the central neurogenic component of physiologic tremor. The amplitude of this component varies greatly among normal people, and it tends to be more evident in conditions producing enhanced physiologic tremor.
Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62794-9643, USA E-mail address:
[email protected] Neurol Clin 27 (2009) 679–695 doi:10.1016/j.ncl.2009.04.003 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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Physiologic tremor is not symptomatic except in fine motor tasks requiring extreme precision (eg, microsurgery, jewelry making) or when enhanced by fatigue, anxiety, hyperthyroidism, or drugs. Beta-adrenergic blockers (eg, propranolol) and robotic aids are useful when treatment is needed. ESSENTIAL TREMOR
Essential tremor is the most common form of pathologic tremor. It affects the hands in nearly all cases and frequently affects the head (at least 34%), face/jaw (approximately 7%), voice (approximately 12%), tongue (approximately 30%), trunk (approximately 5%), and lower limbs (approximately 30%).9,10 It is evident in posture, movement, or both, and patients with advanced essential tremor exhibit intention tremor and impaired tandem walking, consistent with impaired cerebellar function.11 Tremor in repose is uncommon and is observed only in the most advanced patients, who are typically older. The complex pill-rolling hand movements of Parkinson tremor and lower extremity rest tremor are not produced by essential tremor.9 Essential tremor begins at any age, but its prevalence increases with age. Approximately 5%of people over the age of 65 are believed to have essential tremor.12 Many do not seek medical attention, but most find the tremor annoying, disabling, or embarrassing. Some fear the diagnosis of Parkinson disease and seek medical attention for diagnosis, while others desire diagnosis and treatment. Many patients have a family history that is compatible with Mendelian dominant inheritance. Genetic linkage studies have revealed several promising loci, but specific genes have not been found.13 Polygenic inheritance, analogous to the genetics of restless leg syndrome, is suspected. The fundamental electrophysiologic abnormality of essential tremor is an abnormal entrainment of motor unit activity at the frequency of tremor, which is typically 4 to 8 Hz. Many experimental and clinical observations point to the thalamocortical and olivocerebellar pathways as the source of oscillation.11 Louis and coworkers have found abnormally high numbers of axonal torpedoes in the deep cerebellar white matter and reduced numbers of Purkinje cells in the cerebellar cortex of many patients with essential tremor, and Lewy body pathology in the locus ceruleus has been found in other patients.14,15 Despite these signs of neurodegeneration, classic essential tremor produces no neurologic signs other than tremor and, in older advanced cases, unsteady tandem walking. Ethanol is surprisingly effective in reversing the intention tremor and unsteady tandem gait in advanced patients.16 The reversibility of these ‘‘cerebellar’’ signs suggests that essential tremor is primarily a functional disturbance of motor pathways produced by excessive rhythmic entrainment of motor pathways, not a primary cerebellar degeneration. The ultimate identification of the genes for essential tremor should lead to a clarification of this controversy. Many investigators believe that the underlying pathophysiology of essential tremor involves synaptic or neuronal membrane dysfunction that leads to tremorogenic oscillation and synchrony in motor networks. A gamma-aminobutyric acid (GABA)-A receptor alpha-1 subunit knockout mouse has tremor that responds to medications used for essential tremor, and this model illustrates how essential tremor could be caused by a fairly widespread electrophysiologic disturbance with no discernible microscopic pathology.17 Harmaline and related beta-carboline alkaloids (eg, ibogaine) enhance the inhibition-rebound properties of olivary neurons and other neurons, causing increased rhythmicity and neuronal entrainment, which ultimately produces excitotoxic damage to Purkinje cells.18 The tremor produced by harmaline
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in laboratory animals resembles essential tremor, and the response of these conditions to medications is similar but not identical.19 Based on these animal models, ethanol and primidone could have direct actions on the neuronal oscillator or could uncouple the oscillation from segmental spinal pathways. Beta-blockers act peripherally by reducing the sensitivity of sensory receptors (eg, muscle spindles) and by increasing the low-pass filtering properties of skeletal muscle. A central mode of action is also possible. Zesiewicz and colleagues20 recently reviewed the available evidence for pharmacotherapy of essential tremor. Propranolol is the only drug that is approved by the Food and Drug Administration for the treatment of essential tremor, and primidone and propranolol are the only medications with level A evidence of efficacy. Drugs with level B efficacy are alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate, and none of these drugs is more effective than primidone or propranolol. None of these treatments is specific for essential tremor. Primidone and propranolol each produce an average 50% reduction in hand tremor. However, the response to these medications is variable. Greater than 80% suppression of tremor is rare, and some patients respond poorly to all medications. The response to one medication does not predict the response to another, and response to medication varies, even in large families with familial essential tremor. Combination therapy is often more effective than monotherapy. Propranolol is the most effective beta-adrenergic blocker. Some mildly affected patients take 10 to 40 mg on an as-needed basis (eg, before a stressful meeting), but most patients prefer 60 mg/d to 240 mg/d of the long-acting formulation. These dosages are usually well tolerated, but the side effects of fatigue, bradycardia, hypotension, depression, and impotence are occasionally dose-limiting. Reactive airway disease (eg, asthma or chronic obstructive pulmonary disease), heart block, and congestive heart failure are contraindications for propranolol, and patients who have brittle diabetes should be warned that propranolol might reduce the autonomic symptoms of hypoglycemia. The initial dosage of primidone should be one-fourth or one-half of a 50 mg tablet at bedtime because 20% of patients have an intolerable first-dose reaction consisting of various combinations of drowsiness, confusion, nausea, vertigo, weakness, and dysequilibrium. Patients who experience this reaction are often reluctant to continue taking primidone. However, most patients are able to gradually increase the dosage over several weeks to an endpoint of tremor reduction or drug intolerance. The usual dosage is 50 to 350 mg/d in 1 to 3 divided doses.20 Many patients experience dramatic transient benefit from ethanol. However, most physicians do not encourage regular use of this drug because ethanol is addictive and intoxicating. Nevertheless, judicious use at mealtime is not discouraged, particularly when patients have difficulty feeding. Other alcohols are being explored as possible treatments for essential tremor.21,22 Given our limited understanding of essential tremor, no medication has been developed specifically for essential tremor. The efficacy of primidone and propranolol was initially discovered fortuitously. Essential tremor is so common that fortuitous trials of numerous medications occur every day, and vigilant patients and clinicians occasionally observe a change in essential tremor. Unfortunately, most of these anecdotal observations are not substantiated in controlled studies. Stereotactic thalamotomy and deep brain stimulation (DBS) in the ventrolateral thalamus (ventralis intermedius [Vim]) are the most effective treatments for essential tremor. DBS is now the preferred procedure because it is largely reversible and allows programmable optimization of the benefit/side-effect ratio.20,23 Nevertheless,
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problems related to lead placement (skin erosion, lead breakage) and stimulator malfunction are not uncommon, and thalamic DBS, like thalamotomy, may cause dysarthria, dysphagia, somatosensory loss, paresthesias, cognitive impairment, dysequilibrium, ataxia, infection, intracranial hemorrhage, and rarely death. One or more side effects occur in approximately 20% of patients undergoing unilateral DBS, but most side effects are reduced or abolished by adjusting the stimulus parameters. Bilateral thalamotomy is contraindicated due to the high incidence of complications, but bilateral thalamic DBS is possible with an overall complication rate of about 30%, dysarthria and impaired balance being most common.20 Marked suppression of limb tremor is achieved with DBS in approximately 70% to 90% of patients. Good control of limb tremor is maintained for more than 5 years in most patients, but efficacy is gradually lost in some. The reason for lost efficacy is believed to be suboptimal lead placement and disease progression in many patients, but a true physiologic tolerance to DBS may also occur.24 The role of thalamic DBS in the treatment of head and voice tremor is less certain. Many essential tremor patients undergo bilateral surgery for their hand tremor, and many of these patients have experienced reduced head and voice tremor.25–27 These midline tremors respond poorly to medications.20 However, it is unclear whether disabling midline tremor is ever a primary indication for DBS.20 The mechanism of action of thalamic DBS is uncertain, and its effect is not specific for essential tremor. Most investigators believe that thalamic DBS interrupts resonant tremorogenic oscillation in the thalamocortical loop, regardless of the primary site(s) of pathology. Recently, the critical stereotactic target has been questioned by Herzog and coworkers, who found that stimulation of neighboring subthalamic structures is more effective than stimulation of Vim.28 Several investigators have found that subthalamic DBS is effective in essential tremor,29,30 and both Parkinson tremor and essential tremor respond to subthalamic deep brain stimulation when these diseases occur in the same patient.31 The critical target in this anatomically compact area is unclear and could be the subthalamic nucleus, zona incerta, or prelemniscal radiation, which carries cerebellar and somatosensory afferents to the ventrolateral thalamus.30 Regardless, these observations raise the possibility that tremorogenic oscillation in the basal ganglia could participate in the pathogenesis of essential tremor. PARKINSON TREMOR
Rest tremor in the upper or lower extremities is the most specific feature of Parkinson disease. The frequency is 3 to 5 Hz or occasionally a little faster. Rest tremor in the hand is called pill-rolling tremor because the tremulous hand movement resembles the repetitive rolling of a pill or other small object between the thumb and other fingers. Parkinson rest tremor is suppressed by voluntary muscle activation but may re-emerge during sustained posture or movement, after a variable delay of several seconds (hence the term re-emergent tremor).32 There is little or no difference in the frequency of re-emergent tremor and rest tremor, since they are simply different manifestations of the same phenomenon. A second high-frequency form of Parkinson action tremor has a frequency of 5 to 10 Hz and, like essential tremor, begins immediately with voluntary muscle activation. Action tremor and rest tremor have been produced in monkeys with intracarotid injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MTPT),33 and there is no compelling reason to believe that these 2 forms of tremor have a different pathophysiology.34,35 Disabling re-emergent tremor is typically seen in patients with disabling rest tremor. High-frequency action tremor is usually not disabling unless it is caused by some other
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neurologic disorder. In the absence of comorbid conditions, Parkinson patients typically have little or no tremor in their handwriting and drawings. Therefore, disabling tremor in these tasks should raise the suspicion of another tremor disorder, in isolation or in combination with Parkinson disease. For example, essential tremor and Parkinson disease are common disorders that frequently occur in the same patient. Nigrostriatal cell loss is probably sufficient to produce Parkinson tremor,36 and it causes tremorogenic neuronal oscillation in the motor cortex,37 ventrolateral thalamus,38,39 globus pallidus,40 and subthalamic nucleus.41 A stereotactic lesion or high-frequency stimulation in any of these locations suppresses tremor, so their collective oscillation, rather than individual oscillation, may be necessary for Parkinson tremor.42,43 The cerebellum is abnormally active in patients with Parkinson tremor, but the cerebellum is not necessary for the production of rest tremor.44 Tremor is but 1 symptom of Parkinson disease, and the treatment of Parkinson disease is dictated by the entire symptom complex. Nevertheless, some patients have so-called tremor-predominant disease, in which there is disabling tremor and very little bradykinesia and rigidity.45 The variability in tremor may be due to the variable distribution of dopaminergic loss46 or the loss of other neurotransmitters, such as serotonin.47 Moreover, tremor could be caused by deleterious compensatory changes in motor pathway function that follow the loss of dopaminergic neurons, analogous to the tremors that occur weeks or months following a stroke or brain trauma, discussed later in this article. Regardless, clinicians should not be surprised if Parkinson tremor responds poorly to levodopa.48 The dopamine agonists (eg, pramipexole and ropinirole) reduce tremor in patients that are optimally treated with levodopa.49 Occasional patients require the addition of an anticholinergic or amantadine. A systematic trial-and-error approach is required. The drugs used for essential tremor are frequently tried in Parkinson patients that do not respond to first-line medications, but these unusual patients typically must choose between inadequate tremor control and deep brain stimulation.50 Of all the motor signs and symptoms of Parkinson disease, tremor has the least site specificity and typically responds very well to surgery.51,52 Thalamic Vim is an effective stereotactic surgical site for treating Parkinson tremor but not rigidity or bradykinesia. Stereotactic destruction and DBS of the posteroventrolateral internal pallidum and the subthalamus are effective treatments for tremor and also reduce bradykinesia and rigidity.52,53 In the subthalamic area neighboring the ventrolateral thalamus, the subthalamus, zona incerta, pallidothalamic fibers, and cerebellothalamic fibers probably all participate in tremorogenesis.54,55 CEREBELLAR INTENTION TREMOR
Cerebellar intention tremor occurs in the ipsilateral extremities of laboratory primates with lesions in the deep cerebellar nuclei (dentate, globose, and emboliform) or in the efferent fibers of these nuclei in the brachium conjunctivum, in route to the contralateral ventrolateral thalamus. The critical nuclear lesion appears to be the globose-emboliform (interpositus).56 Classic intention tremor in humans is produced by lesions in the cerebellum or in the brachium conjunctivum pathway from the deep cerebellar nuclei to the contralateral ventrolateral thalamus.57,58 Small lesions in the vicinity of the ventrolateral thalamus may produce intention tremor with no other signs of ataxia, but lesions in the brainstem, brachium conjunctivum, and cerebellum are always associated with other neurologic signs.57,58 The rhythm and amplitude of cerebellar intention tremor are often irregular, and proximal limb muscles are usually involved more than distal ones. The frequency of
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cerebellar intention tremor is commonly cited as 3 to 5 Hz, but animal and human studies have shown that tremor frequency is influenced by reflex arc length and by the inertia and stiffness of the body part.58–60 These observations are consistent with the mechanistic involvement of somatosensory feedback loops. The persistence of tremor following somatosensory deafferentation61 is probably due to the participation of visual feedback62 and thalamocortical oscillation19 in tremorogenesis. Studies in monkeys have shown that the cerebellothalamocortical pathway plays a pivotal role in feedforward motor control, and damage to this pathway makes the nervous system excessively reliant on feedback control, which is woefully slow and unstable.19 Cerebellar feedforward control is needed for timely deceleration of a limb as it approaches its intended destination, otherwise past-pointing or overshoot occurs, followed by terminal oscillation. This oscillation typically increases as the limb approaches its target. The mechanism of this crescendo terminal accentuation of tremor is uncertain, but resonance in the ventrolateral thalamocortical loop undoubtedly contributes because Vim and the neighboring cerebellothalamic fibers are effective stereotactic targets for intention tremor.28 The drugs used for essential tremor are typically tried in patients with disabling intention tremor, regardless of etiology. However, medications are notoriously ineffective for intention tremor, except when it is caused by advanced essential tremor. Even then, the available medications are often inadequate, resulting in a need for thalamic DBS. The literature contains many anecdotal reports of response to various drugs but no controlled trials demonstrating efficacy. It should be noted that severe cortical tremor (discussed in this article) resembles intention tremor, and cortical tremor may respond very well to the drugs used for cortical myoclonus (see article 8). There is only limited published experience with DBS in the treatment of cerebellar intention tremor. Thalamic and subthalamic DBS is effective in reducing the tremorogenic oscillation, but it does not improve the other signs of ataxia, which are due to the loss of cerebellar feedforward motor control. Therefore, clinicians must be very careful to select patients who are primarily affected by rhythmic tremor, not by other aspects of ataxia (eg, dysmetria, decomposition of movement, dysdiadochokinesia, postural instability, dysarthria), which could be exacerbated by DBS.28,63 Even with careful patient selection, a good response to DBS is less likely and less28,63 predictable than in essential tremor and Parkinson disease. Careful stereotactic target selection is important, and the best target is still a matter of investigation. Herzog and colleagues28 studied DBS in patients with advanced essential tremor and multiple sclerosis (demyelination in the brachium conjunctivum) and found that the optimum target was the subthalamic white matter (H field of Forel), not Vim. HOLMES (RUBRAL) TREMOR
Holmes tremor is a striking combination of 2- to 5-Hz rest, postural, and intention tremor of an extremity, and it may occasionally affect the neck and torso.64–66 This unusual tremor has been called rubral tremor because it is caused by lesions in the vicinity of the red nucleus. However, isolated lesions in the red nucleus are not tremorogenic, so participants of the 1997 Tremor Symposium in Kiel, Germany, proposed that this tremor be called Holmes tremor, which is now the conventional term.67 In most cases, Holmes tremor begins weeks to months after thalamic or midbrain trauma or stroke, so secondary or compensatory changes in nervous system function seem to participate in tremorogenesis. The nature of these deleterious secondary changes is unclear.
Tremor
A combination of damage to neighboring cerebellothalamic and nigrostriatal or pallidothalamic fiber tracts is needed to produce Holmes tremor.19 Some patients have reduced striatal 18F-fluorodopa uptake,66 which explains why levodopa, dopaminergic agonists, and anticholinergics occasionally are beneficial for the rest tremor. Unfortunately, Holmes tremor, like cerebellar intention tremor, rarely responds well to medications. The drugs used for essential tremor are usually tried but are typically ineffective. Holmes tremor may respond to stereotactic thalamotomy and DBS in Vim.68,69 However, extensive experience is not available, and some patients respond poorly, possibly due to the ambiguities of target selection. Although Vim is the most common target, globus pallidus interna and the subthalamic area have been used alone or in combination with Vim.64,70–72 PALATAL TREMOR
Palatal tremor (also known as palatal myoclonus) consists of vertical oscillations of the soft palate at 1 to 3 Hz. There are 2 forms of palatal tremor, essential and symptomatic. Essential palatal tremor causes an annoying ear click but no other neurologic signs or symptoms. The pathophysiology of essential palatal tremor is unclear,73 but some patients have complete or partial voluntary control.74 Therefore, some cases may be psychogenic, an unusual motor skill, or an unusual tic disorder. Recognizing the varied and uncertain pathophysiology of this disorder, Zadikoff and coworkers proposed the term isolated palatal tremor (IPT) instead of essential palatal tremor and recommended that clinicians attempt to classify their patients into primary IPT (etiology unclear) and secondary IPT (eg, psychogenic, unusual skill).74 The ear click of essential palatal tremor is produced by movements of the eustachian tube that are caused by contraction of the tensor veli palatini. Botulinum toxin injection of this muscle can abolish the ear click, if necessary. There have been anecdotal reports of response to medications. The response to sumatriptan is most convincing but highly variable.75,76 Symptomatic palatal tremor occurs in patients with damage to the dentato-olivary pathway, which causes secondary hypertrophic olivary degeneration.73 The palatal movements of symptomatic palatal tremor are usually asymptomatic but occasionally move the eustachian tube enough to cause an ear click. In contrast to essential palatal tremor, the levator veli palatini muscle is rhythmically active in symptomatic palatal tremor.77,78 Symptomatic palatal tremor is usually associated with other brainstem and cerebellar signs, depending upon the nature and extent of underlying pathology.73 Synchronous movements of the tongue, floor of the mouth, larynx, face, diaphragm, intercostal muscles, eyes, extremities, and trunk are not uncommon. Secondary hypertrophic olivary degeneration and palatal myoclonus develop weeks to months after a stroke in the dentato-olivary pathway.79–81 Many investigators believe that the hypertrophied olives oscillate at 1 to 3 Hz, producing abnormal movements at the same frequency.82 Loss of dentato-olivary GABAergic inhibition of the gap junctions among olivary neurons could cause greater synchrony among olivary neurons. Hong and coworkers83 proposed that this oscillation initially produces no symptoms, but the persistent synchronous 1- to 3-Hz climbing fiber input to the cerebellar cortex eventually alters the interaction between interneurons and Purkinje cells in the cerebellar cortex, resulting in enhanced Purkinje cell excitability, which amplifies the olivary oscillation to a level that produces palatal tremor. Patients with symptomatic palatal myoclonus frequently have intention tremor or Holmes tremor in 1 or more limbs.84 Interestingly, DBS in Vim has successfully
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suppressed these tremors without any effect on the palatal tremor.70,85 Therefore, symptomatic palatal tremor appears to be a fairly unique example of a tremor disorder that is unresponsive to thalamic DBS, consistent with its proposed pathophysiology.82
TREMOR DUE TO PERIPHERAL NERVE PATHOLOGY
Patients with acquired and hereditary peripheral neuropathies frequently exhibit symptomatic 3- to 10-Hz action tremors. Some patients with hereditary neuropathy have tremor that is indistinguishable from essential tremor.86 Others exhibit tremor with the electrophysiologic properties of enhanced physiologic (mechanical reflex) tremor or cerebellar tremor.87 The sensory loss and velocity of nerve conduction usually have little or no relation to the frequency and amplitude of neuropathic tremor, and the neuromuscular illnesses in most patients do not cause direct damage to the central nervous system.87–89 Consequently, deleterious compensatory changes in central nervous system function are hypothesized to produce tremorogenic oscillation in otherwise normal central sensorimotor networks. The cerebellum has been implicated, but the details are far from clear.90 Some (many?) patients may have a subclinical or hereditary predisposition to tremor.86,91 The treatment of neuropathic tremor should first address the underlying neuropathy, if possible. Symptomatic treatment has not been studied on controlled trials. The medications used in essential tremor are commonly tried. There are no reports of treatment with DBS.63 TASK-SPECIFIC, FOCAL, AND DYSTONIC TREMORS
A variety of isolated (monosymptomatic) focal and task-specific tremors have been described. Most are rare.92 However, focal and task-specific dystonias are common and are commonly tremulous. Isolated action tremor can be the initial symptom of dystonia, and dystonia may develop years after the onset of isolated tremor in the neck, trunk, or limbs.93–95 Consequently, many specialists believe that most isolated focal and task-specific tremors are a form of dystonia, and long-term follow-up frequently confirms this impression. It is unclear whether some cases could be variants of essential tremor (eg, isolated tremor of the head, tongue, voice, or jaw) or a separate disorder. This controversy will not be resolved until specific biomarkers are found for essential tremor. Tremulous cervical dystonia is frequently suppressed by sensory tricks (geste antagoniste), whereas essential tremor is not.96,97 The response of any focal or taskspecific tremor to a sensory trick should be regarded as a sign of underlying dystonia. Primary writing tremor is the most extensively studied form of task-specific tremor. Patients with this condition exhibit disabling tremor during the act of writing but experience little or no tremor during other activities. It is unclear whether primary writing tremor is a variant of focal dystonia, a variant of essential tremor, or a separate disease entity.98–102 The same can be said for the rare isolated tremors of the voice, chin, tongue, and smile.67,92 There are no controlled therapeutic trials for these conditions. The medications for essential tremor are usually tried and are beneficial to some patients. Botox is a treatment option, given the probable relationship of many cases to focal dystonia. A few patients with severe writing tremor have been treated successfully with Vim thalamotomy and DBS.63
Tremor
ORTHOSTATIC TREMOR
Orthostatic tremor is a very rhythmic 13- to 18-Hz postural tremor that causes patients to feel unsteady when they attempt to stand still.103–107 This tremor affects the lower limbs, torso, upper limbs, neck, and cranium.105 Patients with orthostatic tremor complain of unsteadiness while standing and are often unaware of the tremor per se. Even when symptomatic, this tremor is difficult to see unless there is subharmonic 7- to 9-Hz oscillation. Palpation of the affected muscles may be helpful,105,108 but this tremor is best detected with surface EMG electrodes. The rhythmic 13- to 18-Hz motor unit activity is very intense and is uniquely coherent (time-locked) in muscles throughout the body.108 No other form of tremor is strongly coherent among muscles of the upper and lower body and between the left and right sides of the body.108 Essential tremor, Parkinson disease, myoclonus (cortical tremor), and other conditions may cause lower extremity tremor and postural unsteadiness, but the electrophysiologic properties of orthostatic tremor are not found unless the patient has true orthostatic tremor. The electrophysiologic abnormalities of orthostatic tremor are pathognomonic, and the distinction between orthostatic tremor and other forms of lower extremity tremor (‘‘pseudo-orthostatic tremor’’) is important because the success of treatment and choice of treatment vary significantly among these conditions.109 The unusually high frequency of orthostatic tremor (13–18 Hz) and the marked coherence among ipsilateral and contralateral muscles are not seen in essential tremor, Parkinson disease, and other tremor disorders. Orthostatic tremor is a distinct entity, not a variant of essential tremor or Parkinson disease.67,110 Gerschlager and colleagues111 suggested that comorbid tremorogenic conditions like Parkinson disease and essential tremor may increase or otherwise modify the clinical expression of orthostatic tremor, which they called ‘‘orthostatic tremor plus.’’ Orthostatic tremor does not cause other neurologic signs, such as bradykinesia, rigidity, and extremity ataxia, and the presence of such signs should alert the clinician to a comorbid condition. Orthostatic tremor patients walk normally and seldom fall. They feel very unsteady when standing with eyes closed, even though there is little change in postural sway.112,113 There is increasing evidence that the strong high-frequency oscillation of orthostatic tremor entrains proprioceptive feedback to a degree that precludes or reduces normal feedback from postural sway.112 Hence, patients feel unsteady, particularly when they stand with eyes closed.113 Similar mechanisms may be at play when other tremor disorders produce postural unsteadiness (see Essential tremor). The pathophysiology of orthostatic tremor has been studied extensively, but our understanding of this tremor is still incomplete. Orthostatic tremor must emerge from a central source of oscillation because the 13- to 18-Hz frequency of orthostatic tremor is too high to originate in lower extremity reflex loops, and a central source of oscillation is needed to produce the dramatic rhythmicity and synchrony of this tremor in muscles of the limbs, torso, and cranium. Involvement of cranial muscles suggests that the oscillator is above the spinal cord.105 Like many other tremors, orthostatic tremor is associated with increased cerebellar blood flow, as measured with H215O positron emission tomography (PET).114 Oscillation in the posterior fossa, with involvement of the motor cortex, is supported by transcranial magnetic and electrical stimulation studies.115,116 Guridi and coworkers recently treated a patient with ventralis intermedius DBS and produced complete suppression of the tremor.117 Rhythmic cortical EEG activity was
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phase-locked with the tremor, and fluorodeoxyglucose PET revealed bilateral motor cortex and cerebellar vermis hypermetabolism. These data clearly demonstrate involvement of the thalamocortical loop, as well as cerebellar pathways, in the pathogenesis of orthostatic tremor. Orthostatic tremor is relatively rare, and most therapeutic trials have involved small numbers of patients without placebo controls. In general, the response to pharmacotherapy has been inconsistent and frequently inadequate.111,118 Clonazepam, primidone, gabapentin, and dopaminergic111,118 drugs are most frequently reported as beneficial. The efficacy of gabapentin was demonstrated in a double-blind placebocontrolled cross-over trial with 6 patients.119 Katzenschlager and colleagues120 found reduced striatal dopamine transporter binding in 11 patients using 123I-labeled N-(3fluoropropyl)-2b-carbomethoxy-3b-(4-iodophenyl)nortropane single photon emission computed tomography (123I-FP-CIT-SPECT) imaging, but these patients did not benefit significantly from levodopa. In contrast to essential tremor, orthostatic tremor usually does not respond to ethanol.111,118 CORTICAL TREMOR
An irregular 7- to 14-Hz action tremor, resembling essential tremor, occurs in patients with cortical myoclonus and is called cortical tremor.121–123 Many investigators prefer the term rhythmic cortical myoclonus.124 Cortical tremor can be acquired or hereditary and is present in patients with asterixis.125 The enhanced C-reflex and giant sensory evoked potentials in many patients are consistent with the presence of enhanced cortical irritability and transcortical reflexes. An EEG transient preceding the EMG bursts of cortical tremor has been demonstrated with EEG back-averaging,123,126,127 and the tremor is coherent with magnetoencephalographic recording from motor cortex.125 Thus, the 7- to 14-Hz oscillation of cortical tremor probably emerges from abnormal cortical or thalamocortical oscillation. Cortical tremor generally responds to the same drugs used for cortical myoclonus, such as clonazepam and levetiracetam.128 DRUG-INDUCED TREMOR
Many drugs produce parkinsonian rest tremor (neuroleptics), postural tremor (betaadrenergic agonists, valproic acid, thyroxin, tricyclic antidepressants, and methylxanthines), kinetic tremor (lithium), and combinations thereof (lithium, amiodarone, and valproic acid).129 Little is known about the mechanisms of these tremors. It has long been suspected but never proven that people with subclinical essential tremor and subclinical Parkinson disease are more susceptible to tremorogenic drugs.130 Treatment consists of stopping or reducing the offending agent when possible. Drug-induced action tremors often respond to beta blockers such as propranolol. Neuroleptic-induced rest tremor usually responds to an anticholinergic medication or amantadine, and switching patients from a typical neuroleptic to an atypical neuroleptic is usually beneficial.129 PSYCHOGENIC TREMOR
There are 2 basic types of psychogenic tremor: coherent type and co-contraction type, which are equally common. Electrophysiology is useful in the diagnosis of both types, particularly the coherent type.131 The coherent type is a conscious or subconscious rhythmic movement of the affected joint. The tremor frequency is usually 6 Hz or less because voluntary rhythmic
Tremor
movement at higher frequencies is very difficult and exhausting. People with the coherent form of psychogenic tremor cannot rhythmically move the same or contralateral extremity at a different frequency, except at subharmonics of the psychogenic tremor frequency. The performance of rhythmic movement at various frequencies either suppresses psychogenic tremor or causes its frequency to shift to that of the voluntary movement. Such tremor interruptions and frequency shifts are easily captured with polyelectromyography and accelerometry.132,133 The co-contraction type of psychogenic tremor is produced by a conscious or subconscious coactivation of the muscles of the affected body part. This coactivation produces an enhanced physiologic tremor or physiologic clonus.134 Tremor occurs only when there is abnormally increased joint stiffness, produced by coactivation of the muscles. This dependence of tremor on coactivation is detected during passive manipulation of the wrist. The amplitude of coactivation tremor is proportional to the degree of coactivation (‘‘coactivation sign’’), and the tremor stops during interruptions in coactivation, as when patients are distracted. To treat psychogenic tremor, one must identify and treat the underlying psychiatric disturbance(s). Unfortunately, the long-term prognosis is frequently poor. Early diagnosis and therapeutic intervention improve the odds of significant improvement or remission.133,135 SUMMARY
No tremor is understood completely, and pharmacotherapy for all tremor disorders is inadequate. Fortunately, deep brain stimulation (DBS) is effective for the most common and disabling tremor disorders. Our understanding of pathologic tremors has increased at an accelerating pace during the past 30 years, and this will hopefully lead to improved pharmacotherapy in the near future. ACKNOWLEDGMENTS
Supported by the Spastic Paralysis Research Foundation of Kiwanis International, Illinois-Eastern Iowa District. REFERENCES
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120. Katzenschlager R, Costa D, Gerschlager W, et al. [123I]-FP-CIT-SPECT demonstrates dopaminergic deficit in orthostatic tremor. Ann Neurol 2003;53:489–96. 121. Ikeda A, Kakigi R, Funai N, et al. Cortical tremor: a variant of cortical reflex myoclonus. Neurology 1990;40:1561–5. 122. Oguni E, Hayashi A, Ishii A, et al. A case of cortical tremor as a variant of cortical reflex myoclonus. Eur Neurol 1995;35:63–4. 123. Toro C, Pascual-Leone A, Deuschl G, et al. Cortical tremor. A common manifestation of cortical myoclonus. Neurology 1993;43:2346–53. 124. Young RR. What is a tremor? Neurology 2002;58:165–6. 125. Timmermann L, Gross J, Kircheis G, et al. Cortical origin of mini-asterixis in hepatic encephalopathy. Neurology 2002;58:295–8. 126. Okuma Y, Shimo Y, Shimura H, et al. Familial cortical tremor with epilepsy: an under-recognized familial tremor. Clin Neurol Neurosurg 1998;100:75–8. 127. Terada K, Ikeda A, Mima T, et al. Familial cortical myoclonic tremor as a unique form of cortical reflex myoclonus. Mov Disord 1997;12:370–7. 128. Bourdain F, Apartis E, Trocello JM, et al. Clinical analysis in familial cortical myoclonic tremor allows differential diagnosis with essential tremor. Mov Disord 2006;21:599–608. 129. Morgan JC, Sethi KD. Drug-induced tremors. Lancet Neurol 2005;4:866–76. 130. Burn DJ, Brooks DJ. Nigral dysfunction in drug-induced parkinsonism: an 18Fdopa PET study. Neurology 1993;43:552–6. 131. Raethjen J, Kopper F, Govindan RB, et al. Two different pathogenetic mechanisms in psychogenic tremor. Neurology 2004;63:812–5. 132. McAuley J, Rothwell J. Identification of psychogenic, dystonic, and other organic tremors by a coherence entrainment test. Mov Disord 2004;19:253–67. 133. McKeon A, Ahlskog JE, Bower JH, et al. Psychogenic tremor: long term prognosis in patients with electrophysiologically-confirmed disease. Mov Disord 2009;24:72–6. 134. Deuschl G, Ko¨ster B, Lu¨cking CH, et al. Diagnostic and pathophysiological aspects of psychogenic tremors. Mov Disord 1998;13:294–302. 135. Jankovic J, Vuong KD, Thomas M. Psychogenic tremor: long-term outcome. CNS Spectr 2006;11:501–8.
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Genetic s a nd Treatment of Dystonia Cordelia S. Schwarz, MD, Susan B. Bressman, MD* KEYWORDS Dystonia DYT1 Genetics Basal ganglia Deep brain stimulation Botulinum toxin
Advances in molecular biology have revealed mutations in increasing numbers of genes that cause several forms of primary and secondary dystonia. Studies of the biologic function of these genes using cellular and animal models have led to important insights into the pathophysiology of dystonia. These results, in turn, allow for a more accurate counseling of patients regarding prognosis and progression of the disease. A better understanding of the physiologic function of the mutated genes ultimately holds promise for the identification of novel targets for pharmacologic intervention. CLASSIFICATION OF DYSTONIA
Dystonia is a hyperkinetic movement disorder that is characterized by involuntary, sustained, repetitive postures, and movements that are directional in nature. Physiologically, these movements are a result of co-contraction of agonist and antagonist muscles.1 Dystonia is a clinically and etiologically heterogeneous condition classified according to age of onset (early vs late onset), distribution (focal, segmental, or generalized), and etiology (primary or secondary) (Box 1), (Box 2). The clinical spectrum of dystonia is broad, ranging from generalized disabling contractions, which are much more common in those with childhood-onset, to localized or focal contractions often seen in those with adult-onset, most commonly affecting the arm (eg, writer’s cramp), cervical muscles (eg, torticollis), and cranial muscles (eg, spasmodic dystonia, blepharospasm). Primary dystonia refers to a form of dystonia that shows no additional neurologic features except for tremor and no evidence for a neurodegenerative process or an acquired cause. Onset can be early (before age 22) or late. During the last 20 years, 5 genetic loci have been mapped in families with primary dystonia; further, the genes for 2, DYT1 and DYT6, have been identified, of which, DYT6 is very recent. DYT1 and DYT6 cause primary dystonia that usually onsets early. The etiology of most adult-onset primary dystonia remains unknown. It is likely that many forms Department of Neurology, Beth Israel Medical Center, Phillips Ambulatory Care Center, 10 Union Square East, Suite 5D, New York, NY 10003, USA * Corresponding author. E-mail address:
[email protected] (S.B. Bressman). Neurol Clin 27 (2009) 697–718 doi:10.1016/j.ncl.2009.04.010 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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Box 1 Causes of primary (torsion) dystonia A. Child or adolescent onset, usually limb-onset and spreads to other regions DYT1 (TORIA, coding for torsinA), recurring heterozygous GAG deletion Other genes (eg, DYT2) not yet localized B. Mixed phenotype (families with primarily adolescent– and early adult–onset in arm, neck, or cranial muscles and some spread to other regions) DYT6 (THAP1), different heterozygous mutations DYT13 on chromosome 1p (gene not identified) in an Italian family with cervical/cranial involvement C. Adult cervical, cranial, or brachial onset, usually focal or segmental DYT7 on chromosome 18 (gene not identified) in a German family with torticollis Other genes/causes not yet localized Data from Bressman SB. Genetics of dystonia. 2003: AAN syllabus.
Box 2 Causes of secondary dystonia A. Associated with hereditary neurologic syndromes 1. Dystonia-plus Dopa-responsive dystonia (DRD/DYT5) GTP cyclohydrolase I (GCH1), different heterozygous mutations Other biopterin-deficient states Tyrosine hydroxylase mutations (most are autosomal recessive) Myoclonus-dystonia Epsilon-sarcoglycan (DYT11), different heterozygous mutations DYT15 on chromosome 18p (gene not identified) in one family Rapid-onset dystonia-parkinsonism ATP1A3 (DYT12) Dystonia-parkinsonism protein kinase, interferon-inducible double stranded RNA dependent activator (PRKRA, DYT16), one autosomal recessive mutation 2. Other inherited disorders associated with degenerative brain changes Autosomal dominant Huntington disease Machado-Joseph disease/SCA3 disease Other SCA subtypes (eg, SCA2, 6, 17) Familial basal ganglia calcifications (Fahr) Dentatorubral-pallidoluysian atrophy Neuroferritinopathy Glucose transporter GLUT1 deficiency
Genetics and Treatment of Dystonia
Autosomal recessive Juvenile parkinsonism (Parkin) Wilson disease Glutaric acidemia NBIA/PKAN/Hallervorden–Spatz disease Lysosomal diseases (GM1, GM2, Niemann-Pick type C [NPC1], metachromatic leukodystrophy, ceroid-lipofuscinosis) Homocystinuria Propionic acidemia Methylmalonic aciduria Ataxia-telangiectasia Ataxia with vitamin E deficiency Recessive ataxia with ocular apraxia (AOA1, AOA2) Neuroacanthocytosis Neuronal intranuclear inclusion disease (NIID), Hemachromatosis X-linked recessive Lubag (X-linked dystonia-parkinsonism, DYT3) Lesch-Nyhan syndrome Deafness/dystonia Pelizaeus-Merzbacher disease Mitochondrial Myoclonic epilepsy associated with ragged red fibers/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke Leber disease B. Due to acquired/exogenous causes Perinatal cerebral injury, encephalitis, infectious and postinfectious, paraneoplastic, head trauma, pontine myelinolysis, primary Antiphospholipid syndrome, stroke, tumor, multiple sclerosis, cervical cord injury or lesion, peripheral injury, complex regional pain syndrome, drugs (especially dopamine receptor blockers, acute and tardive), toxins C. Dystonia due to degenerative parkinsonian disorders of unclear cause Parkinson disease, progressive supranuclear palsy, multisystem atrophy, cortico-basalganglionic degeneration D. Dystonia as a feature of other dyskinetic disorders Tics, other paroxysmal disorders, for example, PKD (DYT 10/EKD1, EKD2); paroxysmal nonkinesigenic dyskinesia (DYT8); CSE (DYT 9) There is no unified genetic classification that systematically catalogs primary and secondary dystonia; there is, however, a genetic classification based on HUGO/ Genome Database nomenclature designating DYT/dystonia loci. It includes all the loci for PTD, a subset of secondary loci, and also loci for the paroxysmal dyskine sias (see Table 1). Data from Bressman SB. Genetics of dystonia. 2003: AAN syllabus.
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of primary dystonia that appear to be sporadic are genetic in nature, which might be concealed by reduced penetrance and variable expression. Early-onset dystonia often first affects a limb, then usually spreads and generalizes, although in some individuals and families with early onset, cervical and cranial muscles may be initially affected. Late-onset dystonia usually starts in the neck, cranial, or brachial muscles and generally remains focal or segmental. Secondary (nonprimary) dystonia includes inherited forms, such as the ‘‘dystoniaplus syndromes’’ (dopa-responsive dystonia, myoclonus-dystonia [M-D], and rapidonset dystonia-parkinsonism), toxic and acquired causes (stroke, drug, perinatal anoxic injury), and dystonia secondary to degenerative parkinsonian disorders. The most commonly used molecular classification scheme for genetic forms of dystonia is derived from the Human Genome Organization (HUGO)/Genome Database nomenclature (http://genenames.org) (Table 1). The HUGO classification is numbered DYT1-18 and is based on the chronologic order of gene mapping or clinical description. One of the loci, DYT14, was later found to be identical to DYT5. This classification includes different etiologic subtypes, namely primary, secondary, and dystonia-plus syndromes. It also includes the loci and genes for the paroxysmal dystonias (DYT8, 9, 10, and 18), which are not discussed further because they are episodic dyskinetic syndromes that can show dystonic features. Two primary dystonia genes have been identified: DYT1 (TorA)2 and DYT6. Further, 4 DYT genes for nonprimary forms are also known: DYT3 (X-linked dystonia-parkinsonism),3 DYT5, which is now known as GCH1,4 DYT11 (SGCE),5 and DYT12 (ATP1A3).6 For most other HUGO subtypes, genetic loci have been determined, except for DYT2, which is an autosomal recessive dystonia in the Spanish Roma population,7 and whispering dysphonia, DYT4.8 These syndromes so far only have been described clinically. PRIMARY TORSION DYSTONIA EARLY-ONSET PRIMARY DYSTONIA AND DYT1
The most commonly identified cause for early limb-onset primary dystonia is an autosomal dominant mutation in the DYT1 gene, which codes for the protein torsinA. It is responsible for a large proportion of early-onset primary torsion dystonia (PTD) (also named dystonia musculorum deformans or Oppenheim disease) across many different populations and shows a reduced penetrance of 30% to 40% and variable expression. The mutation is about 5 times more frequent in Ashkenazi Jews compared with non-Ashkenazim, which has been attributed to a founder mutation in the DYT1 gene in the Ashkenazi population. The DYT1 gene (also known as TOR1A) was identified in 19972 and is located on chromosome 9q34. It encodes a 332-amino acid (37 kDa) ATB-binding protein called torsinA. There is only 1 known pathogenic DYT1 mutation, a GAG deletion in exon 5. The deletion results in the loss of a glutamic acid residue in the C-terminal region of the protein.2 Other coding variations in DYT1 have been found, but none are clearly pathogenic. These include an18-bp deletion (966_983del) in a single atypical family that also harbored a mutation in epsilon sarcoglycan (SGCE),9 a 4–base pair (bp) deletion (934_937delAGAG) that causes a frameshift and truncation starting at residue 312 identified in a single control blood donor not examined neurologically10, and G>A transition at position 863 (G863A) that results in the substitution of an arginine by a glutamine in a single patient with severe fixed dystonia, facial palsy, and long tract signs, with first symptoms in infancy.11 There is also a fourth variation, a single-nucleotide polymorphism (SNP) in the coding sequence for residue 216; this change has been identified to modify clinical expression in DYT1 GAG mutation carriers (see later section).
Table 1 Molecular classification of dystonia Designation
Dystonia Type
Inheritance
Gene Locus
Gene/Product
OMIM Number
DYT1
Early-onset generalized PTD
Autosomal dominant
9q
GAG deletion in DYT1 coding for torsinA
128,100
DYT2
Autosomal recessive TD
Autosomal recessive
Unknown
Unknown
224,500
DYT3
X-linked dystonia parkinsonism, ‘‘lubag’’
X-chromo-somal recessive
Xq
TAF1/DYT3
314,250
DYT4
‘‘Non-DYT1’’ TD, whispering dysphonia
Autosomal dominant
Unknown
Unknown
128,101
DYT5/DYT14
Dopa-responsive dystonia, Segawa syndrome
Autosomal dominant Autosomal recessive
14q 11p
GTP-cyclohydrolase Tyrosine hydroxylase
128,230
Adolescent-onset TD of mixed type
Autosomal dominant
8p
Unknown
602,629
Adult-onset focal TD
Autosomal dominant
18p
Unknown
602,124
DYT8
Paroxysmal nonkinesigenic dyskinesia
Autosomal dominant
2q
Myofibrillo-genesis regulator 1
118,800
DYT9
Paroxysmal choreoathetosis with episodic ataxia and spasticity
Autosomal dominant
1p
Unknown
601,042
DYT10
Paroxysmal kinesigenic choreoathetosis
Autosomal dominant
16p-q
Unknown
128,200
DYT11
Myoclonus-dystonia
Autosomal dominant
7q
Epsilon-sarcoglycan
159,900
DYT12
Rapid-onset dystoniaparkinsonism
Autosomal dominant
19q
Na/K ATPase alpha 3
128,235
DYT13
Multifocal/segmental dystonia
Autosomal dominant
1p
Unknown
607,671
DYT15
Myoclonus-dystonia
Autosomal dominant
18p
Unknown
607,488
DYT16
Dystonia-parkinsonism
Autosomal Recessive
2q31
PRKRA
612,067
DYT17
Focal dystonia
Autosomal recessive
20p11.22-q13.12
Unknown
612,406
Abbreviation: OMIM, Online Mendelian Inheritance in Man. Data from Bressman SB. Genetics of dystonia. 2003: AAN syllabus.
Genetics and Treatment of Dystonia
DYT6 DYT7
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Structure and Function of TorsinA
TorsinA is a member of the AAA1 superfamily of ATPases associated with a variety of cellular activities. This superfamily of chaperone proteins performs critical functions related to protein degradation, membrane trafficking, vesicle fusion and organelle movement, cytoskeletal dynamics, and correct folding of proteins.12,13 TorsinA is almost ubiquitously expressed. Within the brain, it is enriched in cerebellar Purkinje cells, thalamus, globus pallidus, hippocampal formation, and cerebral cortex. Its expression in the brain is restricted to neurons, where it is associated with the endoplasmic reticulum (ER). In cellular models expressing the pathologic mutation, torsinA is redistributed from the ER lumen to the nuclear envelope (NE).14 These cells also display abnormal morphology and thickening of the NE, including altered connections between the inner and outer membranes, and generation of whorled membrane inclusions that appear to ‘‘spin off’’ the ER and NE. These inclusions are associated with the vesicular monoamine transporter VMAT2, a finding that might functionally relate torsinA to the dopaminergic system.15 In addition, torsinA has been found to regulate cellular trafficking of the dopamine transporter and other membrane bound proteins. It has also been shown that mutant torsinA interferes with cytoskeletal events that may affect the development of neuronal pathways in the brain and that unlike wild-type torsinA, which is degraded through the macroautophagy-lysosome pathway, mutant torsinA is degraded prematurely by the proteasome and macroautophagy-lysosome pathways.16 Neuropathologic studies on brains from patients with dystonia have reported no consistent pathologic change with the exception of 1 study of 4 DYT1 brains that described ubiquitin-positive perinuclear inclusion bodies in the midbrain reticular formation and the periaqueductal gray.17 Several transgenic mouse models of DYT1 dystonia have been created. In 1 model, human mutant torsinA is overexpressed using the neuron-specific enolase promoter, which leads to hyperactivity, circling, and abnormal movement in about 40% of the mutant mice. These mice also demonstrate abnormal levels of dopamine metabolites and aggregates in the brainstem, similar to those reported in DYT1 human brains.18 Another transgenic model expressing human mutant torsinA under the control of the cytomegalovirus promoter does not show an overt movement disorder. However, these animals exhibit impaired motor sequence learning on the rotorod.19 In addition, the endogenous mouse locus has been modified in 3 different types of transgenic mice. Knock-in (KI) mice bearing the 3-bp deletion in the heterozygous state, analogous to the human DYT1 dystonia, manifest hyperactivity in the open field, difficulty in beam walking, and possess abnormal levels of dopamine metabolites, but no overt dystonic posturing. These mice also have brainstem neuronal aggregates consistent with human pathologic data. In contrast, mice that are either homozygous KI or knock-out (KO) for the deletion die at birth with apparently normal morphology, but with postmigratory neurons showing abnormalities of the nuclear membranes.20 The fact that both the homozygous KO and KI animals display the same lethal phenotype suggests that DYT1 dystonia results from a loss of function of the torsinA protein. The knock-down mouse model, in which a reduced level of torsinA protein is expressed, displays a phenotype similar to the heterozygous KI mice showing deficits in motor control and dopamine metabolite levels.21 This mouse also supports a loss-of-function model because no deleted torsinA is necessary to produce the phenotype; this loss of function could be because of a dominant negative effect whereby the mutant protein interferes with the wild type protein.
Genetics and Treatment of Dystonia
Overexpression of mutant torsinA in cells leads to the formation of membrane inclusions that are believed to derive from the ER/NE. A nonsynonymous coding variant in the DYT1 gene has been identified, which is located in exon 4 at residue 216 and replaces an aspartic acid (D) at position 216 with a histidine (H) in about 12% of normal alleles.2 When the H allele is overexpressed in cells, similar membrane inclusions as with mutant-torsinA overexpression result. However, when the H allele is co-overexpressed with the mutant torsinA, fewer inclusions are formed. This suggests that the 2 alleles jointly have a canceling effect and raises the possibility that this variant may play a role in the reduced penetrance associated with DYT1 dystonia or in causing other forms of dystonia.22 A recent study assessed the frequency of the 216H allele in 119 GAG deletion carriers with signs of dystonia (manifesting carriers), 113 nonmanifesting carriers without clinical symptoms, and 197 controls.23 There was a significantly increased frequency of the 216H allele in nonmanifesting deletion carriers and a decreased frequency in manifesting carriers compared with the controls. Analysis of haplotypes demonstrated a highly protective effect of the H allele in trans with the GAG deletion; there was also suggestive evidence that the D216 allele in cis is required for disease to be penetrant. However, because the H allele only occurs in less than 20% of the population, it has a relatively small role in explaining reduced penetrance. In addition, 2 studies examined the role of the D216H SNP in focal dystonia, but no associations were identified.24,25 DYT1 Phenotype and Endophenotype
Clinical expression of DYT1 dystonia is very variable, even within families; 70% of gene carriers have no definite signs of dystonia, and among the remaining 30%, dystonia ranges from mild focal to severe generalized. However, there are common DYT1 clinical characteristics that are found across ethnic groups.26 Most people with dystonia due to the DYT1 mutation experience early onset (generally starting after age 3 and before 26), with dystonia first affecting an arm or leg. In about 65% of patients, the disease progresses during a period of 5 to 10 years to a generalized or multifocal distribution, the remainder has segmental (10%) or focal (25%) involvement. One or more limbs ultimately are almost always affected, and over 95% have an affected arm. The dystonia can be jerky or tremulous. The trunk and neck may also be affected in about 25% to 35%, and they may be the regions producing the greatest disability. The cranial muscles are involved in less than 15% to 20% of the cases. In a study of early-onset primary dystonia, cranial involvement was the best clinical predictor of non-DYT1 status.27 Rarely, affected family members were identified with late-onset (up to age 64 years) dystonia. These individuals are generally identified in the course of family studies and often do not seek medical attention. Although the arm is the body region most commonly affected in those with focal disease, isolated involvement of neck or cranial muscles has been reported to occur with low frequency.26,28 In a study of patients with early-onset cervical dystonia, none carried the DYT1 GAG deletion,29 and thus DYT1 rarely causes adult focal dystonia, which constitutes the great majority of primary dystonia.30 The DYT1 GAG deletion accounts for about 80% of early-onset cases in the Ashkenazi population, because of a founder effect and genetic drift, compared with 16% to 53% in early-onset non-Jewish populations. The frequency of the DYT1 mutation among Ashkenazi Jews was estimated in a study to be 1/2000 to 1/6000 (giving a carrier frequency of 1/1000–1/3000);31 this translates into a disease frequency of 1/3,000 to 1/ 9,000 (based on a penetrance of 30%). A study from southeastern France, using direct genotyping of 12,000 newborn dried-blood samples, identified only 1 disease allele.32
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This carrier incidence is consistent with the w5-fold increased frequency of early-onset dystonia in Ashkenazim compared with non-Jews that was found before gene identification.33 These studies also imply that a significant proportion of early-onset cases, especially among non-Ashkenazim, are not because of DYT1. The identification of the DYT1 mutation enables us to explore its range of clinical expression and DYT1 endophenotypes or biomarkers using imaging, electrophysiological, and other techniques. To this end, it is of particular importance to study mutation-carrying family members without overt dystonia (‘‘nonmanifesting carriers’’), who constitute 70% of mutation carriers, and compare them to their non-carrier family members and those manifesting dystonia. Earlier studies had suggested that DYT1 dystonia is comorbid with affective disorder, and this association was systematically studied in DYT1 families.34 This study found that early-onset recurrent major depression is associated with the DYT1 GAG mutation and that this association is independent of motor manifestations of dystonia. Both manifesting and nonmanifesting gene carriers are more likely to have major recurrent depression compared with noncarrier relatives, and their depression begins early in life. These findings suggest that earlyonset recurrent depression is a clinical expression of the DYT1 gene mutation.34 However, there were no differences in frequency of obsessive-compulsive disorder, which is associated with other movement disorders including tics and M-D.35 Other subtle clinical abnormalities noted in nonmanifesting carriers are deficiencies in sequence learning36 and ‘‘probable’’ dystonia on clinical examination. Even though probable dystonia is increased in carriers compared with noncarriers, the finding is not 100% specific. It is therefore recommended that only those with definite signs of dystonia be considered affected in linkage and other genetic studies.37 DYT1 endophenotypes have been investigated using various imaging and neurophysiologic approaches. Eidelberg and colleagues demonstrated a characteristic pattern of glucose use using 18F-fluorodeoxyglucose positron emission tomography and network analysis. The study found covarying metabolic increases in the basal ganglia, cerebellum, and supplementary motor cortex in both ‘‘manifesting’’ and ‘‘nonmanifesting’’ gene carriers.38 Other imaging studies of DYT1 gene carriers, including nonmanifesting carriers, have found decreased striatal D2 receptor binding,39 and microstructural changes involving the subgyral white matter of the sensorimotor cortex.40 In addition, electrophysiologic analyses have found reduced intracortical inhibition and a shortened cortical silent period41 as well as higher tactile and visuotactile temporal discrimination thresholds and temporal order judgments in DYT1 mutation carriers.42 These studies strongly support the presence of broad clinical gene expression, abnormal brain processing, and associated structural brain changes in gene carriers regardless of the presence of overt motor signs of dystonia, expanding the notion of penetrance and phenotype. EARLY-ONSET BUT NOT DYT1
A large group of early-onset PTD, especially among non-Jewish populations, is not because of the DYT1 GAG deletion. Two loci, DYT643 and DYT13,44 have been mapped in families with autosomal dominant transmission and reduced transmission of PTD; DYT6 was mapped in families sharing Amish Mennonite ancestry, and DYT7 in an Italian family. The average age of onset of dystonia associated with the two loci is in adolescence. Overall clinical features in these families differ from DYT1 (although features in any single family member may overlap with DYT1). The family phenotypes for DYT6 and 13 are marked by prominent involvement of cranial and cervical muscles with variable spread. Compared with DYT1, there is less disability from lower extremity
Genetics and Treatment of Dystonia
involvement. An autosomal recessive form of early-onset PTD, DYT17, was mapped to chromosome 20 in a consanguineous Lebanese family. Onset in 3 siblings was in adolescence (14–19 y), cervical muscles were affected first, and similar to DYT6 (see next section), there was progression with severe dysphonia and dysarthria.45 DYT6
The gene for DYT6, THAP1, has been identified.46 In the Amish Mennonite families in which DYT6 was first mapped, a heterozygous 5-bp (GGGTT) insertion followed by a 3-bp deletion (AAC) (134_135insGGGTT; 137_139delAAC, href5‘‘genbank:NM_018,105’’>NM_018,105.2) in exon 2 of the gene was detected. The mutation causes a frameshift at amino acid position number 44 of the protein, resulting in a premature stop codon at position 73. THAP1 is a member of a family of cellular factors sharing a highly conserved THAP domain, which is an atypical zinc finger. Associated with its DNA-binding domain, THAP1 regulates endothelial cell proliferation. In addition to the THAP domain at the N terminus, THAP1 possesses a nuclear localization signal at its C terminus. A proposed disease mechanism is that DYT6 mutations disrupt DNA binding and produce transcriptional dysregulation. Although this gene was initially thought to have a limited role, restricted to related Amish Mennonite families, different THAP1 mutations in families with diverse ancestries have been identified.47 When early-onset non-DYT1 families were screened, mutations in THAP1 were identified in 9 out of 36; most were of German, Irish, or Italian ancestry. One family had the Amish Mennonite founder mutation, whereas the other 8 families each had novel, potentially truncating, or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype, but were different from families without THAP1 mutations. Compared with noncarriers, mutation carriers were younger at onset, and their dystonia was more likely to begin in brachial muscles rather than cervical muscles, become generalized, and include cranial muscles with prominent speech involvement. Determining the ultimate importance of this gene in other dystonia populations, including adultonset focal populations, and determining its pathogenic mechanisms are important next research steps. LATE-ONSET FOCAL AND SEGMENTAL PTD
In contrast to early-onset dystonia, which usually starts in a limb, late- or adult-onset PTD usually starts in cervical or cranial muscles and rarely generalizes. Late-onset PTD is about 9 to 10 times more prevalent than early-onset. Because there is an increased incidence of PTD in first-degree relatives of PTD patients compared with control populations, autosomal dominant inheritance with reduced penetrance (about 12%–15% compared with 30% for early-onset) has been proposed.42,48 Alternatively, there may be a subset of families with late-onset PTD with high penetrance, with the remainder of the patients being sporadic. There are descriptions of large families with more highly penetrant autosomal dominant disease.49,50 One such family with adultonset torticollis was studied resulting in the mapping of DYT7.51 Other loci for adultonset focal PTD have been proposed in clinically similar families that are negative for DYT7.52 The search for genes is complicated by the fact that most of the adult-onset dystonia patients do not have many affected relatives. Therefore, association studies using cases and controls have been used to find genetic risk factors. A polymorphism in the D5 dopamine receptor gene was associated with adult-onset torticollis and
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blepharospasm in 1 study; however, other studies dispute the association.53,54 The DYT1 haplotype has been studied in several different primary dystonia populations; an association was found in the Icelandic and Italian populations,54,55 but no such association was found in Germany and the United States.56 For most PTDs, genetic causation seems to be complex and awaits clarification. SECONDARY DYSTONIA AND DYSTONIA-PLUS
Most secondary dystonia is thought to arise from acquired, psychogenic, or degenerative processes of complex or undetermined etiology. However, a significant minority is associated with inherited diseases, many with identified genes (Box 2). This group includes 3 disorders, dopa-responsive dystonia, M-D, and rapid-onset dystoniaparkinsonism, that are placed in a separate category termed ‘‘dystonia-plus.’’ These ‘‘dystonia-plus’’ conditions are similar to primary dystonia because they are not associated with brain degeneration but are considered secondary because of the presence of clinical features other than dystonia, such as parkinsonism and myoclonus. Other genetic diseases associated with dystonia that do show neuronal degeneration and are usually associated with neurologic signs other than dystonia include: ataxia-telangiectasia, Wilson disease, Huntington disease, the spinocerebellar ataxias, ataxia with vitamin E deficiency, Parkin-associated parkinsonism, the lysosomal storage disorders (GM1 and GM2 gangliosidoses, Niemann-Pick type C, metachromatic leukodystrophy, neuronal ceroid lipofuscinosis), Lesch-Nyhan syndrome, homocystinuria, glutaric acidemia, methylmalonic aciduria, chorea-acanthocytosis, neurodegeneration with brain iron accumulation (formerly Hallervorden-Spatz), X-linked dystoniaparkinsonism, Fahr disease (calcification of the basal ganglia), Rett syndrome, Pelizaeus-Merzbacher disease, and neuroferritinopathy. DOPA-RESPONSIVE DYSTONIA (DYT5, SEGAWA DISEASE)
DRD is a childhood-onset dystonia that presents usually around the age of 5 to 6 years, with dystonia in the lower limbs leading to an abnormal stiff-legged gait, sometimes with plantar flexion and eversion. Dystonia may also affect the arms, the trunk, and, less commonly, the neck. It is often marked by diurnal variations, worsening as the day progresses and improving after sleep. Other clinical features include hyperreflexia and parkinsonism with bradykinesia, hypomimia, and postural instability.57 The clinical spectrum of this disorder has broadened and includes adult-onset parkinsonism, frequent falls, psychiatric features of major depression, obsessive-compulsive disorder and sleep disorders,58 adult-onset oromandibular dystonia,59 developmental delay and spasticity mimicking cerebral palsy,60 scoliosis,61 and generalized hypotonia with proximal weakness.62 The hallmark feature of all clinical subtypes of DRD is a dramatic and sustained response to low-dose levodopa (50–200 mg/d), although rarely (especially in those with compound heterozygous mutations or adult-onset) the dose required may be substantial. Some DRD patients also may have an excellent response to anticholinergics (eg, trihexyphenidyl).63 Most cases of DRD are caused by several heterozygous mutations (including deletions not detectable by qualitative screening) in the GCH1 gene located on chromosome 14 (DYT5).4,64,65 New mutations appear to occur commonly, and reduced penetrance was observed in examined families. Segregation analysis suggests a higher penetrance in women compared with men, but the reason for this higher penetrance is unknown.66 GCH1 is the first and rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is an essential cofactor for tyrosine (and phenylalanine and tryptophan) hydroxylase and thus dopamine synthesis.67 It is evident that some
Genetics and Treatment of Dystonia
cases of DRD are because of compound heterozygous mutations in GCHI as well as homozygous, compound heterozygous, and heterozygous mutations in other enzymes involved in dopamine synthesis, including tyrosine hydroxylase,68 6-pyruvoyltetrahydropterin synthase (6-PTS),69 and sepiapterin reductase.70 These conditions can cause a more severe phenotype with associated hypotonia, severe bradykinesia, drooling, ptosis, miosis, oculogyria, and seizures, reflecting deficiencies of serotonin, norepinephrine, and dopamine. DRD needs to be distinguished from DYT1 and juvenile parkinsonism due to homozygous and compound heterozygous mutations in the parkin gene.71,72 Generally, the presence of early prominent parkinsonism and severe dyskinesias with L-dopa treatment indicate parkin mutations. MYOCLONUS-DYSTONIA (DYT11, DYT15)
From early descriptions of dystonia it was evident that in some patients dystonic movements or jerks may be rapid, about 100 ms, and resemble myoclonus. This may occur in DYT1 and other forms of primary dystonia73 and also as a distinct autosomal dominant disorder. An M-D locus on chromosome 7q21 (DYT11) was mapped in a North American family with 10 affected individuals who had clinical features typical of this disorder.74 This locus was then confirmed and narrowed in other M-D families,75 and in 2001, the gene was identified as Sarcoglycan-Epsilon (SGCE) based on the finding of different loss-of-function mutations in 6 families.76 Large deletions have been shown to account for some of the cases in which no mutations were found previously.77,78 In patients with heterozygous deletions of the entire SGCE gene, the deletion may also involve adjacent genes accounting for additional phenotypes, such as skeletal abnormalities due to a deletion of the neighboring COL1A2 gene. A case of M-D that combined clinical features of M-D and Silver-Russell syndrome (a disorder leading to growth restriction and a characteristic facies) was reported in 2008. The patient was found to have maternal uniparental disomy resulting in 2 silenced maternal SGCE genes, which mimics a deletion of the entire gene.79 The pattern of inheritance in familial M-D is autosomal dominant and shows a reduced penetrance that depends on the transmitting parent.80 Most affected individuals inherit the disorder through their father, a finding consistent with a maternal imprinting mechanism. Imprinting is an epigenetic phenomenon and results in the selective silencing of 1 of the 2 parental alleles. Further support for imprinting of the SGCE gene derives from RNA expression studies that have revealed expression of only the mutated allele in affected individuals and expression of the normal allele in unaffected mutation carriers.81 In addition, differentially methylated regions were identified in the promoter region of the SGCE gene as a characteristic feature of imprinted genes, and methylation of the maternal allele was demonstrated. Penetrance of the disorder does not follow the expected pattern in about 10% of the M-D patients, and loss of imprinting in 1 patient was shown to be associated with bi-allelic expression of the SGCE gene and partial loss of methylation at several CpG dinucleotides. The sarcoglycans are a family of genes that encode components of the dystrophinglycoprotein complex, and mutations in alpha, beta, gamma, and delta sarcoglycan produce recessive muscular limb-girdle dystrophy. SGCE, however, is expressed widely in the brain in neurons of the cerebral cortex, basal ganglia, hippocampus, cerebellum, and the olfactory bulb and is located at the plasma membrane. The precise function of SGCE and the disease mechanisms of the mutated protein are unknown. The proportion of M-D and clinically related phenotypes due to SGCE mutations is still under study. Mutations have been confirmed in many families, including the
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original large kindred showing linkage to the 7q region; but SGCE mutations do not account for all familial M-D and probably are not responsible for most sporadic M-D. There is at least 1 other gene locus for M-D, which was mapped on 18p (DYT15) in 1 family with M-D.82 In families with M-D, affected individuals have myoclonus as the primary sign and it may occur with or without dystonia, which is usually mild. Rarely dystonia is the only feature, often manifesting as writer’s cramp.83 Symptom onset is usually in the first or second decade; males and females are equally affected in most, but not all, families. The neck and arms are involved most commonly, followed by the trunk and bulbar muscles. Trunk contractions may cause falls; less commonly there is involvement of the legs except in the very young, where leg contractions may be a first feature. The myoclonus may occur as isolated jerks at rest and more complex oscillatory or pseudorhythmic bursts, especially as an overflow phenomenon. Neurophysiologic studies support a subcortical origin of the myoclonus.84 Symptoms tend to plateau in adulthood after a period of progression. Affected adults often report that the muscle jerks respond dramatically to alcohol. Obsessive-compulsive disorder and alcohol dependence are frequently observed in carriers of the gene, including family members not affected with motor signs of M-D.85 RAPID-ONSET DYSTONIA-PARKINSONISM (DYT12)
Rapid-onset dystonia-parkinsonism is a rare dystonia-plus syndrome with sudden onset of persistent dystonia and parkinsonism in childhood or early adulthood. Symptoms rapidly evolve over hours to days, often after a major stressor. The symptoms may, however, begin more insidiously and then have a period of rapid worsening. After the period of worsening, symptoms tend to stabilize although improvement may occur.6,86 The phenotype resembles dystonic-parkinsonian Wilson disease with prominent bulbar signs (including risus sardonicus), relatively sustained dystonic limb posturing, waxy effortful rapid successive movements, and postural instability. Inheritance is autosomal dominant and de novo mutations have been observed. The responsible gene is classified as DYT12 and maps to chromosome 19q13. It codes for Na1/K1-ATPase alpha3, a catalytic subunit of the sodium-potassium pump.87 LUBAG (X-LINKED DYSTONIA-PARKINSONISM, DYT3)
Lubag is a form of dystonia that is inherited as an X-linked recessive trait, and the disease gene is TAF1 (TATA binding protein–associated factor 1 gene) multiple transcript system. The disorder occurs in males from the island of Panay in the Philippines88 and can present with either dystonia or parkinsonism, but most patients eventually develop parkinsonism. Pure parkinsonism is considered to be a more benign phenotype.89 The phenotypic spectrum is broad and may also include tremor, myoclonus, chorea, and myorhythmia.90 There also have been reports of heterozygous females with mild dystonia or chorea.91,92 Neuropathologic studies show degeneration and gliosis of the putamen, striatum, and caudate,93 and within the neostriatum, the striosome is selectively involved with sparing of the matrix compartment.94 CLINICAL DIAGNOSIS, GENETIC TESTING, AND COUNSELING
Because of the large number of genetic causes for dystonia diagnosis can be daunting. Family history, if positive, may provide crucial information, but a negative family history is of little significance. DYT1 and DYT6 have reduced penetrance and variable expression, as do many other autosomal dominant causes of dystonia. Aside from
Genetics and Treatment of Dystonia
nonpenetrance (which is the clinical outcome for 70% DYT1 mutation carriers), other causes for a negative family history include mild undiagnosed disease, new mutations, and nonpaternity. For recessive forms of dystonia, family history is often negative, and other clues such as consanguinity need to be pursued in taking a family history. It is therefore advisable to assume a genetic etiology for most early-onset PTD, regardless of family history. Many early-onset patients have the DYT1 mutation, especially those with dystonia starting in childhood or adolescence in an arm or leg, which subsequently generalizes, or those of Ashkenazi Jewish descent. Because all DYT1 dystonia appears to be due to the GAG deletion, screening is relatively easy and is commercially available; genetic testing for the deletion has been recommended for all primary dystonia patients with onset by age 26, for those with an unclear age of onset, and for patients with writer’s cramp or arm involvement, because it may be difficult to accurately determine when writing problems first begin. The testing may also be considered for those with later-onset PTD who have relatives with early-onset dystonia.26 The DYT6 gene, THAP1, has only 3 exons, and screening, once available, should be fairly straightforward. Although the proportion of early-onset PTD because of DYT6 remains to be determined, initial study suggests that a significant proportion of early-onset non-DYT1 patients probably have mutations, especially if there is prominent speech involvement. In addition to DYT1, commercial testing is now available for many other genetic causes of dystonia, including the triplet repeat disorders, DRD, and pantothenate kinase 2. However, most of the identified genetic causes of secondary dystonia (unlike DYT1 and the triplet repeat disorders) are because of many different mutations within the disease gene (eg, DRD/GCH1, M-D/SGCE, Wilson/ATB7B, JPD/Parkin). Therefore, screening may be complex, requiring sequencing of exons and quantitative testing. For some, like Wilson disease, which has hundreds of mutations, direct mutation screening is not performed in the United States. Also, some genetic causes of dystonia have been mapped, but the genes remain to be identified (eg, DYT7, 13, 15, 17). This limits evaluation of these genetic causes to linkage analysis in suitably large families, which is only performed on a research basis. To obtain up-to-date information regarding genetic testing sites, see www.geneclinics.org. Before diagnostic testing is done, genetic counseling is recommended to provide a format to explain the implications of all possible test results. For instance, if a test is negative, a genetic etiology is not necessarily excluded, and this needs to be explained. For example, DYT1 only accounts for a proportion of all autosomal dominant PTD; similarly, mutations in GCH1 and SGCE do not explain all inherited cases of DRD and M-D, respectively. If the test is positive, a diagnosis is secured, but this diagnosis impacts on other at-risk family members. These members, even if asymptomatic, may wish carrier testing, and genetic counseling for all asymptomatic family members must be done before testing. The psychological and social implications of autosomal dominant disorders with markedly reduced penetrance and variable expression are complicated and require considerable time for patient and family education and counseling. TREATMENT OF DYSTONIA
For decades, treatment for most forms of dystonia was limited, relying on only mildly or moderately effective oral medications, which provide symptomatic amelioration of dystonic contractions. However, over the last 2 decades, the landscape of therapeutic options has changed with the introduction of treatments that can provide highly significant benefit, namely, botulinum toxin injections and deep brain stimulation (DBS). Before discussing these options, it is important to consider the diagnosis in the overall approach to treatment; that is, for a minority of secondary dystonias, there are specific
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etiologic-based treatments. Two forms of secondary dystonia with therapy directed at cause, Wilson, and DRD, are singled out for discussion because of the efficacy and import of timely treatment. Best therapy for neurologic Wilson disease, especially initial therapy, is debated. Penicillamine, the first effective therapy, has a high frequency of inducing worsening of neurologic signs when therapy is initiated. Therefore, other agents such as trientene (a chelating agent) and tetrathiomolybdate (which reduces gastrointestinal copper absorption) have been proposed as alternatives, although there are few randomized controlled studies. One double-blind study compared tetrathiomolybdate and zinc to trientine and zinc in 48 patients with neurologic Wilson disease and showed significantly less neurologic deterioration in the tetrathiomolybdate-treated group.95 The other secondary dystonia singled out for discussion is DRD. In the setting of a typical clinical picture (eg, a child with dystonia affecting the gait, diurnal fluctuations, and also mild long track signs and parkinsonism), a dramatic response to low-dose levodopa (usually less than 300 mg/d with 75 mg carbidopa, although rarely higher dosages are needed) is considered diagnostic for DRD (although confirmation of a GCH1 mutation secures the specific etiology). Treatment is initiated with a very low dosage, one-half of a 25/100 carbidopa/levodopa, and increased slowly because, occasionally, dyskinesias can develop if the dosage is raised quickly. Since wearingoff and other response fluctuations in response to levodopa are rare in DRD, there appears to be no advantage to using other dopaminergic agents in DRD; there is no information on the efficacy of other agents except, as stated above, anticholinergics maybe quite effective in some DRD patients.63 Botulinum Toxin
Available since the late 1980s, intramuscular injections of botulinum toxin are considered the first-line treatment for patients with focal dystonia. Formulations of 2 serotypes of toxin, botulinum toxin A and B, have been approved for clinical use in the United States. The primary mechanism of action is blocking the release of acetylcholine into the neuromuscular junction, which causes local temporary chemodenervation and muscle paralysis. Recently, evidence-based practice parameters were published recommending that botulinum neurotoxin treatments should be offered for cervical dystonia and may be considered for blepharospasm, focal upper extremity dystonia, and adductor laryngeal dystonia. Further considerations for use include the treatment of focal lower limb dystonia.96 A comparison study of the efficacy of botulinum A and B in toxin-naı¨ve patients with cervical dystonia showed no difference in treatment outcome and median duration of effect.97 Adverse effects, such as injection site pain and dysphagia, occurred with a similar frequency in the 2 groups, but a mildly dry mouth occurred more frequently in the botulinum B group. One complication of chronic treatment is antigenicity—the development of neutralizing antibodies and resistance to toxin therapy. This appears to be more common with botulin toxin B compared with toxin A.98,99 Screening for neutralizing antibodies using the mouse protection assay may be performed in nonresponders as may functional testing such as injecting the frontalis or corrugator muscle. Dopaminergic Drugs
A trial of levodopa to at least 300 mg/d combined with carbidopa should be performed in every patient with early-onset dystonia to exclude dopa-responsive dystonia, given the heterogeneity of the clinical presentation. Aside from DRD where a sustained dramatic benefit occurs, modest improvements with levodopa therapy have also
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been reported in some patients with other types of dystonia. Levodopa has been reported to be efficacious in 2 cases of M-D.100 Antidopaminergic Drugs
Because of limited effect and the possibility of adverse effects, such as parkinsonism and tardive dyskinesia, neuroleptic drugs are not commonly used for the treatment of primary dystonia. Clozapine, an atypical neuroleptic, has been shown to provide moderate benefit for segmental and generalized dystonia in a small, open-label trial.101 However, its usefulness is limited by potential serious side effects, such as fatal agranulocytosis. Tetrabenazine, an inhibitor of vesicular monoamine transporter 2, does not cause tardive dyskinesias, but can cause transient acute dystonic reaction, parkinsonism, and depression.102 It has proven beneficial in some patients with dystonia, in particular those with tardive dystonia,103 and is now approved in the United States for treatment of Huntington chorea where it is marketed under the name Xenazine. Anticholinergic Drugs
Anticholinergic drugs, such as trihexyphenidyl, are widely used in the treatment of segmental and generalized dystonia.104,105 It is tolerated well in children and is the medical treatment of choice for childhood-onset primary generalized dystonia. It is usually started at a low dose and titrated up very slowly to minimize side effects, such as sedation, confusion, memory difficulty, and hallucinations, which may occur at higher doses. Other Pharmacologic Treatments
Most patients with dystonia require a combination therapy with several modalities of treatment. Benzodiazepines, such as diazepam, lorazepam, and clonazepam are often used for their muscle-relaxant properties. Clonazepam is especially useful in blepharospasm and myoclonic dystonia.76 Other muscle relaxants used include cyclobenzaprine, tizanidine, and baclofen. Baclofen is a presynaptic g-aminobutyric acid-receptor agonist, which can be administered orally or intrathecally in severe cases of spastic dystonia with good results.106 Sodium oxybate (Xyrem) has been shown to improve myoclonus in alcohol-responsive M-D in a single-blind, open-label trial.107 There are several other agents that have been tried with varying results for alleviating symptoms of dystonia, including morphine sulfate and mexiletine. Because of side effects and limited efficacy, these treatments are rarely used. There are isolated reports that zolpidem might be helpful in certain types of dystonia.108 Surgical Treatment
After the success of DBS as a safe and efficacious treatment for Parkinson disease, this surgical approach has been tested in dystonia, with the stimulation target primarily limited to the globus pallidus interna (GPi). Outcomes in patients with primary generalized dystonia overall have been encouraging, with most studies demonstrating significant benefit and a low frequency of adverse advents. One prospective study of 22 patients with generalized dystonia who received bilateral GPi DBS, 7 of whom were DYT1 positive, found sustained improvement in mood, quality-of-life (QOL) scores, and medication reductions after 3 years. Additionally, motor scores for upper and lower limb had significantly improved at year 3 compared with year 1. Variables such as DYT1 gene status, anatomic distribution, or exact location of the electrodes did not predict response.109 One study, however, suggested that patients with shorter
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disease duration may have better outcomes.110 Another recent randomized, shamstimulation controlled trial on DBS in primary segmental or generalized dystonia showed significant QOL improvement only in the active-stimulation group. These results reinforce the favorable impact of DBS on QOL in primary dystonia.111 Aside from generalized primary dystonia, there is also recent evidence that cervical dystonia and a subset of secondary dystonia (especially tardive dystonia) that is refractory to medical treatment and chemodenervation may benefit from DBS.112,113 Increasing knowledge of the mechanism of DBS will enable the physician to individualize therapy plans, depending on patient response to variable stimulation parameters and target sites. For instance, some cervical dystonia may respond best to stimulation at 130 Hz,114 and pallidal stimulation with 60 Hz has been shown to be as effective as higher frequencies in a group of PTD patients, most having DYT1 dystonia.115 A few studies have considered other surgical targets, and cases of cervical or tremor-predominant dystonia responsive to subthalamic stimulation have been reported,116,117 whereas the thalamus might be a better target in some patients with M-D and severe brachial dystonia.118,119 Physical Therapy
Physical therapy is an essential component in the treatment of dystonia to improve posture and prevent contractures. Sometimes braces are helpful for providing ‘‘sensory tricks’’ that can improve dystonia. Patients with cervical dystonia might benefit from neck braces, and patients with writer’s cramp occasionally obtain relief from orthotic hand devices. REFERENCES
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11. Zirn B, Grundmann K, Huppke P, et al. Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1). J Neurol Neurosurg Psychiatry 2008;79: 1327–30. 12. Vale RD. AAA proteins. Lords of the ring. J Cell Biol 2000;150:F13–9. 13. Hanson PI, Whiteheart SW. AAA1 proteins: have engine, will work. Nat Rev Mol Cell Biol 2005;6:519–29. 14. Goodchild RE, Dauer WT. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc Natl Acad Sci U S A 2004;101:847–52. 15. Hewett JW, Zeng J, Niland BP, et al. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. Neurobiol Dis 2006;22:98–111. 16. Giles LM, Chen J, Li L, et al. Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope. Hum Mol Genet 2008;17:2712–22. 17. McNaught KS, Kapustin A, Jackson T, et al. Brainstem pathology in DYT1 primary torsion dystonia. Ann Neurol 2004;56:540–7. 18. Shashidharan P, Sandu D, Potla U, et al. Transgenic mouse model of early-onset DYT1 dystonia. Hum Mol Genet 2005;14:125–33. 19. Sharma N, Baxter MG, Petravicz J, et al. Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation. J Neurosci 2005;25: 5351–5. 20. Dang MT, Yokoi F, McNaught KS, et al. Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia. Exp Neurol 2005;196:452–63. 21. Dang MT, Yokoi F, Pence MA, et al. Motor deficits and hyperactivity in Dyt1 knockdown mice. Neurosci Res 2006;56:470–4. 22. Kock N, Naismith TV, Boston HE, et al. Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier. Hum Mol Genet 2006;15:1355–64. 23. Risch NJ, Bressman SB, Senthil G, et al. Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. Am J Hum Genet 2007;80: 1188–93. 24. Sibbing D, Asmus F, Konig IR, et al. Candidate gene studies in focal dystonia. Neurology 2003;61:1097–101. 25. Kamm C, Asmus F, Mueller J, et al. Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia. Neurology 2006;67:1857–9. 26. Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines for diagnostic testing. Neurology 2000;54:1746–52. 27. Fasano A, Nardocci N, Elia AE, et al. Non-DYT1 early-onset primary torsion dystonia: comparison with DYT1 phenotype and review of the literature. Mov Disord 2006;21:1411–8. 28. Leube B, Kessler KR, Ferbert A, et al. Phenotypic variability of the DYT1 mutation in German dystonia patients. Acta Neurol Scand 1999;99:248–51. 29. Koukouni V, Martino D, Arabia G, et al. The entity of young onset primary cervical dystonia. Mov Disord 2007;22:843–7. 30. Jamora RD, Tan EK, Liu CP, et al. DYT1 mutations amongst adult primary dystonia patients in Singapore with review of literature comparing east and west. J Neurol Sci 2006;247:35–7. 31. Risch N, de Leon D, Ozelius L, et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 1995;9:152–9.
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32. Frederic M, Lucarz E, Monino C, et al. First determination of the incidence of the unique TOR1A gene mutation, c.907delGAG, in a Mediterranean population. Mov Disord 2007;22:884–8. 33. Zeman W, Dyken P. Dystonia musculorum deformans. Clinical, genetic and pathoanatomical studies. Psychiatr Neurol Neurochir 1967;70:77–121. 34. Heiman GA, Ottman R, Saunders-Pullman RJ, et al. Increased risk for recurrent major depression in DYT1 dystonia mutation carriers. Neurology 2004;63: 631–7. 35. Heiman GA, Ottman R, Saunders-Pullman RJ, et al. Obsessive-compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene. Am J Med Genet B Neuropsychiatr Genet 2007;144:361–4. 36. Ghilardi MF, Carbon M, Silvestri G, et al. Impaired sequence learning in carriers of the DYT1 dystonia mutation. Ann Neurol 2003;54:102–9. 37. Bressman SB, Raymond D, Wendt K, et al. Diagnostic criteria for dystonia in DYT1 families. Neurology 2002;59:1780–2. 38. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998;44:303–12. 39. Asanuma K, Ma Y, Okulski J, et al. Decreased striatal D2 receptor binding in nonmanifesting carriers of the DYT1 dystonia mutation. Neurology 2005;64:347–9. 40. Carbon M, Kingsley PB, Su S, et al. Microstructural white matter changes in carriers of the DYT1 gene mutation. Ann Neurol 2004;56:283–6. 41. Edwards MJ, Huang YZ, Wood NW, et al. Different patterns of electrophysiological deficits in manifesting and non-manifesting carriers of the DYT1 gene mutation. Brain 2003;126:2074–80. 42. Fiorio M, Gambarin M, Valente EM, et al. Defective temporal processing of sensory stimuli in DYT1 mutation carriers: a new endophenotype of dystonia? Brain 2007;130:134–42. 43. Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two mennonite families. Ann Neurol 1997;42:670–3. 44. Valente EM, Bentivoglio AR, Cassetta E, et al. Identification of a novel primary torsion dystonia locus (DYT13) on chromosome 1p36 in an Italian family with cranial-cervical or upper limb onset. Neurol Sci 2001;22:95–6. 45. Chouery E, Kfoury J, Delague V, et al. A novel locus for autosomal recessive primary torsion dystonia (DYT17) maps to 20p11.22-q13.12. Neurogenetics 2008;9:287–93. 46. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 2009;41:286–8. 47. Bressman SB, Raymond D, Fuchs T, et al. Mutations in THAP1 (DYT6) in earlyonset dystonia: a genetic screening study. Lancet Neurol 2009;8(5):441–6. 48. Bressman SB, Warner TT, Almasy L, et al. Exclusion of the DYT1 locus in familial torticollis. Ann Neurol 1996;40:681–4. 49. Munchau A, Valente EM, Davis MB, et al. A Yorkshire family with adult-onset cranio-cervical primary torsion dystonia. Mov Disord 2000;15:954–9. 50. Leube B, Rudnicki D, Ratzlaff T, et al. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distribution. Hum Mol Genet 1996;5:1673–7. 51. Jarman PR, del Grosso N, Valente EM, et al. Primary torsion dystonia: the search for genes is not over. J Neurol Neurosurg Psychiatry 1999;67:395–7. 52. Placzek MR, Misbahuddin A, Chaudhuri KR, et al. Cervical dystonia is associated with a polymorphism in the dopamine (D5) receptor gene. J Neurol Neurosurg Psychiatry 2001;71:262–4.
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53. Misbahuddin A, Placzek MR, Chaudhuri KR, et al. A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm. Neurology 2002;58:124–6. 54. Clarimon J, Brancati F, Peckham E, et al. Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm. Mov Disord 2007;22:162–6. 55. Clarimon J, Asgeirsson H, Singleton A, et al. Torsin A haplotype predisposes to idiopathic dystonia. Ann Neurol 2005;57:765–7. 56. Hague S, Klaffke S, Clarimon J, et al. Lack of association with torsinA haplotype in German patients with sporadic dystonia. Neurology 2006;66:951–2. 57. Nygaard TG, Takahashi H, Heiman GA, et al. Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. Ann Neurol 1992;32:603–8. 58. Van Hove JL, Steyaert J, Matthijs G, et al. Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency. J Neurol Neurosurg Psychiatry 2006;77:18–23. 59. Steinberger D, Topka H, Fischer D, et al. GCH1 mutation in a patient with adultonset oromandibular dystonia. Neurology 1999;52:877–9. 60. Nygaard TG, Waran SP, Levine RA, et al. Dopa-responsive dystonia simulating cerebral palsy. Pediatr Neurol 1994;11:236–40. 61. Furukawa Y, Kish SJ, Lang AE. Scoliosis in a dopa-responsive dystonia family with a mutation of the GTP cyclohydrolase I gene. Neurology 2000; 54:2187. 62. Kong CK, Ko CH, Tong SF, et al. Atypical presentation of dopa-responsive dystonia: generalized hypotonia and proximal weakness. Neurology 2001;57: 1121–4. 63. Jarman PR, Bandmann O, Marsden CD, et al. GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs. J Neurol Neurosurg Psychiatry 1997;63:304–8. 64. Hagenah J, Saunders-Pullman R, Hedrich K, et al. High mutation rate in doparesponsive dystonia: detection with comprehensive GCHI screening. Neurology 2005;64:908–11. 65. Ichinose H, Suzuki T, Inagaki H, et al. Molecular genetics of dopa-responsive dystonia. Biol Chem 1999;380:1355–64. 66. Furukawa Y, Lang AE, Trugman JM, et al. Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology 1998;50:1015–20. 67. Furukawa Y. Update on dopa-responsive dystonia: locus heterogeneity and biochemical features. Adv Neurol 2004;94:127–38. 68. van den Heuvel LP, Luiten B, Smeitink JA, et al. A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the dutch population. Hum Genet 1998;102:644–6. 69. Hanihara T, Inoue K, Kawanishi C, et al. 6-Pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study. Mov Disord 1997;12:408–11. 70. Steinberger D, Blau N, Goriuonov D, et al. Heterozygous mutation in 5’-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 2004;5:187–90. 71. Tassin J, Durr A, Bonnet AM, et al. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain 2000;123(Pt 6):1112–21. 72. Khan NL, Graham E, Critchley P, et al. Parkin disease: a phenotypic study of a large case series. Brain 2003;126:1279–92.
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73. Obeso JA, Rothwell JC, Lang AE, et al. Myoclonic dystonia. Neurology 1983;33: 825–30. 74. Nygaard TG, Raymond D, Chen C, et al. Localization of a gene for myoclonusdystonia to chromosome 7q21–q31. Ann Neurol 1999;46:794–8. 75. Vidailhet M, Tassin J, Durif F, et al. A major locus for several phenotypes of myoclonus–dystonia on chromosome 7q. Neurology 2001;56:1213–6. 76. Zimprich A, Grabowski M, Asmus F, et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat Genet 2001; 29:66–9. 77. Asmus F, Hjermind LE, Dupont E, et al. Genomic deletion size at the epsilonsarcoglycan locus determines the clinical phenotype. Brain 2007;130: 2736–45. 78. Grunewald A, Djarmati A, Lohmann-Hedrich K, et al. Myoclonus-dystonia: significance of large SGCE deletions. Hum Mutat 2008;29:331–2. 79. Guettard E, Portnoi MF, Lohmann-Hedrich K, et al. Myoclonus-dystonia due to maternal uniparental disomy. Arch Neurol 2008;65:1380–5. 80. Muller B, Hedrich K, Kock N, et al. Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia. Am J Hum Genet 2002;71:1303–11. 81. Grabowski M, Zimprich A, Lorenz-Depiereux B, et al. The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted. Eur J Hum Genet 2003;11:138–44. 82. Han F, Racacho L, Lang AE, et al. Refinement of the DYT15 locus in myoclonus dystonia. Mov Disord 2007;22:888–92. 83. Kyllerman M, Forsgren L, Sanner G, et al. Alcohol-responsive myoclonic dystonia in a large family: dominant inheritance and phenotypic variation. Mov Disord 1990;5:270–9. 84. Marelli C, Canafoglia L, Zibordi F, et al. A neurophysiological study of myoclonus in patients with DYT11 myoclonus-dystonia syndrome. Mov Disord 2008;23: 2041–8. 85. Saunders-Pullman R, Shriberg J, Heiman G, et al. Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence. Neurology 2002;58:242–5. 86. McKeon A, Ozelius LJ, Hardiman O, et al. Heterogeneity of presentation and outcome in the Irish rapid-onset dystonia-parkinsonism kindred. Mov Disord 2007;22:1325–7. 87. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al. Mutations in the Na1/ K1 -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 2004;43:169–75. 88. Lee LV, Pascasio FM, Fuentes FD, et al. Torsion dystonia in Panay, Philippines. Adv Neurol 1976;14:137–51. 89. Evidente VG, Gwinn-Hardy K, Hardy J, et al. X-linked dystonia (‘‘Lubag’’) presenting predominantly with parkinsonism: a more benign phenotype? Mov Disord 2002;17:200–2. 90. Evidente VG, Advincula J, Esteban R, et al. Phenomenology of ‘‘Lubag’’ or X-linked dystonia-parkinsonism. Mov Disord 2002;17:1271–7. 91. Evidente VG, Nolte D, Niemann S, et al. Phenotypic and molecular analyses of X-linked dystonia-parkinsonism (‘‘lubag’’) in women. Arch Neurol 2004;61: 1956–9. 92. Waters CH, Takahashi H, Wilhelmsen KC, et al. Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women. Neurology 1993;43:1555–8.
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93. Waters CH, Faust PL, Powers J, et al. Neuropathology of lubag (x-linked dystonia parkinsonism). Mov Disord 1993;8:387–90. 94. Goto S, Lee LV, Munoz EL, et al. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann Neurol 2005;58:7–17. 95. Brewer GJ, Askari F, Lorincz MT, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006;63:521–7. 96. Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70:1699–706. 97. Pappert EJ, Germanson T, Myobloc/Neurobloc European Cervical Dystonia Study Group. Botulinum toxin type B vs. type A in toxin-naive patients with cervical dystonia: randomized, double-blind, noninferiority trial. Mov Disord 2008;23:510–7. 98. Jankovic J, Hunter C, Dolimbek BZ, et al. Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia. Neurology 2006;67: 2233–5. 99. Dressler D, Bigalke H. Botulinum toxin type B de novo therapy of cervical dystonia: frequency of antibody induced therapy failure. J Neurol 2005;252:904–7. 100. Luciano MS, Ozelius L, Sims K, et al. Responsiveness to levodopa in epsilonsarcoglycan deletions. Mov Disord 2009;24:425–8. 101. Karp BI, Goldstein SR, Chen R, et al. An open trial of clozapine for dystonia. Mov Disord 1999;14:652–7. 102. Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurother 2006;6:7–17. 103. Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord 2007;22:193–7. 104. Greene P, Shale H, Fahn S. Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Mov Disord 1988; 3:46–60. 105. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986;36:160–4. 106. Woon K, Tsegaye M, Vloeberghs MH. The role of intrathecal baclofen in the management of primary and secondary dystonia in children. Br J Neurosurg 2007;21:355–8. 107. Frucht SJ, Houghton WC, Bordelon Y, et al. A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor. Neurology 2005;65: 1967–9. 108. Evidente VG. Zolpidem improves dystonia in ‘‘Lubag’’ or X-linked dystoniaparkinsonism syndrome. Neurology 2002;58:662–3. 109. Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol 2007;6:223–9. 110. Isaias IU, Alterman RL, Tagliati M. Outcome predictors of pallidal stimulation in patients with primary dystonia: The role of disease duration. Brain 2008;131: 1895–902. 111. Mueller J, Skogseid IM, Benecke R, et al. Pallidal deep brain stimulation improves quality of life in segmental and generalized dystonia: results from a prospective, randomized sham-controlled trial. Mov Disord 2008;23:131–4.
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112. Kiss ZH, Doig-Beyaert K, Eliasziw M, et al. The Canadian multicentre study of deep brain stimulation for cervical dystonia. Brain 2007;130:2879–86. 113. Pretto TE, Dalvi A, Kang UJ, et al. A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes. J Neurosurg 2008;109:405–9. 114. Moro E, Piboolnurak P, Arenovich T, et al. Pallidal stimulation in cervical dystonia: clinical implications of acute changes in stimulation parameters. Eur J Neurol 2009;16:506–12. 115. Alterman RL, Miravite J, Weisz D, et al. Sixty hertz pallidal deep brain stimulation for primary torsion dystonia. Neurology 2007;69:681–8. 116. Blomstedt P, Fytagoridis A, Tisch S. Deep brain stimulation of the posterior subthalamic area in the treatment of tremor. Acta Neurochir (Wien) 2009;151:31–6. 117. Moll CK, Hamel W, Ostertag CB, et al. Subthalamotomy in cervical dystonia: a case study of lesion location and clinical outcome. Mov Disord 2008;23: 1751–6. 118. Kim MJ, Jeon SR, Yoo HW, et al. Effect of thalamotomy on focal hand dystonia in a family with DYT1 mutation. Mov Disord 2008;23:2251–5. 119. Kuncel AM, Turner DA, Ozelius LJ, et al. Myoclonus and tremor response to thalamic deep brain stimulation parameters in a patient with inherited myoclonus-dystonia syndrome. Clin Neurol Neurosurg 2009;111:303–6.
Huntington Disease a nd Other Choreas Francisco Cardoso, MD, PhD KEYWORDS Chorea Ballism Huntington disease Neuroacanthocytosis Sydenham chorea Vascular chorea
Chorea is a syndrome characterized by brief, abrupt involuntary movements resulting from a continuous flow of random muscle contractions. The pattern of movement may sometimes seem playful, conveying a feeling of restlessness to the observer. When choreic movements are more severe, assuming a flinging, sometimes violent, character, they are called ballism. Regardless of its cause, chorea has the same features.1 There are genetic and nongenetic causes of chorea, listed in Box 1. Nongenetic causes include vascular choreas, autoimmune choreas, metabolic and toxic choreas, and drug-induced choreas. Although there are few community-based studies available regarding the prevalence and incidence of choreas, there is information regarding the situation in tertiary care centers. Huntington disease (HD) is the most frequent cause of genetic chorea with reported prevalence rates in North America and Europe ranging from 3 to 7 per 100,000.1 The other genetic conditions causing chorea are rare. According to a recent study from Pennsylvania, Sydenham chorea (SC) accounts for almost 100% of acute cases of chorea seen in children.2 In contrast, the situation is more distinct in adult patients. Although no published data are available, it is likely that levodopa-induced chorea in patients with Parkinson disease (PD) is the most common cause of chorea seen by neurologists. One study of consecutive patients seen at a tertiary hospital found that stroke accounted for 50% of all cases, drug abuse was identified in one third of the patients, and the remaining patients had chorea related to AIDS and other infections and metabolic problems.3 The aim of this article is to provide an overview of the main causes of chorea. The clinical features, causes, pathogenesis, and management are discussed. HUNTINGTON DISEASE
HD is an autosomal-dominant, progressive neurodegenerative disorder typically characterized by a movement disorder, including chorea, cognitive decline, and behavioral changes leading to relentlessly increasing disability and ultimately death. Patients usually develop the first symptoms in their mid-30s to mid-40s. However, the onset
Internal Medicine Department, The Federal University of Minas Gerais, Av Pasteur 89/1107, 30150-290 Belo Horizonte, MG, Brazil E-mail address:
[email protected] Neurol Clin 27 (2009) 719–736 doi:10.1016/j.ncl.2009.04.001 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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Box 1 Causes of Chorea Genetic causes Huntington disease Huntington disease-like illnesses Neuroacanthocytosis McLeod syndrome Wilson disease Benign hereditary chorea (BHC) Spinocerebellar atrophy type 2 Spinocerebellar atrophy type 3 Spinocerebellar atrophy type 17 Dentatorubropallidoluysian degeneration Ataxia-telangiectasia Ataxia associated with oculomotor apraxia Neuroferritinopathy Pantothenate kinase associated degeneration Leigh disease and other mitochondriopathies Lesch-Nyhan disease Immunologic Sydenham chorea (SC) and variants (chorea gravidarum and contraceptive-induced chorea) Systemic lupus erythematosus Antiphospholipid antibody syndrome Paraneoplastic syndromes Acute disseminated encephalomyelopathy Celiac disease Drug-related Amantadine Amphetamine Anticonvulsants Carbon monoxide Central nervous system (CNS) stimulants (methylphenidate, pemoline, cyproheptadine) Cocaine Dopamine agonists Dopamine-receptor blockers Ethanol Levodopa Levofloxacin Lithium Sympathomimetics Theophylline
Choreas
Tricyclic antidepressants Withdrawal emergent syndrome Infections AIDS-related (toxoplasmosis, progressive multifocal leukoencephalopathy, HIV encephalitis) Bacteria - Diphtheria - Scarlet fever - Whooping cough Encephalitis - B19 parvovirus - Japanese encephalitis - Measles - Mumps - West Nile River encephalitis - Others Parasites - Neurocysticercosis Protozoan - Malaria - Syphilis Endocrine-metabolic dysfunction Adrenal insufficiency Hyper/hypocalcemia Hyper/hypoglycemia Hypomagnesemia Hypernatremia Liver failure Vascular Post-pump chorea (cardiac surgery) Stroke Subdural hematoma Miscellaneous Anoxic encephalopathy Cerebral palsy Kernicterus Multiple sclerosis Normal maturation (less than 12 months old) Nutritional (eg, B12 deficiency) Posttraumatic (brain injury)
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in a small proportion of subjects is before the age of 20 years (Westphal variant) or after the age of 70 years.1 Clinical Features
HD is characterized by a triad of movement disorder, cognitive decline, and behavioral changes. Although chorea is the prototypical movement disorder in HD and is usually present with middle-age or elderly onset, the full spectrum of motor impairment in HD includes eye movement abnormalities, parkinsonian features and dystonia (particularly in juvenile HD), myoclonus, tics, ataxia, dysarthria and dysphagia, and spasticity with hyperreflexia and extensor plantar responses.4–8 With progressing illness, chorea is often superseded by dystonia or akineto-rigid parkinsonian features. One study demonstrated that dystonia is found in more than 90% of patients with HD,9 although rarely it becomes as prominent as in idiopathic dystonias. A recent study demonstrated that falls are an important clinical problem in HD, occurring in 60% of patients, and are correlated with motor deficits, cognitive decline, and behavioral changes.10 Behavioral impairment is universal in HD and may occasionally antedate motor manifestations. Major depression is common, diagnosed in more than 40% of subjects, and responsible for increased suicide rates in HD. The spectrum of behavioral abnormalities in HD is broad and includes anxiety or panic attacks, obsessive compulsive symptoms, manic features, psychosis, irritability and aggressive behavior, sexual disinhibition, and apathy.11–17 In a prospective study of a large cohort (681) of subjects with presymptomatic HD, significantly more psychiatric symptoms (specially depression, anxiety, and obsessive-compulsiveness) were reported than for the controls.18 Similarly, psychiatric difficulties are indicators of juvenile HD onset.19 Patients with HD universally go through cognitive decline, mental slowing, impaired problem-solving abilities, and other signs of a frontal dysexecutive syndrome, and they eventually become demented. These patients present with the prototype of socalled subcortical dementia.20–22 Cognitive decline also heralds the juvenile onset of HD.19 A recent investigation has demonstrated that asymptomatic carriers of the HD gene have decreased phonemic fluency.23 HD is relentlessly progressive with death occurring 15 to 20 years after symptom onset with particularly rapid progression in the juvenile Westphal variant. Patients with end-stage HD are typically rigid and akinetic, demented, and mute. Immobility and dysphagia often lead to aspiration pneumonia, the most common cause of death in these patients.24–26 Etiology and Pathogenesis
HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin on chromosome 4p16.3; the exact function of normal huntingtin is still unknown, and it is widely expressed in the human brain.27,28 The normal CAG repeat length in the HD gene is 35 or lower; expansions of 40 or more cause HD with complete penetrance. Individuals with 36 to 39 repeats may also develop HD but penetrance is incomplete.29 A CAG repeat range between 27 and 35 is considered normal allele with particular risk for expansion into the HD range in the paternal germline.30,31 However, there is a report showing that 1 patient with 34 repeats developed HD.32 The mutant protein has been shown to form nuclear aggregates but how this leads to neurodegeneration remains unclear. Current evidence suggests that formation of aggregates of huntingtin is not primarily responsible for neuronal loss in HD. Alternative hypotheses suggested include transcriptional dysregulation, excitotoxicity, altered energy metabolism, impaired axonal transport, and altered synaptic transmission.33,34 Neurodegeneration in HD affects most prominently the striatum with loss
Choreas
of medium spiny neurons and layers III, IV, and V of the cortex with loss of large neurons, and is characterized by the presence of intranuclear inclusion bodies consisting of amyloid-like fibrils that contain mutant huntingtin, ubiquitin, synuclein, and other proteins.35–37 Management
To date there is no effective treatment to modify the relentlessly progressive course of HD.38 Symptomatic treatment of chorea is needed if it causes functional disability or social embarrassment. One principle that generally guides the choice of antichoreic agents is their ability to powerfully block D2 receptors. With the exception of amantadine (see later discussion), all drugs effective in providing symptomatic improvement of chorea have high affinity toward this family of dopamine receptors, which explains why atypical agents, such as quetiapine and clozapine, often used to treat psychosis in patients with movement disorders, are usually ineffective in controlling chorea. Atypical antipsychotics such as olanzapine, quetiapine or risperidone may sufficiently and at least transiently reduce choreic movements but are generally less potent than typical neuroleptics. If the neuroleptics are effective in reducing chorea, they are often associated with unacceptable side effects such as sedation, acute dystonic reaction, tardive dyskinesia, and parkinsonism. Parkinsonism can be a problem in patients with HD; with progression of the illness there is a tendency for development of rigidity and dystonia.39 Mild to moderate chorea in HD may also respond to glutamate antagonists such as amantadine.40,41 Recent controlled data have confirmed that tetrabenazine, a presynaptic dopamine depletory, is efficacious in controlling chorea in HD.42,43 This agent has now been approved by the Food and Drug Administration for symptomatic control of chorea in HD. In a recent open-label study, aripiprazole was found to have efficacy comparable to tetrabenazine in the control of chorea in HD. Further studies are required to confirm this observation.44 Levodopa may be required in patients with Huntington disease with advanced illness and severe rigidity.38 Atypical neuroleptics may also be useful in the management of emotional irritability, aggressiveness, and other forms of erratic behavior.17,45 Depression may respond to classic antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or antimuscarinic drugs, or to newer antidepressants such as mirtazapine, reboxatine, or venlafaxin, but there are no formal trial data to assess the relative efficacy and safety of these agents in HD.17 Occasional reports have claimed mild beneficial effects of treatment with cholinesterase inhibitor to reduce cognitive dysfunction in HD, but there are no adequate studies to support their use.46,47 Surgery to treat chorea is rarely needed. Pallidotomy and pallidal stimulation have also been used in a few patients with HD.48,49 Several patients with Huntington disease have been treated with fetal cell implantation in the striatum. Despite a few positive reports, in most cases no improvement has been observed. Autopsy studies have shown that the grafts survive but do not integrate with host striatum.50,51 OTHER GENETIC CHOREAS
Approximately 3% of patients with an HD phenotype test negative for this condition. Cohort studies have established that, although most phenocopy patients remain undiagnosed, in those patients in whom a genetic diagnosis is reached the commonest causes are neuroacanthocytosis, SCA17, Huntington disease-like syndrome 2, familial prion disease, and Friedreich ataxia. Other causes of HD phenocopies include Huntington disease-like syndrome 1, Huntington disease-like syndrome 3, other spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and iron accumulation disorders.52,53
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Neuroacanthocytosis causes chorea combined with dystonia (especially a selfmutilating oro-mandibullingual dyskinesia), tics, parkinsonism, dementia, seizures, and head of caudate atrophy on neuroimaging studies.54 Several conditions can cause the combination of chorea and acanthocytosis: autosomal recessive choreaacanthocytosis, X-linked McLeod syndrome, Huntington disease-like 2, panthotenate kinase–associated neurodegeneration, and Bassen-Kornzweig disease.55 A study of several patients with McLeod syndrome, including the subject of the original report, demonstrated that their phenotype is similar to the clinical features of patients with HD, with the myopathic findings overtaken by chorea and dementia.56 Another genetic cause of chorea that has received increased attention is benign hereditary chorea (BHC). Not long ago, the existence of this condition was questioned.57 Now it is well established as an autosomal dominant illness, with a mutation in the TITF-1 gene, which codes for a transcription factor essential for the organogenesis of the lungs, thyroid, and basal ganglia.58 The clinical picture of these patients is characterized by a variable combination of chorea, mental retardation, congenital hypothyroidism, and chronic lung disease, hence the term brain-thyroid-lung syndrome, proposed for this disease.59,60 The movement disorder of these patients is differentiated from the hyperkinesia seen in myoclonus dystonia by its continuous nature; in myoclonus dystonia the movements are triggered by motion.61 New studies with clinical-genetic correlation have helped to demonstrate that the clinical spectrum of BHC is wider than previously believed, and includes psychosis and short stature.62,63 The phenotype of BHC and hypothyroidism has been shown to be caused by a novel NKX2.1 mutation.64 Moreover, a new locus on 8q21.3 q23.3 is associated with adult-onset, pure, slowly progressive chorea.65 The list of genetic causes of chorea is long and growing.1 It is beyond the scope of this article to review all of them. Recently, however, there has been interest in a few additional conditions in which progress has been made. For example, paroxysmal nonkinesigenic dyskinesia, Mount-Reback Syndrome, is now known to be caused by mutations of myofibrillogenesis regulator 1 (MR-1) gene mutations, located on 2q35.66,67 Patients with this condition develop episodes of chorea or other movement disorders unrelated to exercise but often in association with the use of nicotine and alcohol.68 A new study showed that there is a defect in the MR-1 mitochondrial targeting sequence.69 Other paroxysmal dyskinesias in which chorea is part of the clinical picture map to genes on 16p12-q12 and 10q22.70 There are no controlled studies of treatment of other genetic causes of chorea. Overall, the principles discussed for HD apply to these conditions. However, there are peculiarities in some cases. A substantial proportion of patients with chorea-acanthocytosis present with a self-mutilating tongue-biting dystonia. This dyskinesia can be disabling, preventing these patients from eating properly and resulting in severe injuries. In the author’s experience, injections of botulinum toxin in the genioglossus muscle can provide substantial and lasting relief. Another clinical feature common in this condition is seizure disorder, requiring the use of antiepileptic drugs. The kinesigenic paroxysmal dyskinesias are sensitive to low doses of antepileptic drugs, whereas Mount-Reback syndrome responds to benzodiazepines.68,71 Finally, there is one report suggesting that levodopa can be effective in the treatment of BHC.72 SYDENHAM CHOREA
SC, the most common form of autoimmune chorea worldwide, is a major feature of acute rheumatic fever (ARF), a nonsuppurative complication of group A b-hemolytic Streptococcus infection. Despite the decline of ARF, it remains the most common
Choreas
cause of acute chorea in children in the United States and a major public health problem in developing areas of the world. Clinically, it is characterized by a combination of chorea, other movement disorders, behavioral abnormalities, and cognitive changes.1,2 Clinical Features
The usual age at onset of SC is 8 to 9 years, but there are reports of patients who developed chorea during the third decade of life. In most series, there is a female preponderance.73 Typically, patients develop this disease 4 to 8 weeks after an episode of group A b-hemolytic streptococcal pharyngitis. It does not occur after streptococcal infection of the skin. The chorea spreads rapidly and becomes generalized, but hemichorea persists in 20% of patients.73,74 Patients display motor impersistence, particularly noticeable during tongue protrusion and ocular fixation. The muscle tone is usually decreased; in severe and rare cases (8% of all patients seen at the Movement Disorders of the Federal University of Minas Gerais, Brazil), this is so pronounced that the patient may become bedridden (chorea paralytica). Patients often display other neurologic and nonneurologic symptoms and signs. There are reports that tics are a common occurrence in SC. However, it is virtually impossible to distinguish simple tics from fragments of chorea. Even vocal tics, found in 70% or more of patients with SC in one study, are not a simple diagnosis in patients with hyperkinesias.75 In a cohort of 108 patients with SC who were carefully followed up at our unit, vocalizations were identified in just 8% of subjects. The term ‘‘tic’’ was avoided because there was no premonitory sign or complex sound and, conversely, the vocalizations were associated with severe cranial chorea. These findings suggest that involuntary sounds present in a few patients with SC result from choreic contractions of the upper respiratory tract muscles rather than true tics.76,77 There is evidence that many patients with active chorea have hypometric saccades, and a few also show oculogyric crisis. Dysarthria and impairment of verbal fluency are common. In a case– control study of patients, a pattern of decreased verbal fluency was described that reflected reduced phonetic, but not semantic, output.78 This result is consistent with dysfunction of the dorsolateral prefrontal basal ganglia circuit. Studying adults with SC, the authors have extended this finding, showing that many functions dependent on the prefrontal area are impaired in these patients. The conclusion of this study is that SC should be included among the causes of dysexecutive syndrome.79 The prosody is also affected in SC. In an investigation of 20 patients with SC, decreased vocal tessitura and increased duration of the speech were shown.80,81 These findings are similar to those observed in Parkinson disease.82 In a recent survey of 100 patients with rheumatic fever, half of whom had chorea, migraine was found to be more frequent in SC (21.8%) than in normal controls (8.1%, P 5 .02).83 This is similar to what has been described in Tourette syndrome (TS).84 In the older literature, there are also references to papilledema, central retinal artery occlusion, and seizures in a few patients with Sydenham chorea. Attention has also been drawn to behavioral abnormalities. Swedo and colleagues85 found obsessive-compulsive behavior in 5 of 13 SC patients, 3 of whom met criteria for obsessive-compulsive disorder, whereas no patient of the rheumatic fever group presented with obsessive-compulsive behavior. In another study of 30 patients with SC, Asbahr and colleagues86 demonstrated that 70% of the subjects presented with obsessions and compulsions, whereas 16.7% of them met criteria for obsessive-compulsive disorder. None of the 20 patients with ARF without chorea had obsessions or compulsions. These results were roughly replicated by a more recent study in which patients with ARF without chorea were found to have more obsessions
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and compulsions than healthy controls.87 This study also tackled the issue of hyperactivity and attention deficit disorder in SC and found that 45% of their 22 patients met criteria for this condition. Recently, Maia and colleagues88 investigated behavioral abnormalities in 50 healthy subjects, 50 patients with rheumatic fever without chorea, and 56 patients with Sydenham chorea. The investigators found that obsessivecompulsive behavior, obsessive-compulsive disorder, and attention deficit and hyperactivity disorder were more frequent in the SC group (19%, 23.2%, 30.4%) than in the healthy controls (11%, 4%, 8%) or in the patients with ARF without chorea (14%, 6%, 8%). In this study, the investigators demonstrated that obsessive-compulsive behavior displays little degree of interference in the performance of the activities of daily living. Another study compared the phenomenology of obsessions and compulsions of patients with SC with subjects diagnosed with tic disorders. The investigators demonstrated that the symptoms observed among the SC patients were different from those reported by patients with tic disorders but were similar to those previously noted among samples of pediatric patients with primary obsessive-compulsive disorder.89 A recent investigation comparing healthy controls with patients with rheumatic fever showed that obsessive-compulsive behavior is more commonly seen in patients with Sydenham chorea with relatives who also have obsessions and compulsions.90 This study makes clear that there is interplay between genetic factors and the environment in the development of behavioral problems in SC. The authors recently reported that, although rare, SC may induce psychosis or trichotillomania during the acute phase of the illness.91,92 An investigation demonstrated that the peripheral nervous system is not targeted in Sydenham chorea.93 SC is a major manifestation of rheumatic fever. Sixty percent to 80% of patients display cardiac involvement, particularly mitral valve dysfunction, in SC, whereas the association with arthritis is less common, seen in 30% of patients; however, in approximately 20% of patients, chorea is the sole finding.73,94 A prospective follow-up of patients with SC with and without cardiac involvement in the first episode of chorea suggests that the heart remains spared in those without lesion at the onset of the rheumatic fever.95 The current diagnostic criteria of SC are a modification of the Jones criteria: chorea with acute or subacute onset and lack of clinical and laboratory evidence of an alternative cause are mandatory findings. The diagnosis is further supported by the presence of additional major or minor manifestations of ARF.78,96,97 The first validated scale to rate SC was published recently. The Universidade Federal de Minas Gerais Sydenham Chorea Rating Scale was designed to provide a detailed quantitative description of the performance of the activities of daily living, behavioral abnormalities, and motor function of patients with SC. It comprises 27 items, and each is scored from 0 (no symptom or sign) to 4 (severe disability or finding).98 Etiology and Pathogenesis
Taranta and Stollerman established the casual relationship between infection with group A b-hemolytic streptococci and the occurrence of SC.99 Based on the assumption of molecular mimicry between streptococcal and central nervous system antigens, it has been proposed that the bacterial infection in genetically predisposed subjects leads to formation of cross-reactive antibodies that disrupt the basal ganglia function. Several studies have demonstrated the presence of such circulating antibodies in 50% to 90% of patients with Sydenham chorea.100,101 A specific epitope of streptococcal M proteins that cross-reacts with basal ganglia has been identified.102 In one study, all patients with active SC had antibasal ganglia antibodies demonstrated by ELISA and Western blot. In subjects with persistent SC (duration
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of disease greater than 2 years despite best medical treatment), positivity was about 60%.103 Recently, neuronal tubulin was found to be the target of antineuronal antibodies.104 The biologic value of the antibasal ganglia antibodies remains to be determined. One study suggests that they may interfere with neuronal function, however. Kirvan and colleagues105 demonstrated that IgM of 1 patient with Sydenham chorea induced expression of calcium-dependent calmodulin in a culture of neuroblastoma cells. Our finding that there is a linear correlation between the increase in intracellular calcium levels in PC12 cells and antibasal ganglia antibody titer in the serum from SC patients further strengthens the hypothesis that these antibodies have a pathogenic value.106 Although some investigations suggest that susceptibility to rheumatic chorea is linked to human leukocyte antigen-linked antigen expression,107 some studies have failed to identify any relationship between SC and human leukocyte antigen class I and II alleles.108 However, an investigation has shown that there is an association between HLA-DRB1*07 and recurrent streptococcal pharyngitis and rheumatic heart disease.109 The genetic marker for ARF and related conditions would be the B-cell alloantigen D8/17.110 Despite repeated reports of the group who developed the assay claiming its high specificity and sensitivity,111,112 findings of other investigators suggest that the D8/17 marker lacks specificity and sensitivity.1 Another suggested genetic risk factor for development of ARF but not SC are polymorphisms within the promoter region of the tumor necrosis factor-a gene.113 Because of the difficulties with the molecular mimicry hypothesis in accounting for the pathogenesis of SC, some studies have addressed the role of immune cellular mechanisms in this condition. Investigating sera and cerebrospinal fluid (CSF) samples from patients of the Movement Disorders of the Federal University of Minas Gerais, Church and colleagues114 found elevation of cytokines that take part in the Th2 (antibody-mediated) response, interleukins 4 (IL-4) and 10 (IL-10), in the serum of patients with acute SC in comparison with persistent SC. They also described interleukin 4 in the CSF of 31% of patients with acute SC, whereas just interleukin 4 was raised in the CSF of patients with persistent SC. The investigators concluded that SC is characterized by a Th2 response. However, as they have found elevated levels of interleukin 12 in patients with acute SC and, more recently, Teixeira and colleagues described an increased concentration of chemokines CXCL9 and CXCL10 in the serum of patients with acute SC,115 it can be concluded that Th1 (cell-mediated) mechanisms may also be involved in the pathogenesis of this disorder. Currently, the evidence suggests that the pathogenesis of SC is related to circulating cross-reactive antibodies. Streptococcus-induced antibodies have been shown to be associated with a form of acute disseminated encephalomyelitis characterized by a high frequency of dystonia and other movement disorders as well as basal ganglia lesions on neuroimaging.116 Antineural and antinuclear antibodies have also been found in patients with TS but their relationship with prior streptococcus infection remains equivocal.117 Management
In the past, physicians emphasized the need for bed rest for the treatment of SC. Currently there is no place for this measure. Because SC results from autoimmune, and not direct bacterial attack against the CNS, quarantine to prevent contamination of others is usually unnecessary.118 The first aim of the treatment of SC is to provide control of the chorea and behavioral problems often associated with this condition. Regardless of the choice of agent for symptomatic control, the physician should attempt a gradual decrease in the dosage
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of the medication (25% reduction every 2 weeks) after the patient remains free of the symptom for at least 1 month. In some patients symptoms are so mild that they do not cause meaningful disability. In these cases, it is possible to avoid any pharmacologic intervention, because spontaneous remission of SC is the rule.97,119 The second aim is prophylaxis of new bouts of ARF. Although it remains unproved whether prophylaxis of streptococcus infection prevents recurrences of SC,120 clearly it decreases the development of new cardiac lesions, which are the source of the most important disability in rheumatic fever. There are no controlled studies of symptomatic treatment of SC and all the recommendations mentioned are off-label use of the cited drugs.118 The first choice is valproic acid at an initial dosage of 250 mg/d that is increased over a 2-week period to 250 mg 3 times a day. If the response is not satisfactory, dosage can be increased gradually up to 1500 mg/d. As this drug has a slow onset of action, a period of 2 weeks should elapse before concluding that the regimen is ineffective. Valproic acid is usually well tolerated although some patients may develop dyspepsia and diarrhea at the beginning of the treatment. Chronic exposure may be associated with action tremor of the hands and, more rarely, liver toxicity. An open-label study demonstrated that carbamazepine (15 mg/kg/d) is as effective as valproic acid (20–25 mg/kg/d) to induce remission of chorea.121 If the patient fails to respond to valproic acid, or, as first line treatment in patients who present with chorea paralytica, the next option is to prescribe neuroleptics. Risperidone, a potent dopamine D2 receptor blocker, is usually effective in controlling the chorea. The initial regimen is usually 1 mg twice a day. If, 2 weeks later, the chorea is still troublesome, the dosage can be increased to 2 mg twice a day. Haloperidol and pimozide are also occasionally used in the management of chorea in SC. However, they are less well tolerated than risperidone. Dopamine D2 receptor blockers must be used with great caution in patients with SC. After observation of development of parkinsonism, dystonia, or both in patients treated with neuroleptics, we performed a case–control study comparing the response to these drugs in patients with SC and TS. Five percent of 100 patients with chorea developed extrapyramidal complications, whereas these findings were not seen among patients with tics matched for age and dosage of neuroleptics.121 Other potential side effects of these agents are sedation, depression, and tardive dyskinesia. There are no published guidelines concerning the discontinuation of antichoreic agents. Our policy is to attempt a gradual decrease of the dosage (25% reduction every 2 weeks) after the patient remains at least free of chorea for 1 month. Finally, the most important measure in the treatment of patients with SC is secondary prophylaxis. Because of the presumably autoimmune origin of SC, there have been attempts to treat patients with rheumatic chorea with corticosteroids. However, this is a controversial area. Despite mentions of effectiveness of prednisone in suppressing chorea, this drug is only used when there is associated severe carditis. We recently reported that methylprednisolone 25 mg/kg/d in children and 1 g/d in adults for 5 days followed by prednisone 1 mg/kg/d is an effective and well-tolerated treatment regimen for patients with SC refractory to conventional treatment with antichoreic drugs and penicillin.98,122 At least one other group has replicated our findings of a good response to steroids in selected patients with SC.123 In one of the few randomized controlled trials in SC, the investigators compared oral prednisone (2 mg/kg/d) and placebo in a double-blind fashion. Simultaneous use of haloperidol was allowed. They concluded that steroid accelerates the recovery but the rate of remission and recurrence is similar in both groups.124 However, this study has some limitations: haloperidol use was not controlled in both groups; it remains uncertain whether the development of side
Choreas
effects such as weight gain and moon face in the steroid group could have potentially compromised the blinding of the study (this is of particular concern considering the high dosage of prednisone); the investigators used a nonvalidated scale to rate the severity of chorea. The current recommendation is to reserve steroids for patients with persistent disabling chorea refractory to antichoreic agents or those who develop unacceptable side effects with other agents. Finally, one open, controlled study of a small number of patients reported that plasma exchange or intravenous immunoglobulin are as effective as oral prednisone to control the severity of chorea in SC.125 Surprisingly, the investigators report the lack of side effects in all groups. Because of the lack of additional studies to confirm the safety and effectiveness of these treatments, their high cost and existence of alternative efficacious therapeutic options, plasmapheresis and immunoglobulin are presently considered as investigational, and do not have a place in routine medical practice. OTHER AUTOIMMUNE CHOREAS
Other immunologic causes of chorea are systemic lupus erythematosus (SLE), primary antiphospholipid antibody syndrome (PAPS), vasculitis, and paraneoplastic syndromes. SLE or PAPS are classically described as the prototypes of autoimmune choreas.126 However, several reports show that chorea is seen in no more than 1% to 2% of large series of patients with these conditions.127,128 Autoimmune chorea has rarely been reported in the context of paraneoplastic syndromes associated with CV2/CRMP5 antibodies in patients with small-cell lung carcinoma or malignant thymoma.129 As these disorders are rare, chorea caused by them is uncommon. Chorea associated with SLE or PAPS has been treated with immunosuppressive measures, especially intravenous methylprednisolone following a dosage regimen as described for SC, and intravenous immunoglobulin.130 As it is accepted that neurologic complications, including chorea, in PAPS are related to ischemic events, antiplatelet agents and even anticoagulants are often prescribed to treat chorea in this condition.131 However, these recommendations are based on reports of openlabel studies involving small numbers of patients and the clinical experience of the physicians.1 VASCULAR CHOREAS
A study in a tertiary referral center showed that cerebrovascular disease was the most common cause of nongenetic chorea, accounting for 21 out of 42 cases.3 Conversely, chorea is an unusual complication of acute vascular lesions, seen in less than 1% of patients with acute stroke. Vascular hemichorea, or hemiballism, is usually related to ischemic or hemorrhagic lesions of the basal ganglia and adjacent white matter in the territory of the middle or the posterior cerebral artery. In contrast to the classic textbook concepts of hemiballism, most patients with vascular chorea have lesions outside the subthalamus.132 Although spontaneous remission is the rule, treatment with antichoreic drugs such as neuroleptics or dopamine depletors may be necessary in the acute phase. In a few patients with vascular chorea, the movement disorder may persist. These patients can be treated effectively with stereotactic surgery such as thalamotomy or posteroventral pallidotomy.133,134 An uncommon cause of chorea is Moyamoya disease, an intracranial vasculopathy that presents with an ischemic lesion or, less commonly, hemorrhagic stroke of the basal ganglia.135 Another rare form of vascular chorea is ‘‘postpump chorea,’’ a complication of extracorporeal circulation. The pathogenesis of this movement disorder is believed to be related to vascular insult of the basal ganglia during the
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surgical procedure. The current evidence supports the notion that the long-term prognosis of PC is poor. In 1 series of 8 patients, for example, 5 subjects had persistent chorea and 1 of them died. In another study, there was a clear distinction between those 8 patients with onset at earlier age (median 4.3 months), all of whom recovered fully, and 11 others, who were older at onset (median age 16.8 months). Among the latter, 4 died and only 1 of the survivors made a complete neurologic recovery.136 SUMMARY
Huntington disease (HD), an autosomal dominant degenerative disease, is the most common genetic cause of chorea. HD, a relentlessly progressive illness, is characterized by a combination of movement disorder, cognitive decline, and behavioral abnormalities. There is no treatment capable of stopping its progression. The most common conditions that mimic HD are neuroacanthocytosis, SCA17, Huntington disease-like syndrome 2, familial prion disease, and Friedreich ataxia. Sydenham chorea (SC) is the most common cause of chorea in children worldwide. Patients with SC present with a variable combination of chorea, obsessive-compulsive behavior, other behavioral abnormalities, and carditis. Management of SC involves prophylaxis of Streptococcus infections with penicillin and antichoreic agents. Stroke is the most common sporadic cause of chorea in adults. Vascular chorea, usually a complication of diabetes mellitus, is often a self-limited condition. REFERENCES
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75. Mercadante MT, Campos MC, Marques-Dias MJ, et al. Vocal tics in Sydenham’s chorea. J Am Acad Child Adolesc Psychiatry 1997;36:305–6. 76. Jankovic J. Differential diagnosis and etiology of tics. Adv Neurol 2001;85: 15–29. 77. Teixeira AL Jr, Cardoso F, Maia DP, et al. Frequency and significance of vocalizations in Sydenham’s chorea. Parkinsonism Relat Disord 2009;15:62–3. 78. Cunningham MC, Maia DP, Teixeira AL Jr, et al. Sydenham’s chorea is associated with decreased verbal fluency. Parkinsonism Relat Disord 2006;12(3): 165–7. 79. Cardoso F, Beato R, Siqueira CF, et al. Neuropsychological performance and brain SPECT imaging in adult patients with Sydenham’s chorea. Neurology 2005;64(Suppl 1):A76. 80. Cardoso F, Oliveira PM, Reis CC, et al. Prosody in Sydenham chorea – I: Tessitura. Mov Disord 2006;21:S359–60. 81. Cardoso F, Oliveira PM, Reis CC, et al. Prosody in Sydenham chorea – II: duration of statements. Mov Disord 2006;21:S360. 82. Azevedo LL, Cardoso F, Reis C. Acoustic analysis of prosody in females with Parkinson’s disease: comparison with normal controls. Arq Neuropsiquiatr 2003;61:999–1003. 83. Teixeira AL Jr, Meira FC, Maia DP, et al. Migraine headache in patients with Sydenham’s chorea. Cephalalgia 2005;25(7):542–4. 84. Kwack C, Vuong KD, Jankovic J. Migraine headache in patients with Tourette syndrome. Arch Neurol 2003;60:1595–8. 85. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1988;155:264–71. 86. Asbahr FR, Negrao AB, Gentil V, et al. Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: a prospective 6-month study. Am J Psychiatry 1998;155:1122–4. 87. Mercadante MT, Busatto GF, Lombroso PJ, et al. The psychiatric symptoms of rheumatic fever. Am J Psychiatry 2000;157:2036–8. 88. Maia DP, Teixeira AL Jr, Quintao Cunningham MC, et al. Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in Sydenham chorea. Neurology 2005;64(10):1799–801. 89. Asbahr FR, Garvey MA, Snider LA, et al. Obsessive-compulsive symptoms among patients with Sydenham chorea. Biol Psychiatry 2005;57:1073–6. 90. Hounie AG, Pauls DL, do Rosario-Campos MC, et al. Obsessive-compulsive spectrum disorders and rheumatic fever: a family study. Biol Psychiatry 2007; 61:266–72. 91. Kummer A, Maia DP, Cardoso F, et al. Trichotillomania in acute Sydenham’s chorea. Aust NZ J Psychiatry 2007;41:1013–4. 92. Teixeira AL Jr, Maia DP, Cardoso F. Psychosis following acute Sydenham’s chorea. Eur Child Adolesc Psychiatry 2007;16(1):67–9. 93. Cardoso F, Dornas L, Cunningham M, et al. Nerve conduction study in Sydenham’s chorea. Mov Disord 2005;20:360–3. 94. Vijayalakshmi IB, Mithravinda J, Deva AN. The role of echocardiography in diagnosing carditis in the setting of acute rheumatic fever. Cardiol Young 2005;15: 583–8. 95. Panamonta M, Chaikitpinyo A, Auvichayapat N, et al. Evolution of valve damage in Sydenham’s chorea during recurrence of rheumatic fever. Int J Cardiol 2007; 119(1):73–9.
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96. Guidelines for diagnosis of rheumatic fever. Jones criteria, 1992 update. Special Writing Group of the Committee of Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardio-Vascular Disease of the Young of the American Heart Association. Guidelines for the diagnosis of rheumatic fever. JAMA 1992; 268:2069–73. 97. Cardoso F, Vargas AP, Oliveira LD, et al. Persistent Sydenham’s chorea. Mov Disord 1999;14:805–7. 98. Teixeira AL Jr, Maia DP, Cardoso F. UFMG Sydenham’s chorea rating scale (USCRS): reliability and consistency. Mov Disord 2005b;20(5):585–91. 99. Taranta A, Stollerman GH. The relationship of Sydenham’s chorea to infection with group A streptococci. Am J Med 1956;20:170–5. 100. Husby G, Van De Rijn U, Zabriskie JB, et al. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 1976;144:1094–110. 101. Cardoso F. Chorea gravidarum. Arch Neurol 2002;59(5):868–70. 102. Bronze MS, Dale JB. Epitopes of streptococcal M proteins that evoke antibodies that cross-react with human brain. J Immunol 1993;151:2820–8. 103. Church AJ, Cardoso F, Dale RC, et al. Anti-basal ganglia antibodies in acute and persistent Sydenham’s chorea. Neurology 2002;59:227–31. 104. Kirvan CA, Cox CJ, Swedo SE, et al. Tubulin is a neuronal target of autoantibodies in Sydenham’s chorea. J Immunol 2007;178(11):7412–21. 105. Kirvan CA, Swedo SE, Heuser JS, et al. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med 2003;9(7):914–20. 106. Teixeira AL Jr, Guimaraes MM, Romano-Silva MA, et al. Serum from Sydenham’s chorea patients modifies intracellular calcium levels in PC12 cells by a complement-independent mechanism. Mov Disord 2005a;20(7):843–5. 107. Ayoub EM, Barrett DJ, Maclaren NK, et al. Association of class II human histocompatibility leukocyte antigens with rheumatic fever. J Clin Invest 1986;77: 2019–26. 108. Donadi EA, Smith AG, Louzada-Junior P, et al. HLA class I and class II profiles of patients presenting with Sydenham’s chorea. J Neurol 2000;247:122–8. 109. Haydardedeoglu FE, Tutkak H, Kose K, et al. Genetic susceptibility to rheumatic heart disease and streptococcal pharyngitis: association with HLA-DR alleles. Tissue Antigens 2006;68:293–6. 110. Feldman BM, Zabriskie JB, Silverman ED, et al. Diagnostic use of B-cell alloantigen D8/17 in rheumatic chorea. J Pediatr 1993;123:84–6. 111. Eisen JL, Leonard HL, Swedo SE, et al. The use of antibody D8/17 to identify B cells in adults with obsessive-compulsive disorder. Psychiatry Res 2001;104: 221–5. 112. Harel L, Zeharia A, Kodman Y, et al. Presence of the d8/17 B-cell marker in children with rheumatic fever in Israel. Clin Genet 2002;61:293–8. 113. Ramasawmy R, Fae KC, Spina G, et al. Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever. Mol Immunol 2007;44:1873–8. 114. Church AJ, Dale RC, Cardoso F, et al. CSF and serum immune parameters in Sydenham’s chorea: evidence of an autoimmune syndrome? J Neuroimmunol 2003;136(1–2):149–53. 115. Teixeira AL Jr, Cardoso F, Souza AL, et al. Increased serum concentrations of monokine induced by interferon-gamma/CXCL9 and interferon-gamma-inducible protein 10/CXCL-10 in Sydenham’s chorea patients. J Neuroimmunol 2004;150(1–2):157–62.
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116. Dale RC, Church AJ, Cardoso F, et al. Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies. Ann Neurol 2001;50:588–95. 117. Morshed SA, Parveen S, Leckman JF, et al. Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders. Biol Psychiatry 2001;50:566–77. 118. Cardoso F. Sydenham’s chorea. Curr Treat Options Neurol 2008;10:230–5. 119. Tumas V, Caldas CT, Santos AC, et al. Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic. Parkinsonism Relat Disord 2007; 13(5):276–83. 120. Korn-Lubetzki I, Brand A, Steiner I. Recurrence of Sydenham chorea: implications for pathogenesis. Arch Neurol 2004;61:1261–4. 121. Teixeira AL, Cardoso F, Maia DP, et al. Sydenham’s chorea may be a risk factor for drug induced parkinsonism. J Neurol Neurosurg Psychiatry 2003;74(9): 1350–1. 122. Cardoso F, Maia D, Cunningham MC, et al. Treatment of Sydenham chorea with corticosteroids. Mov Disord 2003;18:1374–7. 123. Barash J, Margalith D, Matitiau A. Corticosteroid treatment in patients with Sydenham’s chorea. Pediatr Neurol 2005;32:205–7. 124. Paz JA, Silva CA, Marques-Dias MJ. Randomized double-blind study with prednisone in Sydenham’s chorea. Pediatr Neurol 2006;34:264–9. 125. Garvey MA, Snider LA, Leitman SF, et al. Treatment of Sydenham’s chorea with intravenous immunoglobulin, plasma exchange, or prednisone. J Child Neurol 2005;20:424–9. 126. Quinn N, Schrag A. Huntington’s disease and other choreas. J Neurol 1998;245: 709–16. 127. Asherson RA, Cervera R. The antiphospholipid syndrome: multiple faces beyond the classical presentation. Autoimmun Rev 2003;2(3):140–51. 128. Avcin T, Benseler SM, Tyrrell PN, et al. A followup study of antiphospholipid antibodies and associated neuropsychiatric manifestations in 137 children with systemic lupus erythematosus. Arthritis Rheum 2008;59(2):206–13. 129. Honnorat J, Cartalat-Carel S, Ricard D, et al. Onco-neural antibodies and tumor type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 2009;80(4):412–6. 130. Lazurova I, Macejova Z, Benhatchi K, et al. Efficacy of intravenous immunoglobulin treatment in lupus erythematosus chorea. Clin Rheumatol 2007;26(12):2145–7. 131. Levine SR, Brey RL. Neurological aspects of antiphospholipid antibody syndrome. Lupus 1996;5:347–53. 132. Ghika-Schmid F, Ghika J, Regli F, et al. Hyperkinetic movement disorders during and after acute stroke: the Lausanne Stroke Registry. J Neurol Sci 1997;146:109–16. 133. Cardoso F, Jankovic J, Grossman RG, et al. Outcome after stereotactic thalamotomy for dystonia and hemiballismus. Neurosurgery 1995;36:501–7. 134. Choi SJ, Lee SW, Kim MC, et al. Posteroventral pallidotomy in medically intractable postapoplectic monochorea: case report. Surg Neurol 2003;59:486–90. 135. Gonzalez-Alegre P, Ammache Z, Davis PH, et al. Moyamoya-induced paroxysmal dyskinesia. Mov Disord 2003;18:1051–6. 136. Medlock MD, Cruse RS, Winek SJ, et al. A 10-year experience with postpump chorea. Ann Neurol 1993;34:820–6.
Touret te Syndrome Joohi Jimenez-Shahed, MDa,b,* KEYWORDS Tourette syndrome Tics Pathophysiology Management Co-morbidities
The major features of what is now known as Tourette syndrome (TS) were first published in 1885 by Georges Gilles de la Tourette.1 His name was later ascribed to the condition by his mentor, Jean-Martin Charcot, who had asked him to study and describe the affliction in a series of 9 patients at the Saltpeˆtrie`re Hospital in France. Long considered a rare, bizarre, and psychogenic condition, the organic and neurobiologic basis for TS remains to be fully elucidated to this day. However, the prevailing opinion on TS is that it is a common neuropsychiatric disorder with probable genetic and neurodevelopmental underpinnings. Obstacles to defining the true epidemiology of TS include the lack of early diagnostic criteria, lack of a diagnostic test, fluctuations in symptoms, variability of comorbidities, differences in study methodology and case ascertainment, and regional or ethnic differences in identification of those with tic disorders.2 However, based on a review of the existing literature and personal communications, Robertson3 has concluded that TS is largely present across all cultures worldwide, with fairly uniform phenomenology, and with similar prevalence figures of 0.4% to 3.8% reported in children aged 5 to 18 years. An overall international prevalence figure of 1% is proposed, although rates seem to be much lower in sub-Saharan Africa and African Americans. Males are approximately 5 times as likely to be affected with TS.4
PHENOMENOLOGY AND DIAGNOSIS OF TIC DISORDERS
Tics are defined as involuntary or semivoluntary, sudden, intermittent, repetitive movements (motor tics) or sounds (phonic tics).5 Simple motor tics are brief and meaningless motions that often last less than 1 second, typically involve 1 group of muscles, are generally easily camouflaged as normal movements and are not noticed by others.6 Examples include eye blinking, facial grimacing, mouth movements, shoulder shrugs, head jerks, and arm or leg jerks. Such tics can be further
a
Department of Neurology, Plummer Movement Disorders Center, Scott & White Healthcare, 2401 South 31st Street, Temple, TX 76508, USA b Department of Internal Medicine, Texas A & M Health Sciences Center, 1 Chisholm Trail Road, Suite 400, Round Rock, TX 78681, USA * Corresponding author. E-mail address:
[email protected] Neurol Clin 27 (2009) 737–755 doi:10.1016/j.ncl.2009.04.011 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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classified as tonic (isometric contractions), clonic (abrupt in onset and rapid), or dystonic (slightly slower movements that cause a brief abnormal posture). Complex motor tics, on the other hand, are slower, longer, and more purposeful movements that may resemble normal motions or gestures, but could be more intense or occur in an inappropriate context.6 They often involve multiple muscle groups, may occur in orchestrated bouts or sequences lasting several seconds, and generally call attention to the individual engaging in them. Echopraxia (in which a person mimics the gestures of others), copropraxia (the production of obscene gestures), and self-injurious behaviors are examples of complex motor tics. Simple phonic tics are brief and meaningless vocalizations that often consist of a single sound.6 Examples include sniffing, coughing, throat clearing, grunting, barking, squeaking or squealing, hissing, or animal noises, although some of these may be better described as motor tics that cause a sound to be produced. Complex phonic tics are more purposeful utterances that are more forceful or intense than natural vocalizations, and can include syllables, words, phrases, or abnormal speech patterns (eg, changes in rate, volume, or rhythm).6 They generally occur in an inappropriate context and call attention to the individual. Echolalia (echoing sounds or words heard elsewhere), pallilalia (repetition of one’s own or another person’s phrases or sentences), and coprolalia (obscene words or phrases) are all examples of complex phonic tics. In general, tics are suppressible, but this is often associated with an ‘‘inner tension,’’ which drives further tic activity.6 Tics are often preceded by a premonitory sense or urge, which is subsequently relieved by performing the tic. They will often worsen in periods of stress, anxiety, fatigue, or excitement, and abate with distraction or with intense focus on an activity. Periods of relaxation may paradoxically be associated with either an increase (‘‘releasing’’ after prolonged suppression, eg, after a child returns home from school) or decrease in tic activity (after a period of excitement, eg, resting on the sofa after playing a video game). Tics may be performed repetitively until a ‘‘just right’’ feeling occurs,7 likening them to compulsive acts. Finally, positive or negative reinforcement of tic activities (eg, by parents or caregivers) can also increase tic activity, whereas reinforcement for tic-free intervals reduces tic frequency.8 Ultimately, tics wax and wane in intensity, frequency, distribution, and number over seconds, hours, days, weeks, or even months,9 thus contributing to difficulty differentiating TS from other tic conditions. Tics are recognized on clinical grounds and can be classified into 1 of several different diagnostic entities according to 2 major schema: the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),10 or the Tourette Syndrome Classification Study Group (TSSG).11 In the DSM-IV, the major differentiating features between diagnoses of Tourette syndrome, chronic motor or vocal tic disorder, transient tic disorder, or tic disorder not otherwise specified concern total duration of time during which tics have been observed, and whether motor or phonic tics are present (Table 1). Epidemiologic data suggest that chronic and transient tic disorders are much more common than TS (Table 1).12 The TSSG criteria differ from the DSM-IV criteria with regard to age at onset (before 21 years versus 18 years), total duration of symptoms, and the need for direct observation of tics by the examiner (in person or by videotape examination), or an acceptable description of tic activity by a reliable witness. These diagnostic variables may contribute to a delay in designation of actual TS cases, or lead first to consultation from multiple practitioners (eg, ear-nose-throat specialists, allergists, or ophthalmologists).13
Tourette Syndrome
Table 1 DSM-IV classification of tic disorders Tic Disorder not Otherwise Specified
Tourette Syndrome
Chronic Motor or Vocal Tic Disorder
Transient Tic Disorder
Tics
Multiple motor and at least 1 phonic
Single or multiple motor or phonic
Single or multiple motor or phonic
Motor or phonic
Duration of illness
1 year
1 year
At least 4 weeks, no more than 12 months
Do not meet any criteria listed for other tic disorders
Tic-free interval
No more than 3 months
No more than 3 months
n/a
n/a
Age at onset
Before 18 years
Before 18 years
Before 18 years
n/a
Prevalence
1% worldwide3
2%–5%12
3%–15%12
Unknown
Abbreviation: n/a, not applicable. Data from Diagnostic and statistical manual of mental disorders, 4th edition. DSM-IV. Washington, DC: American Psychiatric Association; 1994 p. 100–5.
SPECTRUM OF COMORBIDITIES IN TS
Although the hallmark of TS is the presence of motor and vocal tics, the clinical spectrum encompasses a variety of psychiatric comorbidities.5 Comorbidities are present in at least 50% of cases; the most common is attention deficit disorder (with or without hyperactivity, AD/HD) and obsessive-compulsive disorder (OCD).14 AD/HD is generally accepted to occur in 40% to 70% of TS cases and the average age at onset is 4 years, whereas OCD is usually is reported in 20% to 60% of cases and the average age at onset is 7 years.14 Tics will generally manifest somewhere in time between the onset of these 2 comorbidities, with motor tics presenting in a rostral-caudal fashion of bodily involvement, and phonic tics progressing from simple to complex phenomenology.5 Other comorbidities may also be apparent, such as phobias, anxiety, oppositional defiant disorder, and other mood disorders.14 Non-tic features may be the predominant feature or the greatest source of disability in many cases, and any child presenting with such complaints should be carefully questioned about the presence of coexistent tic behaviors. A detailed history of potential comorbidities should be undertaken in children presenting with tics, as their presence may indicate a diagnosis of TS. The presence of AD/HD is a common cause of academic, social, and behavioral dysfunction in children with or without TS. AD/HD is a source of impaired executive functioning, which involves the development and implementation of an approach to a task that is not habitually performed, and the use of self-regulation to select and sustain actions and guide behaviors.15 Characteristics of executive dysfunction include poor impulse control, mental inflexibility, emotional dysregulation, and difficulties with independent task initiation, working memory, planning/organizing, and selfmonitoring. In cases of TS with comorbid AD/HD, executive and cognitive dysfunction is more likely to occur than in those without AD/HD.15–17 As a consequence, school performance may be impaired, with poor performance on homework or class projects due to careless errors or difficulties with initiating, planning, sequencing, and prioritizing assigned tasks.18 Furthermore, children with TS and comorbid AD/HD tend to experience high rates of psychopathology, including OCD, anxiety, conduct disorder/oppositional defiant disorder, and mood disorders.19 Such children are
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also significantly more likely to demonstrate anger control problems, sleep problems, social skills deficits, and sexually inappropriate behavior compared with TS cases without AD/HD.20 It is important to recognize this comorbidity, as its presence often leads to an earlier diagnosis of TS,20 thus allowing for earlier referral for appropriate supportive services. OCD in TS may be more appropriately termed ‘‘obsessive-compulsive behaviors’’ (OCBs),21 as many children have mild symptoms that would not meet DSM-IV criteria for OCD. Generally speaking, children with TS and OCBs are less likely to perform compulsive acts in response to an anxiety-provoking obsession. Rather, there are often clear sensory phenomena that precede repetitive acts in TS. Specifically, patients with TS and comorbid OCBs will more commonly experience bodily sensations (eg, tactile, muscular-skeletal/visceral), mental urges, a sense of inner tension, feelings of incompleteness, and a ‘‘just right’’ feeling before repetitive acts.22 The OCBs in TS are more likely to concern mental play, echophenomena, touching, and self-injurious behaviors.23 By contrast, compulsions in OCD without tics are more often characterized by aggressive repetitive thoughts, contamination worries and washing compulsions, symmetry, cleaning/ordering/arranging, or hoarding that are driven by anxiety or distress over a persistent idea, thought, or impulse.23,24 Robertson25 reviewed the literature on mood disorders in TS and found a reported prevalence of 13% to 76% for depression and depressive symptomatology. Depression is likely multifactorial in TS, relating to the disease process itself, overall severity of illness, presence of AD/HD and OCD (both are associated with depression), side effects of medications, number of comorbidities, and family history. Using direct psychiatric interviews and standardized rating scales in 1596 schoolage children from a community-based population, Kurlan and colleagues14 found that OCD, anxiety disorders (separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia), mood disorders (major depression, mania), and oppositional defiant disorder (ODD) occurred significantly more commonly amongst children with tics, and the frequency of many of these increased with greater tic severity (defined as Yale Global Tic Severity Scale, YGTSS, total tic score >20). Those specifically diagnosed with TS in this population had increased frequency of OCD, AD/HD, anxiety disorders, and ODD (but not mood disorders) compared with children not diagnosed with TS. Another study of 3006 school children using rating scales based on DSM-IV criteria that were completed by teachers26 found that, in general, children with AD/HD and tics had greater symptom severity scores for ODD, conduct disorder, and generalized anxiety than those with AD/HD only, tics only, or normal controls. Coffey and colleagues27 found that adult subjects with TS and OCD combined had higher rates of mood, anxiety, disruptive behavior, substance use, and OCD spectrum disorders (body dysmorphic disorder and trichotillomania) than subjects with either TS or OCD alone. Thus, it is apparent that comorbidities in TS are common and can influence each other, with the presence of one comorbidity increasing the likelihood and severity of others in the same patient. The exact combination of TS with comorbidities cannot be predicted in any individual or population, nor do the comorbidities follow any consistent pattern of occurrence. In one study seeking to define subphenotypes of TS based on comorbidities, 24% of 596 individuals with TS comprising a sib pair were found to have TS only, 32% had TS 1 OCD, 10% had TS 1 AD/HD, and 34% had TS 1 OCD 1 AD/HD.28 In addition, comorbidities such as AD/HD and OCD in TS may be a major source of disability and impairment on ratings of health-related quality of life, rather than the tics themselves.29 A study of 71 TS patients using questionnaires completed by parents found that the most significant predictor of
Tourette Syndrome
psychosocial quality of life was severity of AD/HD symptoms,29 suggesting that this comorbidity in particular should be vigorously targeted for intervention. Finally, the presence of comorbidities may also play a role in worsening primary TS symptoms. Cheung and colleagues30 found that ‘‘malignant TS’’ (defined as R2 emergency room visits or R1 hospital admission for TS-related symptoms) was associated with greater severity of motor symptoms and the presence of R2 behavioral comorbidities, especially OCBs. PATHOPHYSIOLOGY OF TICS AND TS
TS along with its typical comorbidities is postulated to be a neurodevelopmental disorder involving multiple neurotransmitter systems within cortical–basal ganglia– thalamo–cortical loops.31,32 Functional neuroimaging studies in TS, which examine changes in cerebral blood flow using a variety of techniques during normal tic activity, active tic suppression, and quiet resting, corroborate this; changes can be seen in the midbrain, striatum, and associated limbic and frontal cerebral cortical regions.33 Several morphometric studies have also suggested asymmetry or reduction in basal ganglia and frontal lobe structures in TS. Results from these studies are not consistent, likely due to methodologic and population differences.33 The differences in the way these studies control for comorbidities in TS may also impact their interpretation.34 After reviewing morphometric studies of patients with TS and comorbid AD/HD, Plessen and colleagues34 suggest that the frontostriatal volume reductions described in TS are core features of AD/HD and likely represent poor inhibitory control, whereas reduced caudate volumes with activation and hypertrophy of prefrontal regions (involved in tic suppression) are core features of TS alone. The investigators also found that coexistent AD/HD does not statistically affect the findings of basal ganglia volume differences in subjects with TS. Peterson and colleagues35 conducted the largest study to date (154 children and adults with TS without prior neuroleptic exposure and 130 healthy controls), and found that caudate nucleus volumes were significantly reduced amongst TS cases, and lenticular nucleus volumes were reduced in adults with TS and children with TS 1 OCD. These studies highlight that TS is not merely a tic disorder and that the systems involved underlie the pathophysiology of tics as well as other neuropsychiatric features. According to the theory proposed by Albin and Mink,31 tics may occur when a focus of inappropriate activity within distinct clusters of striatal matrisomes leads to aberrant inhibitory input to a specific set of globus pallidus interna (GPi) or substantia nigra pars reticulata (SNr) neurons. In turn, these GPi/SNr neuronal groups yield reduced inhibition to the thalamus, thereby releasing thalamocortical loops from tonic suppression and producing involuntary movements. The distinct, repetitive, predictable pattern of a tic is determined by which matrisomal clusters were originally activated; multiple tics would result from activation of multiple sets of matrisomes. There is evidence of somatotopy within the striatum to support this view,36 with discrete segregation of primary motor cortex (M1) and supplementary motor area (SMA) body maps, and within these, maintenance of a strict topographic organization. Parallel processing through striatopallidal and pallidothalamic pathways further supports preservation of a strict motor pattern and thus, the ‘‘stereotyped’’ pattern of tics. Finally, using diffusion tensor imaging, Makki and colleagues37 have shown that microstructural abnormalities exist in the striatum and thalami of children with TS compared with normal controls. In this study, TS patients demonstrated increased parallel diffusivity in the bilateral putamen, increased perpendicular diffusivity in the right thalamus, and reversed asymmetry of fractional anisotropy in the thalamus, with a significant positive
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correlation between perpendicular diffusivity in the right thalamus and tic severity. Although this study did not control for medication use, the investigators suggest that these white matter tract changes may represent alterations in the input and output from various components of the cortical–basal ganglia–thalamo–cortical loops. Causes of aberrant striatal activity could include decreased intrastriatal inhibition or abnormal dopaminergic neurotransmission.31 In a postmortem analysis of the brains of 3 patients with severe TS compared with those of age- and sex-matched normal controls, Kalanithi and colleagues38 found a statistically significant (40%–54%) reduction in parvalbumin-positive GABAergic interneurons in the striatum and a 129% increase in similar cells of the GPi. These striatal interneurons receive cortical input and inhibit adjacent medium spiny neurons, likely by increasing their firing threshold. A reduction in their number could lead to inappropriate firing of matrisomal clusters31 or their desynchrony,32 and hence production of tics. The GPi interneurons project into the thalamus, and exert inhibitory effects on the firing rate and intrinsic activity of the ventrolateral and intralaminar thalamic nuclei. The consequences of an increase in the number of these cells are less clear, but could include the generation of abnormal pallidal oscillations, with downstream thalamic effects.32 Frey and Albin 33 speculate that a migrational defect of the parvalbumin staining cells could underlie the pathophysiology of tics in TS. Recent evidence surrounding SLITRK1 mutations (discussed earlier) may support the notion of migrational defects underlying TS pathogenesis. Several radionuclide neuroimaging studies provide evidence of abnormal dopaminergic function as a cause for TS, demonstrating abnormalities of dopaminergic nerve terminals, although the exact mechanisms remain to be elucidated.39–44 A study by Yeh and colleagues44 demonstrated smaller declines of dopamine transporter binding in the right caudate of 8 drug-naive TS patients after administration of methylphenidate using [99mTc]TRODAT-1 SPECT imaging; Singer and colleagues43 found evidence of increased methylphenidate-induced putamenal dopaminergic release in 7 TS patients using [11C]raclopride positron emission tomography (PET). Both studies suggest abnormalities of phasic dopamine transporter function. By contrast, studies of postsynaptic dopaminergic function are equivocal,45–48 although methodological differences with regard to prior or active neuroleptic exposure impact on the interpretation of these results. Regardless, the phenomenology of TS closely parallels the age-dependent development of descending and ascending basal ganglia pathways, which in turn are mediated by serotonergic and dopaminergic projections to the striatum.49 In normally developing brains, striatal dopamine levels increase 2 to 3 times through adolescence, then decrease through adulthood, based on postmortem analyses.50 An abnormality of dopaminergic neurotransmission during this time period could therefore impact basal ganglia development, resulting in aberrant firing patterns, and producing signs and symptoms of TS that later improve as the balance is restored. A heritable component to TS has been recognized since its first description, and bilineal transmission of TS has been observed in several studies.51–53 The frequency of this increases when the phenotype is broadened to include common comorbidities. Walkup and colleagues54 performed a complex segregation analysis on 53 children with TS and 154 first-degree relatives, and suggested a major locus with a multifactorial background. The multifactorial background was proposed to account for 40% of the phenotypic variance of the disorder, with 100% of homozygotes, 2.2% of heterozygote men, and 0.3% of heterozygote women being affected. In this group of TS patients, 38% were considered homozygotes and 62% heterozygotes. A large genetic linkage study across the entire genome55 of 2040 individuals (238 nuclear families including 304 independent sib pairs and 18 multigenerational families) found evidence of linkage to a region of chromosome 2p.
Tourette Syndrome
Varied descriptions of chromosomal translocations and inversions in patients or families with symptoms of TS have also failed to yield a clear locus for TS. Despite this, recent interest has surrounded the report of a de novo 13q31.1 chromosomal inversion in a child with TS and no family history. Abelson and colleagues56 identified 3 genes within 500 kb of the 2 breakpoints of the inversion, and selected SLITRK1 (Slit and Trk-like 1) as a candidate TS gene for further study. In flies, Slit proteins regulate axonal guidance, cell migration, and axonal branching, and trk is a neurotrophin receptor.57 Both genes are specifically expressed in developing and mature neuronal tissues, and modulate neurite outgrowth in cultured neuronal cells. One frameshift mutation and 2 independent occurrences of an SLITRK1 variant in the binding site for microRNA were found in 174 unrelated TS probands that were not present in 3600 control chromosomes.56 Furthermore, the investigators found that expression of the SLITRK1 mRNA and the microRNA binding site occurred in brain areas implicated in TS. Subsequent analyses of SLITRK1 variants in large cohorts of unrelated TS patients or affected families have disputed the notion of a major pathogenic role for SLITRK1 in TS,58–62 although Miranda and colleagues63 did find evidence of association of a single polymorphism and haplotypes of 3 tagging polymorphisms in 154 affected nuclear families. More recently, Stillman and colleagues64 have shown that SLITRK1 has a developmentally regulated expression pattern in projection neurons of the corticostriatal–thalmaocrotical circuits, that it is transiently expressed in the striosomal compartment, and that it is associated with the direct output pathway of the basal ganglia. SLITRK1 may therefore contribute to the development of cortical–basal ganglia–thalamo–cortical circuits in normally maturing brains, and mutations could cause pathology in brain regions of interest in TS. Much more study is needed, but the results of these preliminary SLITRK1 investigations may encourage future research pertaining to neurodevelopmental gene candidates in TS.
CLINICAL COURSE AND PROGNOSIS
Tics in TS generally start between the ages of 3 to 8 years, and as mentioned earlier, develop craniocaudally with simple tics followed later by more complex tics, and still later by vocal tics.5,65 In a 1975 birth cohort of TS patients, Leckman and colleagues66 found that mean age at tic onset was 5.6 (SD 2.3) years, the worst-ever period of tic activity was generally observed around age 10 years (SD 2.4), and that tics increased in severity and frequency over time. In 22% of patients, the tics were severe enough to jeopardize school functioning. Social and educational dysfunction in children with TS may include placement into special education classes, being held back 1 year in school, or disciplinary problems in the school or community.67 Nearly 50% of 42 individuals with TS in this cohort66 were tic-free by the age of 18 years, although estimates vary across other studies.68–70 Estimates based on self-reports may be biased, however, as up to 50% of patients claiming to be tic-free actually still had tics by videotape analysis.67 One author has proposed a ‘‘rule of thirds’’ when discussing TS outcomes with patients and families: tics remit in one third by adolescence, get better in one third, and continue to worsen in one third.69 In adulthood, 1 study found that 22% of patients experience mild or greater tics.70 In another group of adults with childhood-onset TS, 24% had moderate/severe tics.71 Thirty-two percent of adults with childhood-onset TS continued to have significant social, occupational, or educational dysfunction.67 Despite this, nearly all children with TS graduate from high school and the majority will achieve higher education or
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gainful employment.67,71 For reasons that are not well understood, some patients experiencing initial remission of tics will develop recurrent symptoms later in life.72 Predictors of tic severity are also not well understood. Bloch and colleagues70 found that a child with a YGTSS R20 (marked severity range) was 2.8-fold more likely to have marked to severe tics in adulthood compared with a child with tics of only modest severity (YGTSS 10–20). Symptoms of AD/HD were not associated with tic severity in this study. In another report,73 the same investigators found that poor performance with the dominant hand on the Purdue Pegboard test predicted worse adulthood tic severity, and combined poor performance of tests of visuomotor integration and the pegboard (dominant or nondominant hand) also predicted worse global psychosocial functioning in adulthood. Childhood caudate volumes have also been found to correlate significantly and inversely with severity of tics and OCD in early adulthood.74 OCD symptom severity peaks about 2 years after worst-ever tic activity,70 but does not relate to tic or AD/HD severity. Rather, for every 10-point increase in childhood intelligent quotient (IQ), subjects were 2.8-fold more likely to express OCD symptoms at follow-up. OCD severity was found to be likely to worsen with time. Thus, children with TS may be more likely to suffer continued difficulties with psychiatric comorbidities rather than tics as they get older. MANAGEMENT OF TS AND COMORBIDITIES IN CHILDHOOD
In addition to achieving adequate symptom control, treatment goals for TS and its related comorbidities should include improvement of social functioning, self-esteem, and quality of life.18 Patients and families should be counseled that complete control of symptoms is often not achieved. Recognition and treatment of comorbidities is crucial, as the presence of each of these can impact the other. Management strategies for tics in TS can range from psychosocial interventions and therapy to use of pharmacologic agents, and beyond to more aggressive therapies such as botulinum toxin injections or neurosurgery.18 Psychosocial interventions may include reassurance and environmental modifications (eg, at school), education of family, teachers, classmates, and other school personnel, identification and minimization of external triggers, and cognitive behavioral therapy (CBT). Successful CBT methods described for TS consist of awareness training, assertiveness training, cognitive therapy, relaxation therapy, or habit reversal therapy,75,76 and can be used alone or as valuable adjuncts to pharmacologic interventions in appropriate patients. Alpha2-adrenergic agonists such as clonidine and guanfacine are good first-line pharmacologic agents for treatment of tics, especially if they are mild.77–79 The use of clonidine may further result in improved anxiety, insomnia, hyperactivity, and impulsivity in TS patients with comorbid AD/HD,80 but guanfacine may be better tolerated.79 Dopamine receptor blocking drugs (DRBDs) remain the most efficacious treatment for tics in TS;81 only haloperidol and pimozide have been approved by the US Food and Drug Administration (FDA) for this indication.82–84 Fluphenazine has better safety and tolerability, but controlled studies are lacking.85,86 Atypical agents, including risperidone,78,87–89 olanzapine,90,91 and ziprasidone.92 have also been reported to be beneficial for tic management in TS in placebo-controlled trials. Ariprazole shows promise in several open-label reports,93–96 but no randomized controlled trials are currently reported. Unfortunately, potential side effects abound with typical and atypical DRBDs, including increased appetite and weight gain, sedation, acute dystonic reactions, akathesia, parkinsonism, hyperlipidemia, hyperglycemia, hyperprolactinemia, electrocardiographic changes, and tardive dyskinesia (TD).97 The risk of TD in children
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and adolescents is low, estimated at 5.9% in 1 study,98 but is significantly higher in adults,99 warranting incorporation into routine counseling to patients and families about TS treatment options. Definitive non-DRBD options for tic management are limited due to lack of sufficient evidence, but are important to consider in view of their more favorable side-effect profile, especially in adult patients. Topiramate is an antiepileptic drug that can potentiate inhibitory neurotransmission of g-aminobutyric acid (GABA), thus reducing abnormal neuronal firing or balancing GABAergic and glutamatergic signals within the basal ganglia.100 Case reports have described its positive effects on tics in TS,101 and an open-label retrospective chart review of TS patients treated with topiramate for tics has found moderate efficacy in 75% of treated patients, either in monotherapy or as adjunct to other agents.102 In this series of 41 patients (mean age 14.83 5.63 years, range 9–27 years), treatment was observed for 9.43 7.03 months at mean dosages of 146.34 113.68 mg/d (range 50–600 mg/d). A randomized placebo-controlled trial of topiramate in 20 TS patients has recently concluded, with statistically significant improvements in tics as rated by the YGTSS total tic score (14.29 10.47 points in treated patients versus 5.00 9.88 points during placebo treatment).103 The mean dosage was 118 mg/d. There are limited data on other agents with the potential to improve tics in TS. Tetrabenazine is a monoamine-depleting medicine that had recently been approved by the FDA for management of chorea in Huntington disease. Its use in TS has been described,104 and it has particular advantages over DRBDs in that it carries no known risk of TD and is generally weight neutral.105 Amongst the more common potential side effects are sedation, parkinsonism, and depression. Cannabinoid receptors are widespread throughout the output nuclei of the basal ganglia, and agonists may increase GABAergic transmission and alter glutamate release and dopamine uptake.106 A single, randomized crossover trial demonstrated that delta-9-tetrahydrocannabinol can significantly reduce tics on some rating scales without adverse effects on neuropsychological performance.107 Although their use in TS may be counterintuitive, dopamine agonists at low doses may stimulate presynaptic autoreceptors, which then decrease dopamine release, thereby possibly improving tics. In 2 randomized, double-blind trials,108,109 pergolide was shown to significantly reduce YGTSS scores. In an 8-week open-label study of 15 patients, treatment with ropinirole 0.25 to 0.5 mg twice a day resulted in a gradual but significant improvement in tic frequency, severity, and global impression of severity by week 4, with further improvements noted from weeks 4 to 8.110 A multicenter, randomized, placebo-controlled trial of pramipexole for tics in TS is currently underway. The use of botulinum toxin type A injections in the treatment of focal problematic tics has also been described, with effects attributed to reductions in premonitory urges rather than muscle weakening. In 5 patients, each with blepharospastic and cervical dystonic tics, open-label injection into the involved muscles reduced tic frequency and the urge to perform the tic.111 In another open-label study, Kwak and colleagues112 described the treatment of 35 patients over 115 sessions, with injections at the site of the most problematic tic. Mean peak effect on a subjective rating scale was 2.8 (range 0–4), mean duration of benefit was 14.4 weeks (maximum 45 weeks), and mean latency to onset of benefit was 3.8 days (maximum 10 days). Furthermore, 21 (84%) of 25 patients also experienced reduction in their premonitory sensations. Marras and colleagues113 treated patients with simple motor tics in 1 session in a randomized, double-blind, controlled clinical trial, and found reduced tic frequency and reduced urges at 2 weeks, but patients did not report an overall benefit from the treatment. Tics may have been milder and treatment may not have
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been optimized in this study. Treatment of refractory vocal tics has also been described.114–116 Further investigation into the efficacy and mechanism of benefit of botulinum toxin injections is certainly warranted, although for practical reasons, their applicability is limited to treatment of specific focal tics. The management of comorbid AD/HD in TS poses some challenges, because treatment generally requires stimulant medications, which generally carry a contraindication for the treatment of AD/HD in children with tics or TS. Interpretation of reports of tic emergence after starting stimulant treatment or tolerance of stimulants in patients with existent tic disorders is confounded by the natural waxing and waning of tic activity, such that occurrence or disappearance of tics cannot be definitively attributed to initiation or withdrawal of stimulant medications.117 In more recent studies, use of stimulant medications resulted in behavioral improvements that outweighed the low risk of tic exacerbation, and in the long term, tics either did not worsen or the exacerbation actually attenuated.118–120 In a randomized placebo-controlled trial of methylphenidate and clonidine in patients with tics and AD/HD, the Tourette Syndrome Study Group80 demonstrated that the proportion of individuals subjectively reporting tic exacerbations was similar amongst those treated with methylphenidate (20%), clonidine (26%), or placebo (22%). Furthermore, measured tic severity actually decreased in all treatment groups. Detailed analysis of group data from 22 studies led Erenberg117 to conclude that stimulants are not associated with increased tic activity when used in patients with tics compared with controls, although individual patients may experience exacerbations. In cases of suspected exacerbation, stimulant withdrawal with later rechallenge is recommended.117 Atomoxetine is a nonstimulant selective presynaptic norepinephrine transporter inhibitor used to treat AD/HD, and has been studied in a randomized placebocontrolled trial in patients with TS or chronic motor tic disorder.121 This study found significant improvements in AD/HD with accompanying nonsignificant reductions in tics. Side effects included increased heart rate, decreased appetite, nausea, and decreased body weight. Spencer and colleagues122 performed a post hoc subgroup analysis of just those study subjects with TS and showed statistically significant reductions in AD/HD and tic rating scales. However, 31.1% of atomoxetine-treated patients and 23.2% of those assigned to placebo discontinued use due to lack of clinical effect, mostly at the time of possible transition to an open-label extension. The mainstay of treatment of pediatric OCD is selective serotonin reuptake inhibitors (SSRIs) with or without cognitive behavioral therapy.123 Strategies for patients refractory to these measures include trying alternative SSRIs or clomipramine, or augmenting SSRI therapy with an atypical neuroleptic, most commonly risperidone.124 Predictors of poor response to usual first-line measures have been described and include the coexistence of tic disorders, early onset, presence of hoarding, predominance of compulsions, poor insight and somatic obsessions, and the presence of certain personality disorders.124 In a retrospective case-controlled analysis of treatment response to fluvoxamine in OCD, the presence of comorbid tics was associated with a less robust improvement in symptoms.125 Using data from the Pediatric OCD Treatment Study,123 March and colleagues126 found that enrolled subjects with or without comorbid tics experienced a similar degree of improvement with CBT but a less robust response to monotherapy with sertraline. In patients with TS and comorbid OCD, Miguel and colleagues124 suggest that first-line therapies for OCD (clomipramine, fluoxetine, fluvoxamine, sertraline, paroxetine, or citalopram) and first-line treatment of tics should be initiated. Thereafter, for refractory cases, typical augmentation
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strategies should be applied. Although the use of venlafaxine, a serotonin-norepinephrine reuptake inhibitor, in OCD has been described as a reasonable alternative to SSRIs,127,128 it has not been examined specifically in patients with TS. The use of deep brain stimulation (DBS) for the management of severe TS refractory to medication has been described by several investigators, and guidelines for its application have been described.129 Suggested inclusion criteria are: age R25; chronic and severe tic disorder with severe functional impairment (documented by standardized video assessments and with a minimum total tic severity score on the YGTSS of 35 for >12 months); failed conventional medical therapy; failed or not a candidate for behavioral therapies; stable and optimized treatment of comorbid medical, neurologic, and psychiatric disorders for 6 months; and patients who are involved and compliant with psychological interventions. Major exclusion criteria and neurologic and neuropsychological assessments were also recommended. Poysky and Jimenez-Shahed130 have suggested that these guidelines should take younger patients into consideration. Given the potential for significant psychosocial and educational difficulties in such severe cases, earlier intervention may lead to a better functional outcome than if therapy is delayed until after the formative years. Three DBS targets have been described, including the centromedial parafascicular complex of the thalamus (CM-Pf),131–135 GPi,132,136–138 and anterior limb of the internal capsule/nucleus accumbens region (ALIC/NAcc).139–141 Some investigators have described comparative effects of stimulation at different sites in the same patient.142–144 The CM-Pf target originally proposed for TS patients by Visse-Vandewalle and colleagues131 was based on Hassler and Dieckmann’s description of stereotactic thalamotomy in TS.145 Although substantial tic reductions have been described with stimulation at this site and in the GPi, no clear evidence exists to favor employment of one over the other. Interpreters of the available data regarding DBS in TS must take into consideration the small numbers of reported cases, that outcomes are not reported in a uniform fashion across studies, and that patient characteristics differ with regard to the presence of comorbidities. In the only prospective randomized trial of DBS in TS, Maciunas and colleagues134 studied bilateral CM-Pf stimulation in 5 patients. Four stimulation conditions using both electrodes were assessed in a random fashion: on/on, on/off, off/on, and off/off. When both electrodes were active, a statistically significant reduction in motor and phonic tics was found using video- and questionnaire-based assessments. However, despite these encouraging results, DBS in TS should be restricted to carefully screened patients who are refractory to medication using standardized outcome measures at predefined intervals. Further study is needed before determining ideal candidates for DBS, the true effectiveness (and adverse effects) of DBS in TS, and the appropriate target. SUMMARY
Our understanding of TS, although incomplete, is expanding with the use of current scientific methods. The neurodevelopmental hypothesis of TS is substantiated by several lines of evidence pertaining to its natural history, neuroimaging, and genetics. Dysfunction of the cortical–basal ganglia–thalamo–cortical pathways underlies the pathophysiology of tics and comorbidities in TS. Comorbidities are common and contribute to the disability experienced by patients with TS, and therefore should be identified and addressed early. Their presence influences psychosocial and educational functioning, overall TS severity, and prognosis. DRBDs are the mainstay of tic therapy but the potential for adverse effects warrants consideration of alternative options.
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Neurosurgery is an emerging treatment option for severe cases that are refractory to medication, although there is limited evidence to support its widespread use at this time.
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77. Leckman JF, Hardin MT, Riddle MA, et al. Clonidine treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1991;48(4):324–8 (Grade A). 78. Gaffney GR, Perry PJ, Lund BC, et al. Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 2002;41(3):330–6 (Grade A). 79. Chappell PB, Riddle MA, Scahill L, et al. Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry 1995;34(9):1140–6 (Grade B). 80. Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002;58(4):527–36 (Grade A). 81. Scahill L, Erenberg G, Berlin CM Jr, et al. Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx 2006;3(2):192–206. 82. Shapiro AK, Shapiro E. Controlled study of pimozide vs. placebo in Tourette’s syndrome. J Am Acad Child Psychiatry 1984;23(2):161–73 (Grade A). 83. Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1989;46(8):722–30 (Grade A). 84. Sallee FR, Nesbitt L, Jackson C, et al. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. Am J Psychiatry 1997; 154(8):1057–62 (Grade A). 85. Goetz CG, Tanner CM, Klawans HL. Fluphenazine and multifocal tic disorders. Arch Neurol 1984;41(3):271–2 (Grade B). 86. Silay YS, Vuong KD, Jankovic J. The efficacy and safety of fluphenazine in patients with Tourette syndrome. Neurology 2004;62(Suppl 5):A506 (Grade B). 87. Bruggeman R, van der Linden C, Buitelaar JK, et al. Risperidone versus pimozide in Tourette’s disorder: a comparative double-blind parallel-group study. J Clin Psychiatry 2001;62(1):50–6 (Grade A). 88. Dion Y, Annable L, Sandor P, et al. Risperidone in the treatment of Tourette syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol 2002;22(1):31–9 (Grade A). 89. Scahill L, Leckman JF, Schultz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 2003;60(7):1130–5 (Grade A). 90. Onofrj M, Paci C, D’Andreamatteo G, et al. Olanzapine in severe Gilles de la Tourette syndrome: a 52-week double-blind cross-over study vs. low-dose pimozide. J Neurol 2000;247(6):443–6 (Grade A). 91. Stephens RJ, Bassel C, Sandor P. Olanzapine in the treatment of aggression and tics in children with Tourette’s syndrome – a pilot study. J Child Adolesc Psychopharmacol 2004;14(2):255–66 (Grade B). 92. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 2000;39(3):292–9 (Grade B). 93. Yoo HK, Kim JY, Kim CY. A pilot study of aripiprazole in children and adolescents with Tourette’s disorder. J Child Adolesc Psychopharmacol 2006;16(4):505–6 (Grade B). 94. Davies L, Stern JS, Agrawal N, et al. A case series of patients with Tourette’s syndrome in the United Kingdom treated with aripiprazole. Hum Psychopharmacol 2006;21(7):447–53 (Grade B). 95. Miranda CM, Castiglioni TC. [Aripiprazole for the treatment of Tourette syndrome. Experience in 10 patients]. Rev Med Chil 2007;135(6):773–6 (Grade B) [in Spanish].
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96. Seo WS, Sung HM, Sea HS, et al. Aripiprazole treatment of children and adolescents with Tourette disorder or chronic tic disorder. J Child Adolesc Psychopharmacol 2008;18(2):197–205 (Grade B). 97. Robertson MM. Tourette syndrome, associated conditions and the complexities of treatment. Brain 2000;123(Pt 3):425–62. 98. Connor DF, Fletcher KE, Wood JS. Neuroleptic-related dyskinesias in children and adolescents. J Clin Psychiatry 2001;62(12):967–74. 99. Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics? Mov Disord 2006;21(5):589–98. 100. Arnone D. Review of the use of Topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 2005;4(1):5. 101. Abuzzahab FS, Brown VL. Control of Tourette’s syndrome with topiramate. Am J Psychiatry 2001;158(6):968 (Grade B). 102. Kuo SH, Jimenez-Shahed J. Topiramate in treatment of Tourette’s syndrome (TS). Mov Disord 2008;23(Suppl 1):S145–6 (Grade B). 103. Jankovic J, Jimenez-Shahed J, Brown LW. A randomized, double-blind, placebo-controlled study of topiramate in the treatment of Tourette syndrome. Submitted for publication. 104. Kenney C, Hunter C, Mejia N, et al. Tetrabenazine in the treatment of Tourette syndrome. J Pediatr Neurol 2007;5(1):9–13 (Grade B). 105. Ondo WG, Jong D, Davis A. Comparison of weight gain in treatments for Tourette syndrome: tetrabenazine versus neuroleptic drugs. J Child Neurol 2008; 23(4):435–7. 106. Mu¨ller-Vahl KR, Schneider U, Kolbe H, et al. Treatment of Tourette’s syndrome with delta-9-tetrahydrocannabinol. Am J Psychiatry 1999;156(3):495 (Grade A). 107. Mu¨ller-Vahl KR, Schneider U, Prevedel H, et al. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J Clin Psychiatry 2003;64(4):459–65 (Grade A). 108. Gilbert DL, Sethuraman G, Sine L, et al. Tourette’s syndrome improvement with pergolide in a randomized, double-blind, crossover trial. Neurology 2000;54(6): 1310–5 (Grade A). 109. Gilbert DL, Dure L, Sethuraman G, et al. Tic reduction with pergolide in a randomized controlled trial in children. Neurology 2003;60(4):606–11 (Grade A). 110. Anca MH, Giladi N, Korczyn AD. Ropinirole in Gilles de la Tourette syndrome. Neurology 2004;62(9):1626–7 (Grade B). 111. Jankovic J. Botulinum toxin in the treatment of dystonic tics. Mov Disord 1994; 9(3):347–9 (Grade B). 112. Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in the treatment of tics. Arch Neurol 2000;57(8):1190–3 (Grade B). 113. Marras C, Andrews D, Sime E, et al. Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial. Neurology 2001;56(5): 605–10 (Grade B). 114. Salloway S, Stewart CF, Israeli L, et al. Botulinum toxin for refractory vocal tics. Mov Disord 1996;11(6):746–8 (Grade B). 115. Trimble MR, Whurr R, Brookes G, et al. Vocal tics in Gilles de la Tourette syndrome treated with botulinum toxin injections. Mov Disord 1998;13(3): 617–9 (Grade B). 116. Porta M, Maggioni G, Ottaviani F, et al. Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci 2004;24(6):420–3 (Grade B).
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117. Erenberg G. The relationship between Tourette syndrome, attention deficit hyperactivity disorder, and stimulant medication: a critical review. Semin Pediatr Neurol 2005;12(4):217–21. 118. Gadow KD, Sverd J, Sprafkin J, et al. Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Arch Gen Psychiatry 1999;56(4):330–6 (Grade A). 119. Castellanos FX, Giedd JN, Elia J, et al. Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry 1997;36(5):589–96 (Grade A). 120. Gadow KD, Sverd J, Sprafkin J, et al. Efficacy of methylphenidate for attentiondeficit hyperactivity disorder in children with tic disorder. Arch Gen Psychiatry 1995;52(6):444–55 (Grade A). 121. Allen AJ, Kurlan RM, Gilbert DL, et al. Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Neurology 2005;65(12): 1941–9 (Grade A). 122. Spencer TJ, Sallee FR, Gilbert DL, et al. Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome. J Atten Disord 2008;11(4):470–81 (Grade A). 123. Pediatric OCD. Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessivecompulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 2004;292:1969–76 (Grade A). 124. Miguel EC, Shavitt RG, Ferra˜o YA, et al. How to treat OCD in patients with Tourette syndrome. J Psychosom Res 2003;55(1):49–57. 125. McDougle CJ, Goodman WK, Leckman JF, et al. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. J Clin Psychopharmacol 1993;13(5):354–8 (Grade B). 126. March JS, Franklin ME, Leonard H, et al. Tics moderate treatment outcome with sertraline but not cognitive-behavior therapy in pediatric obsessive-compulsive disorder. Biol Psychiatry 2007;61(3):344–7. 127. Dell’Osso B, Nestadt G, Allen A, et al. Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: a critical review. J Clin Psychiatry 2006;67(4):600–10 (Grade B). 128. Phelps NJ, Cates ME. The role of venlafaxine in the treatment of obsessivecompulsive disorder. Ann Pharmacother 2005;39(1):136–40. 129. Mink JW, Walkup J, Frey KA, et al. Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome. Mov Disord 2006; 21(11):1831–8. 130. Poysky J, Jimenez-Shahed J. Reply: patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome. Mov Disord 2007;22(9):1366–7. 131. Visser-Vandewalle V, Temel Y, Boon P, et al. Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases. J Neurosurg 2003;99(6):1094–100. 132. Ackermans L, Temel Y, Cath D, et al. Deep brain stimulation in Tourette syndrome: two targets? Mov Disord 2006;21(5):709–13. 133. Bajwa RJ, de Lotbiniere AJ, King RA, et al. Deep brain stimulation in Tourette syndrome. Mov Disord 2007;22(9):1346–50. 134. Maciunas RJ, Maddux B, Riley DE, et al. Prospective, randomized double blind trial of bilateral deep brain stimulation in adults with Tourette syndrome. J Neurosurg 2007;107(5):1004–14 (Grade A).
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135. Servello D, Porta M, Sassi M, et al. Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: the surgery and stimulation. J Neurol Neurosurg Psychiatry 2008;79(2):136–42. 136. Diederich NJ, Kalteis K, Stamenkovic M, et al. Efficient internal pallidal stimulation in Gilles de la Tourette syndrome: a case report. Mov Disord 2005;20(11): 1496–9. 137. Shahed J, Poysky J, Kenney C, et al. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities. Neurology 2007;68(2): 159–60. 138. Dehning S, Mehrkens JH, Mu¨ller N, et al. Therapy-refractory Tourette syndrome: beneficial outcome with globus pallidus internus deep brain stimulation. Mov Disord 2008;23(9):1300–2. 139. Flaherty A, Williams ZM, Amirnovin R, et al. Deep brain stimulation of the anterior internal capsule for the treatment of Tourette syndrome: technical case report. Neurosurgery 2005;57(4 Suppl 1):E403. 140. Kuhn J, Lenartz D, Mai JK, et al. Deep brain stimulation of the nucleus accumbens and the internal capsule in therapeutically refractory Tourette syndrome. J Neurol 2007;254(7):963–5. 141. Za˛bek M, Sobstyl M, Koziara H, et al. Deep brain stimulation of the right nucleus accumbens in a patient with Tourette syndrome. Case report. Neurol Neurochir Pol 2008;42(6):554–9. 142. van der Linden C, Colle H, Vandewalle V, et al. Successful treatment of tics with bilateral internal pallidum (GPi) stimulation in a 27-year-old male patient with Gilles de la Tourette’s syndrome (GTS). Mov Disord 2002;17(Suppl 5):S341. 143. Shields DC, Cheng ML, Flaherty AW, et al. Microelectrode-guided deep brain stimulation for Tourette syndrome: within-subject comparison of different stimulation sites. Stereotact Funct Neurosurg 2008;86(2):87–91. 144. Welter ML, Mallet L, Houeto JL, et al. Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol 2008;65(7):952–7. re otaxique des tics et cris inarticule s ou 145. Hassler R, Dieckmann G. Traitement ste re s comme phe nome`ne d’obsession motrice au cours de coprolaliques conside la maladie de Gilles de la Tourette. [Stereotaxic treatment of tics and inarticulate cries or coprolalia considered as motor obsessional phenomena in Gilles de la Tourette’s disease]. Rev Neurol 1970;123:89–100 [in French].
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Pathophysiolo gy a nd Treatment of Myo clonus John N. Caviness, MD KEYWORDS Myoclonus Motor Cortex Electrophysiology Pathophysiology Treatment
INTRODUCTION, CLINICAL CLASSIFICATION, AND EVALUATION
The pathophysiology of myoclonus is complex and can be conceptualized at many levels. Myoclonus is defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or inhibitions.1 The abrupt character of the movement suggests that there is a sudden change in the firing of certain neuron populations that affect motorneurons. Because the movement systems of the brain, spinal cord, and peripheral nerves comprise numerous levels and feedback loops, it is no surprise that there are multiple ways to suddenly alter motorneuron activity in a way that causes myoclonus. Moreover, a wide variety of diseases and conditions may create a type of neuronal dysfunction that causes myoclonus.2 When including all known etiologies, myoclonus has an average annual incidence of 1.3 cases per 100,000.3 Clinical Classification
The major categories of myoclonus in the popular etiologic classification scheme of Marsden and colleagues1 are as follows: physiologic, essential, epileptic, and symptomatic (secondary) (Box 1). The individual disorders/conditions that are listed for each major category have been upd ated over the years.2 Each of the major categories is associated with different clinical presentations. Physiologic myoclonus occurs in neurologically normal people. There is minimal or no associated disability, and physical examination reveals no relevant abnormality. Jerks during sleep are the most familiar examples of physiologic myoclonus. Essential myoclonus refers to myoclonus that is the primary or only clinical finding. Essential myoclonus is idiopathic, sporadic, or hereditary and progresses slowly or not at all. Some families with hereditary essential myoclonus manifest a genetic mutation. Epileptic myoclonus refers to the presence of myoclonus in the setting of epilepsy—that is, a chronic seizure disorder. Myoclonus can occur as one component of a seizure, the only seizure manifestation,
Department of Neurology, Mayo Clinic,13400 East Shea Blvd, Scottsdale, AZ 85259, USA E-mail address:
[email protected] Neurol Clin 27 (2009) 757–777 doi:10.1016/j.ncl.2009.04.002 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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Box 1 Clinical classification of myoclonus I. Physiologic myoclonus (healthy individuals) A. Sleep jerks (eg, hypnic jerks) B. Anxiety-induced C. Exercise-induced D. Hiccough (singultus) E. Benign infantile myoclonus with feeding II. Essential myoclonus (primary symptom, non-progressive history) A. Hereditary (autosomal dominant) B. Sporadic III. Epileptic myoclonus (seizures dominate, part of chronic seizure disorder) A. Fragments of epilepsy Isolated epileptic myoclonic jerks Epilepsia partialis continua Idiopathic stimulus-sensitive myoclonus Photosensitive myoclonus Myoclonic absences in petit mal epilepsy B. Childhood myoclonic epilepsy Infantile spasms Myoclonic astatic epilepsy (Lennox-Gastaut) Cryptogenic myoclonus epilepsy (Aicardi) Awakening myoclonus epilepsy of Janz (juvenile myoclonic epilepsy) C. Progressive myoclonus epilepsy: Baltic myoclonus (Unverricht-Lundborg) IV. Symptomatic myoclonus (secondary, progressive, or static encephalopathy dominates) A. Storage disease Lafora body disease GM2 gangliosidosis (late infantile, juvenile) Tay-Sachs disease Gaucher disease (noninfantile neuronopathic form) Krabbe leukodystrophy Ceroid-lipofuscinosis (Batten) Sialidosis (cherry-red spot) (types 1 and 2) B. Spinocerebellar degenerations Ramsay Hunt syndrome Friedreich ataxia Ataxia-telangiectasia
Pathophysiology and Treatment of Myoclonus
C. Other spinocerebellar degenerations Basal ganglia degenerations Wilson disease Torsion dystonia Hallervorden-Spatz disease Progressive supranuclear palsy Huntington disease Parkinson disease Multisystem atrophy Corticobasal degeneration Dentatorubropallidoluysian atrophy D. Dementias Creutzfeldt-Jakob disease Alzheimer disease Dementia with Lewy bodies Frontotemporal dementia Rett syndrome E. Infectious or postinfectious Subacute sclerosing panencephalitis Encephalitis lethargica Arbovirus encephalitis Herpes simplex encephalitis Human T-lymphotropic virus I HIV Postinfectious encephalitis Miscellaneous bacteria (streptococcus, clostridium, other) Malaria Syphilis Cryptococcus Lyme disease Progressive multifocal leukoencephalopathy F. Metabolic Hyperthyroidism Hepatic failure Renal failure Dialysis syndrome Hyponatremia Hypoglycemia Nonketotic hyperglycemia
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Multiple carboxylase deficiency Biotin deficiency Mitochondrial dysfunction Hypoxia Metabolic alkalosis Vitamin E deficiency G. Toxic and drug-induced syndromes H. Physical encephalopathies Posthypoxia (Lance-Adams) Posttraumatic Heat stroke Electric shock Decompression injury I. Focal nervous system damage CNS Poststroke Postthalamotomy Tumor Trauma Inflammation (eg, multiple sclerosis) Mo¨bius syndrome Developmental Idiopathic Peripheral nervous system Hematoma J. Malabsorption Celiac disease Whipple disease K. Eosinophilia-myalgia syndrome L. Paraneoplastic encephalopathies M. Opsoclonus-myoclonus syndrome Idiopathic Paraneoplastic Infectious Other N. Exaggerated startle syndrome Hereditary Sporadic O. Hashimoto encephalopathy
Pathophysiology and Treatment of Myoclonus
P. Multiple system degenerations Allgrove syndrome DiGeorge syndrome Membranous lipodystrophy Q. Unknown Familial Sporadic Data from Marsden CD, Hallett M, Fahn S. The nosology and pathophysiology of myoclonus. In: Marsden CD, Fahn S, editors. Movement disorders. London: Butterworths; 1982. p. 196–248.
or one of multiple seizure types within an epileptic syndrome. The most common example of this category is the juvenile myoclonic epilepsy of Janz, which falls under the rubric of idiopathic generalized epilepsy. Symptomatic (secondary) myoclonus manifests in the setting of an identifiable underlying disorder, neurologic or non-neurologic. Mental status abnormalities and ataxia are common clinical associations in symptomatic myoclonic syndromes. Symptomatic causes of myoclonus comprise a widely diverse group of disease processes and include neurodegenerative diseases, storage diseases, toxic metabolic states, diffuse brain injuries, infections, focal nervous system damage, paraneoplastic syndromes, and other medical illnesses.1,2 Most clinically relevant cases of myoclonus are in the symptomatic category, followed by the epileptic and essential categories.3
Evaluation
The properties of the myoclonus and other aspects of the clinical presentation determine what type of evaluation and testing should be performed.2 For example, if an infectious or inflammatory syndrome is present, a cerebrospinal fluid examination is necessary. Knowledge of the various disorders in a well-delineated differential diagnosis for a particular patient will facilitate the proper diagnostic confirmation. An important first step is to derive from a history and physical examination the appropriate clinical category among physiologic, essential, epileptic, and symptomatic. Special attention should be given to the presence of concomitant medical conditions, family history of similar problems, and exposure to toxins and drugs known to cause myoclonus. Numerous drugs are known to cause or contribute to myoclonus, and examples are given in Box 2. If a drug is suspected to cause a patient’s myoclonus, a cautious decreaseg or discontinuation of the medication should be considered. The result of the medication change may be therapeutic as well as diagnostic. When the cause of the myoclonus is unexplained even after this initial evaluation, the following minimal testing should be performed: Electrolytes (including bismuth, Ca21, Mg21)and glucose Renal function tests Hepatic function tests Drug and toxin screen Electroencephalography
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Box 2 Drugs that are associated with myoclonus Psychiatric medications Cyclic antidepressants Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors Lithium Tardive syndrome (antipsychotic use) Anti-infectious agents Narcotics Anticonvulsants Anesthetics Contrast media Cardiac medications Calcium channel blockers Antiarrhythmics Drug withdrawal Other medications Data from Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet Neurol 2004;3:598–607.
Brain imaging Paraneoplastic testing This testing mainly evaluates metabolic, toxic, and structural brain lesions; seizure disorders; and cancer-related causes of myoclonus. If these tests do not reveal the diagnosis, then more advanced testing should be considered. This testing may include cerebrospinal fluid examination, enzyme activity, imaging for cancer, tissue biopsy, and other tests.2 Body imaging for cancer should be considered even though paraneoplastic testing is negative. In some cases, genetic testing may be considered. Before genetic testing is done, the patient should be fully aware of the implications for positive and negative results. If appropriate, genetic counseling is recommended. In those instances where the cause of myoclonus is not known, detailed consideration of the myoclonus pathophysiology is recommended. The pathophysiologic mechanism of the myoclonus complements its placement within the etiologic classification scheme. Ascertainment of myoclonus pathophysiology in the clinic setting is feasible, because the pathophysiology of myoclonus may be probed with noninvasive clinical neurophysiology testing. Definition of the myoclonus pathophysiology has strong implications for neurologic localization, diagnosis, and treatment. PATHOPHYSIOLOGY OF MYOCLONUS
Etiologic classification provides an organizational scheme within which causes of myoclonus with similar clinical presentation are grouped. However, classifying myoclonus according to its neurophysiology provides insight with regard to its pathophysiology. The classification also gives localizing information for the myoclonus and thus
Pathophysiology and Treatment of Myoclonus
can provide at least partial localization for diagnosis of the underlying process. Since most myoclonus treatments are based on attempting to normalize the dysfunctional physiology mechanisms, ascertaining the physiology of the myoclonus directs one toward the most effective treatment.2 Clinical Neurophysiology Methods for Studying Myoclonus
The brevity of myoclonus and its dramatic clinical presentation has led naturally to the idea that it is generated from a source that somehow transmits a hyperexcitable drive to motorneurons, which causes the jerk movement in positive myoclonus. Clinical examination can provide clues to the myoclonus source, but myoclonus research has relied heavily on clinical neurophysiology methods to provide corroborative evidence for pinpointing the source localization. These methods have great clinical usefulness for myoclonus as well. The equipment for invoking these methods is commonly available, but the clinician should use available resources for recognizing and interpreting the pattern of findings for various myoclonus sources.4,5 The specific electrophysiologic methods used in the clinical neurophysiologic study of myoclonus usually include, but are not limited to, multichannel surface electromyography (EMG) recording with testing for long latency EMG responses to mixed nerve stimulation, electroencephalography (EEG), EEG-EMG polygraphy with back-averaging, and evoked potentials (eg, median nerve stimulation somatosensory-evoked potential [SEP]).4 Positive and negative findings from these methods are used to determine the physiologic type of myoclonus.5 The different physiologic types of myoclonus are organized into a classification scheme whose major categories represent the source of myoclonus generation along the neuraxis. The main physiologic categories for myoclonus classification are:
Cortical Cortical-Subcortical Subcortical-Suprasegmental Segmental Peripheral
Further subdivision is based on detailed electrophysiologic and examination findings. Multiple myoclonus physiology types can occur in the same patient. The discussion on myoclonus pathophysiology will be organized by the physiologic classification scheme. Cortical
The cerebral cortex is the most common origin for myoclonus. The establishment of a cortical origin for the myoclonus may have diagnostic implications. Such etiologies that may demonstrate cortical myoclonus include posthypoxic syndrome, progressive myoclonus epilepsy syndromes, drugs and toxins, neurodegenerative syndromes, various dementias, focal lesions, and other entities of unknown cause, sporadic and familial (Box 3). Cortical myoclonus predominately affects those body parts with the biggest cortical representations, the limbs and head. The motor cortex in humans is known to particularly control fine or fractionated movements rather than acting across multiple muscle segments. As a result, the jerks are most often multifocal or focal, but segmental and generalized myoclonus also occur. The authors know that motor areas of the cerebral cortex are most involved in creating voluntary action, and accordingly, the myoclonus is exacerbated by voluntary muscle activation. It is the action of myoclonus that usually produces the most disability in these patients. At rest, myoclonus is
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Box 3 Etiologies for which cortical myoclonus has been described Posthypoxic myoclonus Progressive myoclonic epilepsy syndromes - Unverricht-Lundborg disease - Mitochondrial disease - Ceroid lipofuscinosis - Lafora body disease - Sialidosis Drugs and Toxins - Tricyclic antidepressant medication - Lithium - Levodopa - Methyl bromide Neurodegenerative syndromes - Alzheimer disease - Parkinson disease - Multiple system atrophy - Spinocerebellar degeneration - Huntington disease Creutzfeldt-Jakob disease Subacute sclerosing panencephalitis Celiac disease Rett syndrome Down syndrome Angelman syndrome Focal lesions from numerous causes Syphilis Traumatic encephalopathy Unknown—sporadic Unknown—familial Data from Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet Neurol 2004;3:598–607.
usually less prominent, unless the major clinical manifestation is a focal motor seizure. Myoclonus induced by reflex stimulation (by way of transcortical loop) occurs commonly, and its characterization is important for physiologic classification. It is the most common situation for a patient to have myoclonus with a combination of action and reflex precipitants and a smaller presence at rest.
Pathophysiology and Treatment of Myoclonus
Electrophysiologic properties from clinical neurophysiology methods
The important electrophysiologic characteristics for cortical myoclonus are:4 1. 2. 3. 4.
25 to 100 ms-duration surface EMG discharges Focal cortical EEG transient preceding myoclonus by less than 40 ms (arm) Enhanced long-latency EMG responses to mixed nerve stimulation Enlarged cortical P25-N33 somatosensory components
An example of the short-duration surface EMG discharges in cortical myoclonus is given in Fig. 1. The myoclonus EMG discharges typically demonstrate an agonistantagonist co-contracting pattern that may extend across muscle segments. Often, the myoclonus EMG discharges occur in high-frequency rhythmic bursts or trains. However, the visual appearance of the myoclonus is usually irregular because the rhythmic trains are intermittent, and there is marked variability between the amplitude of the myoclonus EMG discharges within and between trains. When the trains are small and almost continuous, the term ‘‘cortical tremor’’ is sometimes applied.6 The premyoclonus EEG transient can sometimes be observed grossly on the EEG, but it is useful to perform EEG back-averaging for more sensitive detection and to assess the time-locked nature of the EEG transient to the motion detection or myoclonus EMG discharge. An example is shown in Fig. 2. The transient is localized over
Fig.1. Surface EMG tracing from right wrist extensors in a patient with right arm myoclonus. The ‘‘Myoclonus 1’’ trigger marks are located at three myoclonus EMG discharges. The myoclonus EMG discharges show a sudden, brief, synchronous event that corresponded with the right wrist myoclonus.
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Fig. 2. Back-averaged premyoclonus EEG transient over left motor cortex contralateral to the right wrist myoclonus from the patient whose myoclonus EMG discharges are in Fig. 1.
the contralateral sensorimotor cortex. The transient is a biphasic or triphasic spike beginning with a positive deflection whose peak precedes the onset of the myoclonic discharge by an average of 20 ms for arm (range 10–40 ms). Many cortical myoclonus patients demonstrate myoclonus after stimulation (reflex myoclonus). The reflex myoclonus may be clinically demonstrable by touch or muscle stretch. In the case of upper extremity myoclonus, briskly abducting the thumb may evoke a reflex myoclonic jerk. This can be confirmed with EEG-EMG polygraphy, but it is usually easier to prove reflex myoclonus by testing for long-latency EMG responses to electrical nerve stimulation. A reproducible gross EEG transient may or may not precede the myoclonus EMG discharge with each stimulus. For the hand, median nerve stimulation can show EMG discharges at 50 ms latency or greater (range 40–60) from the stimulus artifact trigger mark.4 Repetitive discharges may be seen, at intervals of 20 40 ms.7 At rest, in a normal individual, no response should be present. Care must be taken that the arm muscles are relaxed so as to avoid a false positive response. Enlargement of the cortical SEP P25-N33 parietal wave from median nerve stimulation is important evidence for cortical reflex myoclonus physiology. A key characteristic of the enlarged P25-N33 wave is the similar morphology and topography to the averaged time-locked EEG transient that precedes the myoclonus EMG discharge elicited by muscle action or at rest. Additionally, the interval between the P25 peak and the onset of any long-latency EMG response, which is simultaneously recorded, is usually similar to the latency from the back-averaged EEG transient to the onset of the myoclonus EMG discharge. When cortical myoclonus arises dramatically from rest in a paroxysmal manner, it is more often thought of as partial epilepsy with motor symptomatology. Nevertheless, the basic movement phenotype is usually of focal myoclonus, either occurring as paroxysms of repetitive focal jerks, or as epilepsia partialis continua when occurring
Pathophysiology and Treatment of Myoclonus
for extended periods of time. Focal or more widespread cerebral cortical processes can cause focal motor seizures. There are a variety of ictal EEG changes that may be seen in the appropriate contralateral motor area for the focal motor seizure manifestation. Repetitive focal spike, spike and wave, sharp wave, rhythmic theta or delta activity, or desynchronization may occur. In many cases, no grossly observable EEG activity is seen, and back-averaging may uncover a transient in some of those cases. In the case of epilepsia partialis continua, the above-mentioned transients will be periodic and may even occur with the pattern of periodic lateralizing epileptiform discharges. Most of the cortical myoclonus patients have one or more of the three major cortical physiology subtypes:5 (1) cortical origin myoclonus without reflex activation, (2) cortical reflex myoclonus, (3) focal motor seizures. All of these cortical origin subtypes need electrophysiologic properties #1 and #2 mentioned above to suggest a cortical source classification. It is the exaggerated reflex features of enhanced long-latency EMG reflexes to nerve stimulation (#3) and/or enlarged cortical SEP components (#4) that are typical of cortical reflex myoclonus. The paroxysmal occurrence from rest of cortical myoclonus shows the focal motor seizure phenotype.
Studies of cortical myoclonus using research methods
Back-averaging EEG studies performed with routine EEG positions can localize premyoclonus cortical transients to contralateral sensorimotor cortex. Exact localization can be performed with advanced techniques used in research. Fig. 3 shows dipole localization of the abnormal EEG transient in a patient with upper extremity action myoclonus using EEG source localization software CURRY 6.0 (Compumedics Neuroscan, Charlotte, North Carolina). This shows that the physiologic abnormality that produces the right wrist myoclonus is in a highly focal neocortical location. Fig. 4 shows that the same myoclonus cortical electrical activity also overlaps the Talairach coordinates of the precentral gyrus (motor cortex) on MRI. These data provide evidence that the primary motor cortex is the most likely generation site for cortical myoclonus in this particular patient.
Fig. 3. The abnormal electrical discharge dipole (red) is shown localizing to a very focal area near the left central sulcus for the patient whose right wrist myoclonus electrophysiology is depicted in Figs. 1 and 2.
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Fig. 4. The abnormal electrical discharge dipole (red) mapped on an averaged MRI from the patient whose electrophysiology is depicted in Figs.1^3. The dipole is demonstrated to be on the Talairach coordinates of the precentral gyrus/motor cortex (shaded with blue).
Magnetoencephalography (MEG) has the ability to perform better localization and amplitude sensitivity for horizontal dipoles when compared with EEG. Uesaka and colleagues8 found that among 6 subjects with cortical myoclonus, one case localized to precentral gyrus only, one localized to precentral and postcentral gyrus, and five cases localized to the postcentral gyrus only. In this study, the initial cortical somatosensory-evoked magnetic fields localized to the postcentral gyrus. Uesaka and colleagues suggested that patients with enlarged SEPs are likely to have myoclonus arise from the postcentral gyrus. In contrast, Mima and colleagues9 found the MEG cortical correlate for all six of their myoclonus subjects to localize to the precentral gyrus. In another report, Mima and colleagues10 found that enlarged cortical somatosensory-evoked magnetic fields localized to the precentral gyrus in four subjects and to the postcentral gyrus in one subject. These varied results suggest that either there are true locus differences between cortical myoclonus cases or methodological differences account for different source localization results. Coherence has been used to provide information about the relationship between cortical EEG signals and muscle activity in myoclonus patients. Coherence is a frequency domain measure of correlation between 2 signals. Brown and colleagues11 have found changes in EEG-EMG and EMG-EMG coherence patterns for subjects with myoclonus. They have suggested that myoclonus patients show pathologic exaggerations of physiologic central rhythmicity relating to movement and that the precise pattern of coherence has possible diagnostic value. In some cases, elevated coherence is more sensitive than EEG-EMG back-averaging. Caviness and colleagues12 have found elevated corticomuscular coherence in the small distal myoclonus of Parkinson disease. This suggests that motor cortical rhythms are pathologically coupled to motor neurons in some cases of Parkinson disease. They also found that corticomuscular coherence is elevated even when myoclonus does not occur and that it elevates further around the time of myoclonus. This suggests that abnormal coupling between EEG motor rhythms generated in pyramidal dendrites and spinal motorneurons is elevated and unstable in cortical myoclonus. Cortical myoclonus summary: concepts of cortical myoclonus generation
Since the first half of the last century, authors have suggested that cortical myoclonus generation was characterized by a lack of inhibition in neuronal circuits. Although this must be correct at some level, this physiologic explanation of myoclonus is too simplistic, and evidence for where and how this lack of inhibition arises has not
Pathophysiology and Treatment of Myoclonus
been generated. Regarding localization of the cortical source, recent studies seem to favor a role for the primary motor cortex over that of the primary sensory cortex. The observation of increased corticomuscular coherence in myoclonus suggests a defect in the gating of oscillatory networks in the motor cortex, but the precise defect in neuronal circuitry responsible is not known. None of these concepts rule out involvement of subcortical structures, and historically the cerebellar system has been suggested to play a role in cortical myoclonus generation. It is possible that the specifics of cortical myoclonus generation differ with etiology and patient. Evidence from pathology, pharmacology, and animal model studies has yet to pinpoint a specific neuronal circuit lesion as the cause of cortical myoclonus. The most unifying theme for the diverse causes of cortical myoclonus is the diffuse nature of the brain disorder. Pathologic studies show diffuse changes, and no single location shows consistent involvement.13–15 In posthypoxic myoclonus, the decrease in serotonin metabolites and response to the serotonin precursor 5-hydroxytryptophan has suggested deficient serotonin activity in this cause of cortical myoclonus, but it is unclear whether all causes of cortical myoclonus are based on decreased serotonin activity.13,15 It is known that serotonin overactivity can cause myoclonus, and numerous drugs that affect a variety of chemical systems can cause myoclonus.2 Thus, it is unlikely that serotonin or any other single system is the necessary and sufficient lesion for cortical myoclonus to occur. Animal models for cortical myoclonus have also used diffuse and various lesions, and analogy to the human cortical myoclonus is uncertain.16 In summary, hard evidence would suggest that cortical myoclonus is precipitated by a cortical transient that represents an abnormal sudden and synchronous discharge of pyramidal neurons in the context of diffuse brain pathology. At this point, it is difficult to have confidence in a more specific mechanistic explanation. As far as the intrinsic cortical mechanism is concerned, the end result may be a ‘‘lack of inhibition of cortical neurons.’’ However, it is not known whether this constitutes a lack of inhibitory inputs, rebound excitation from excessive inhibition, alteration of intrinsic pyramidal neuron firing properties, or some combination of these mechanisms to cause sensorimotor pyramidal neurons to discharge too synchronously. It is critical to decipher which of these possibilities is important and how its basic mechanism may be treated. Cortical-Subcortical Myoclonus
There is strong evidence that some generalized seizure phenomena arise from paroxysmal, abnormal, and excessive oscillation in bidirectional connections between cortical and subcortical sites.17–19 The term ‘‘cortical-subcortical’’ myoclonus refers to myoclonus arising from this type of physiology and other similar phenomena. For these entities, the abnormal influence of the subcortical input is critical. Despite the subcortical involvement, the cortical discharge precedes and drives the myoclonus event. This myoclonus usually occurs in paroxysms from rest and can be associated with other seizure phenomena that may even be more clinically significant than the myoclonus itself. The myoclonus is often generalized or bilaterally synchronous, but focal or multifocal distributions occur as well. It is this myoclonus physiology that exists within the primary generalized epileptic syndromes with myoclonus. The hallmark of the physiology for cortical-subcortical myoclonus is the generalized spike-and-wave EEG discharge. The myoclonus EMG discharge duration is less than 100 ms and is time-locked to the spike discharge. The generalized spike-and-wave discharges may be associated with the myoclonus (ictal) or occur between the myoclonus events (interictal). Different forms and frequencies distinguish the epileptic syndromes that include myoclonus. The 4 Hz to 6 Hz spike or polyspike and wave
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generalized discharge is typical for juvenile myoclonic epilepsy. A 2.5 Hz (slow spike and wave) interictal pattern is characteristic for the Lennox-Gastaut syndrome, which at times is associated with myoclonic seizures, but the ictal myoclonus may be associated with faster frequencies. The 3 Hz spike and wave occurs ictally in absence seizures whether or not they are associated with myoclonus. The type of abnormality that gives rise to such bidirectional overexcitation between cortical and subcortical areas entails intrinsic electrical abnormalities at the neuron level. Thus, it is no surprise that genetic mutations relating to ion channels and ion buffering have been associated with various myoclonic epilepsy syndromes.20–22 Subcortical-Suprasegmental
The clinical and neurophysiologic characteristics of subcortical myoclonus are more variable than for those in cortical or cortical-subcortical myoclonus. In this category, there is no evidence for intrinsic abnormal cortical excitability (eg, EEG transient correlation, enlarged cortical SEP waves, EMG reflex responses with cortical latency) that can be tightly correlated to the myoclonus. The myoclonus EMG duration is highly variable among entities in this group and ranges from 25 to 300 ms. The temporal relationship between agonists and antagonists muscle activation depends on the specific type of subcortical-suprasegmental myoclonus. The source locations within this category extend from the basal ganglia to the spinal cord. However, in all examples, the source transmits its excitatory influence to muscle segments far beyond its location (suprasegmental). Assignment of a case to the subcortical category can be problematic if it is based largely on absence of evidence for abnormal cortical excitability or circumstantial findings rather than direct evidence. There are two major groups of subcortical-suprasegmental myoclonus: (1) hereditary essential myoclonus (myoclonus-dystonia) and (2) myoclonus caused by simultaneous rostral and caudal recruitment of muscle segments along the neuraxis from a localized source—includes reticular reflex, propriospinal, and subcortical reflex myoclonus. Hereditary essential myoclonus usually shows an autosomal dominant hereditary pattern. Major features include upper extremity and trunk/neck involvement with notable worsening with action, onset before age 20 years with a fairly benign course, absence of other severe neurologic deficits, and normal EEG. Alcohol responsiveness is common enough to be characteristic. There is dystonia of a similar distribution in many cases for which hereditary essential myoclonus has been renamed as the myoclonus-dystonia syndrome. Of the known gene mutations, 3-sarcoglycan is the most common, but there are families in which the genetic locus is not known. Roze and colleagues23 characterized the clinical-electrophysiologic characteristics of those patients with mutations in the 3-sarcoglycan gene. Their cases showed an average EMG duration of 95 ms with a range of 25 to 256 ms. They found no features of cortical hyperexcitability including a lack of back-averaged cortical potentials time-locked to the myoclonus. 3-Sarcoglycan seems to be most highly expressed in subcortical regions, but its function is not known.24 3-Sarcoglycan knockout mice demonstrate myoclonus and defects in subcortical monoaminergic neurotransmitter systems.25 It is possible that such subcortical defects transmit an excitatory influence onto motor cortical areas through the thalamus to produce the myoclonus and dystonia in this syndrome. The myoclonus caused by simultaneous rostral and caudal recruitment of muscle segments along the neuraxis from a localized source elicits jerks that may be generalized or bilateral and widespread. Often, this myoclonus is reflex sensitive. The EMG duration may range from 25 to 300 ms, and muscles in the same segment show nearly synchronous activation. However, the simultaneous rostral and caudal recruitment
Pathophysiology and Treatment of Myoclonus
order is the characteristic finding of the surface EMG polygraphy. The rostral and caudal spread occurs more slowly than what is observed in the corticospinal pathways seen in cortical myoclonus. If any EEG activity is observed, it is seen after the first muscle is activated and is not time-locked in a meaningful way to the EMG activation. Reticular reflex myoclonus is the prime example.26 The myoclonus source is the lower brainstem reticular formation. Brainstem motor systems are particularly involved in axial and bilateral movements and are tightly linked to subcortical reflex centers. Thus brainstem myoclonus is generalized, especially axial, and very stimulus-sensitive. The exaggerated startle jerks of hyperekplexia have a related pathophysiology, but no doubt arises from a different lower brainstem neuronal circuitry.27 Gene mutations in the glycine and gamma-aminobutyric acid receptor have been found to be causes of exaggerated startle syndrome. Propriospinal myoclonus, described by Brown and colleagues,28 has a locus in the cervical or thoracic spinal cord region. It is believed that rostral and caudal recruitment occurs by way of propriospinal pathways from the source locus. The myoclonic jerks may be trunk extension or flexion and are commonly reflex sensitive to touch. Spinal structural lesions of various types have been associated with the locus for propriospinal myoclonus. Subcortical reflex myoclonus has been described for which the exact locus is unknown but is believed to be somewhere between the midpons and thalamus.29 This causes a descending order of recruitment. Segmental
Segmental myoclonus has its generator at a particular segment or contiguous segments of the brainstem and/or spinal cord. This segmental generator produces movements at that particular segment or contiguous segments close to the source locus. The most common type of segmental myoclonus is palatal myoclonus. A variety of etiologies may cause segmental myoclonus but vascular, tumor, trauma, infectious, and idiopathic and/or ‘‘essential’’ diagnoses account for most cases. There is usually fairly persistent, rhythmic activation of muscles corresponding to the brainstem/spinal segment(s) involved. This myoclonus is relatively unaffected by state of consciousness, motor activity, or stimulus. However, exceptions do occur and in these instances, oscillatory movements occur in trains or episodes and may be modulated by voluntary movement and sensory stimulation. The EMG usually shows synchronous activation of the affected muscles. The typical frequency is in the range of 0.5 to 3 Hz, and the typical EMG discharge duration varies widely between 50 to 500 ms. The EEG and somatosensory-evoked potential are normal. Brainstem auditory-evoked potentials (BAEP) have had abnormal findings in some individuals with palatal myoclonus.30 These inconsistent BAEP abnormalities probably represent the same lesion type, but not the same location as that responsible for the palatal myoclonus pathophysiology. In spinal segmental myoclonus, mixed nerve stimulation can evoke EMG discharges in the affected muscles at latencies longer than 40 ms, but such findings are variable, and the latency values vary from case to case. These reflex discharges may reflect hyperexcitability of polysynaptic pathways that contribute to the generation of the myoclonus.31,32 The type of neuronal circuitry defect that creates these oscillatory movements in brainstem or spinal cord is unknown. It is known that when a partial lesion or denervation of brainstem or spinal gray matter occurs, abnormal firing of some remaining neurons occurs.33 The pattern of abnormal firing is rhythmic or irregular bursting of action potentials. It has been postulated that this abnormal excitation overflows to motorneuron pools, which in turn causes the segmental myoclonus.34 In the example of palatal myoclonus,
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denervation of the inferior olive from dentate-inferior olive pathway lesions may play a key role in producing the abnormal movement. Palatal myoclonus is the most common type of segmental myoclonus. The movement is rhythmic and usually bilateral with a rate between 1 to 4 Hz, with other rates being less common. Because of its smooth oscillatory nature, some clinicians choose the term ‘‘palatal tremor’’ over palatal myoclonus. A distinction is made between ‘‘essential palatal myoclonus’’ (EPM) and ‘‘symptomatic palatal myoclonus’’ (SPM).35 EPM is associated with activation of the levator veli palatini muscle and with no identifiable MRI lesion, and it is unlikely to involve other muscles. SPM is associated with activation of the tensor veli palatini, an identifiable MRI brainstem lesion in the dentate-inferior olive pathway, involvement of other muscles, cerebellar dysfunction, and an older age of onset. EPM patients are more likely to state that their ear click is the chief complaint, whereas SPM patients are more concerned with the other associated neurologic problems rather than the palatal movements per se. Important differences in electrophysiologic testing have also been found.36 EPM shows a complete suppression with sleep, but sleep only produces mild variations in rate with SPM. The palatal movement cycle only exerts remote effects on tonic EMG activity of extremity muscles in SPM. As shown by studies of blink reflex activity, jaw jerk, and masseteric silent period, EPM had only polysynaptic brainstem reflex abnormalities, whereas SPM patients can have abnormalities of monosynaptic, oligosynaptic, and polysynaptic brainstem reflexes. Peripheral
Peripheral myoclonus refers to myoclonic jerks that are driven from a peripheral site.37 The best-documented example is hemifacial spasm as was pointed out by Jankovic and Pardo.38 Such EMG discharges are characterized by marked duration variability from discharge to discharge. The EMG discharges that are supplied by the same nerve are synchronous. In peripheral myoclonus, the spectrum of EMG discharge duration may merge continuously with those EMG discharges that are responsible for movements that are longer lasting. It should be recognized that the literature contains other uses of the term ‘‘peripheral myoclonus.’’ For example, some studies report myoclonus associated with peripheral nervous system lesions, but posit that the myoclonus itself is centrally generated and results from ‘‘central reorganization.’’ TREATMENT
The first consideration is given to reversing any underlying etiology of the myoclonus. The most straightforward example is that of drug-induced myoclonus, and discontinuation of the drug usually eliminates the myoclonus. Other potentially reversible causes of myoclonus are an acquired abnormal metabolic state, removable toxin, or an excisable lesion. However, in the majority of myoclonus cases, treatment of the underlying disorder usually is neither possible nor effective, and symptomatic treatment is justified if the myoclonus is disabling enough. The best strategy for symptomatic treatment is derived from using the physiologic classification as a surrogate for the myoclonus pathophysiology. A drug treatment used for one physiologic classification may not work well in another or may even worsen the condition. If the myoclonus physiology classification cannot be determined, then presuming the myoclonus physiology that usually occurs in that particular diagnosis is a reasonable way to proceed cautiously. If the diagnosis and myoclonus physiology are unknown, there is little to guide an approach to treatment. In this instance, the drugs that work in cortical myoclonus may be tried first because cortical
Pathophysiology and Treatment of Myoclonus
myoclonus physiology is the most common. However, the clinician should be prepared for poor results until the reason for the myoclonus is better understood. There is sparse controlled evidence on the treatment of myoclonus. Side effects are commonly dose-limiting. The following discussion about treatment is outlined under the physiologic classification of the myoclonus. Cortical Myoclonus Treatment
Drug treatment presumably attempts to normalize inhibitory processes within the sensorimotor cortex. Levetiracetam, piracetam, sodium valproate, and clonazepam are the four most effective agents. Multiple drug combinations may be necessary, but there may be increased side effects. Amelioration of the myoclonus is rare. However, important improvement may be attained with decreased disability. Levetiracetam and Piracetam—These are related drugs and have had limited controlled study.39–44 Their mechanism of action remains unknown, but their binding to the synaptic vesicle protein 2A may be important for moderating neurotransmitter release. Both are well tolerated and generally nonsedating. Because of their relatively favorable side effect profile, these drugs are used initially or as an add-on treatment. There are anecdotal reports for levetiracetam responsiveness in many of the specific etiologies of cortical myoclonus listed in Box 3. Daily dosages of levetiracetam range from 1000 to 3000 mg and dosages of piracetam range from 2.4 to 21.6 g. An abrupt withdrawal may precipitate a severe worsening of myoclonus, and in the case of piracetam, seizures may occur. Sodium valproate—many patients need doses of 1200 to 2000 mg/d for myoclonus treatment.45 Transient gastrointestinal upset may occur during initial treatment, usually with nausea and vomiting, but sometimes with abdominal pain and diarrhea. Hair loss, tremor, hepatotoxicity, and drowsiness may also occur. Clonazepam—Large doses of clonazepam are often necessary (as much as 6 mg/d or more) but should be introduced slowly.45 Undue drowsiness and ataxia are the only major adverse effects and can sometimes be overcome by gradually increasing the dosage. Abrupt reductions and withdrawals can result in a marked deterioration in myoclonus and withdrawal seizures. Unfortunately, tolerance to this drug is common and may develop over a period of several months. Other agents—Primidone and phenobarbital are useful at times, but generally are limited to add-on therapy or when seizures coexist with the myoclonus.45 Zonisamide may help as an add-on therapy.46 Phenytoin and carbamazepine are helpful in only a minority of patients. In others, phenytoin may exacerbate myoclonus. Vigabatrin may also lead to a paradoxic increase in myoclonus in some patients. These examples serve as a useful reminder that antiseizure medications, old and new, have the potential to worsen myoclonus in certain patients. Sodium oxybate, the sodium salt of g-hydroxybutyric acid, has been reported to decrease cortical myoclonus in a few patients.47 Cortical-Subcortical Myoclonus Treatment
The myoclonus in primary generalized epilepsies falls under this physiologic classification. As such, conventional antiseizure medications for generalized epilepsy are used. Valproic acid is the major drug of choice for these disorders. The favorable controlled evidence for efficacy is mostly for juvenile myoclonic epilepsy.48 Less impressive results are seen in other childhood myoclonic epilepsy syndromes. Lamotrigine may be used alone or as an adjunct to valproic acid but has the potential to worsen the myoclonic seizures.49 Ethosuximide, zonisamide, and clonazepam are mainly used as adjuncts. Polypharmacy may be useful but is limited by side effects.
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Paradoxically, antiseizure medications, including phenytoin, carbamazepine, and lamotrigine, which are often used for partial seizures, sometimes increase seizures or myoclonus in these syndromes. Intravenous valproic acid can be useful in myoclonic seizure status.50 Subcortical-Suprasegmental Myoclonus Treatment
Standard antiepileptic treatments are usually not helpful in subcortical myoclonus. In essential myoclonus (including myoclonus-dystonia), treatments such as clonazepam and benzhexol (anticholinergic) are the most useful. Sodium oxybate, the sodium salt of g-hydroxybutyric acid, has been reported to decrease myoclonus in a few cases of myoclonus-dystonia.47 Deep brain stimulation of the thalamus or globus pallidus has had success in case reports and awaits confirmation in a larger number of patients.51 Reticular reflex myoclonus and opsoclonus-myoclonus respond partially to clonazepam.52 The opsoclonus-myoclonus syndrome has recently been reported to be responsive to intravenous immunoglobulin therapy, but this may be treating the underlying autoimmune disorder rather than the myoclonus per se.53 In childhood, the opsoclonus-myoclonus syndrome may occur with a neuroblastoma, and treatment considerations differ from the adult form. Clonazepam is the first line of therapy for propriospinal myoclonus and in exaggerated startle syndromes such as hyperekplexia. Segmental Myoclonus Treatment
Palatal myoclonus can be challenging to treat. The list of drugs with anecdotal success in palatal myoclonus includes but is not limited to clonazepam, carbamazepine, baclofen (Lioresal), anticholinergics, tetrabenazine, valproic acid, phenytoin, lamotrigine, sumatriptan, and piracetam.38 Because ear clicking is so disabling when it occurs in palatal myoclonus, surgical treatments including tensor veli palatini tenotomy and occlusion of the eustachian tube have been tried with variable success.54 Botulinum toxin injections have worked in some cases, but these injections may be difficult to perform, and spread of the toxin can produce significant side effects.55 Clonazepam, in dosages up to 6 mg/d, is the drug of first choice in spinal segmental myoclonus but usually leads to only partial improvement at most. Diazepam, carbamazepine, tetrabenazine, and levetiracetam may prove useful. Botulinum toxin injections for the pain and movements of spinal segmental myoclonus are sometimes successful.56 Peripheral Myoclonus Treatment
For the quick movements in hemifacial spasm, botulinum toxin injection is the established first line therapy.37 Other causes of peripheral myoclonus have also responded to botulinum toxin injections.57 Drugs for peripheral myoclonus are almost always unsatisfactory, but carbamazepine shows improvement in a few cases. REFERENCES
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25. Yokoi F, Dang MT, Li J, et al. Myoclonus, motor deficits, alterations in emotional responses and monoamine metabolism in 3-sarcoglycan deficient mice. J Biochem 2006;140:141–6. 26. Hallett M, Chadwick D, Adam J, et al. Reticular reflex myoclonus: a physiological type of human post-hypoxic myoclonus. J Neurol Neurosurg Psychiatr 1977;40: 253–64. 27. Brown P. Hyperekplexia. Handbook of clinical neurophysiology. Amsterdam: Elsevier; 2003. p. 479–89. 28. Brown P, Thompson PD, Rothwell JC, et al. Axial myoclonus of propriospinal origin. Brain 1991;114:197–214. 29. Cantello R, Gianelli M, Civardi C, et al. Focal subcortical reflex myoclonus. Arch Neurol 1997;54:187–96. 30. Westmoreland BF, Sharbrough FW, Stockard JJ, et al. Brainstem auditory evoked potentials in 20 patients with palatal myoclonus. Arch Neurol 1983;40:155–8. 31. Hopkins AP, Michael WF. Spinal myoclonus. J Neurol Neurosurg Psychiatr 1974; 37:1112–5. 32. Kono I, Ueda Y, Araki K, et al. Spinal myoclonus resembling belly dance. Mov Disord 1994;9(3):325–9. 33. Davis SM, Murray NMF, Galea-Debono A, et al. Stimulus-sensitive spinal myoclonus. J Neurol Neurosurg Psychiatr 1981;44:884–8. 34. Di Lazzaro V, Restuccia D, Nardone R, et al. Changes in spinal cord excitability in a patient with rhythmic segmental myoclonus. J Neurol Neurosurg Psychiatr 1996;61:641–4. 35. Deuschl G, Mischke G, Schenck E, et al. Symptomatic and essential rhythmic palatal myoclonus. Brain 1990;113:1645–72. 36. Deuschl G, Toro C, Balls-Sole J, et al. Symptomatic and essential palatal tremor 1. Clinical, physiological and MRI analysis. Brain 1994;117:775–88. 37. Valls-Sole J. Electrodiagnostic studies of the facial nerve in peripheral facial palsy and hemifacial spasm. Muscle Nerve 2007;36:14–20. 38. Jankovic J, Pardo R. Segmental myoclonus. Clinical and pharmacologic study. Arch Neurol 1986;43:1025–31. 39. Brown P, Steiger MJ, Thompson PD, et al. Effectiveness of piracetam in cortical myoclonus. Mov Disord 1993;8:63–8. 40. Ikeda A, Shibasaki H, Tashiro K, et al. Clinical trial of piracetam in patients with myoclonus: nationwide multiinstitution study in Japan. Mov Disord 1996;11: 691–700. 41. Koskiniemi M, Vleymen B, Hakamies L, et al. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomized, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatr 1998;64:344–8. 42. Fedi M, Reutens D, Dubeau F, et al. Long-term efficacy and safety of piracetam in the treatment of progressive myoclonus epilepsy. Arch Neurol 2001;58:781–6. 43. Frucht SJ, Louis ED, Chuang C, et al. A pilot tolerability and efficacy study of levetiracetam in patients with chronic myoclonus. Neurology 2001;57:1112–4. 44. Genton P, Gelisse P. Antimyoclonic effect of levetiracetam. Epileptic Disord 2000; 2:209–12. 45. Obeso JA, Artieda J, Rothwell JC, et al. The treatment of severe action myoclonus. Brain 1988;112:765–77. 46. Kyllerman M, Ben-Menachem E. Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. Epilepsy Res 1998;29:109–14.
Pathophysiology and Treatment of Myoclonus
47. Frucht SJ, Houghton WC, Bordelon Y, et al. A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor. Neurology 2005;65: 1967–70. 48. Wallace SJ. Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide. Epilepsy Res 1998;29: 147–54. 49. Buchanan N. The use of lamotrigine in juvenile myoclonic epilepsy. Seizure 1996; 5:149–51. 50. Sheth RD, Gidal BE. Intravenous valproic acid for myoclonic status epilepticus. Neurology 2000;54:1201. 51. Magarinos-Ascone CM, Regidor I, Martinez-Castrillo JC, et al. Pallidal stimulation relieves myoclonus-dystonia syndrome. J Neurol Neurosurg Psychiatr 2005;76: 989–91. 52. Caviness JN, Forsyth PA, Layton DD, et al. The movement disorder of adult opsoclonus. Mov Disord 1995;10:22–7. 53. Pless M, Ronthal M. Treatment of opsoclonus-myoclonus with high-dose intravenous immunoglobulin. Neurology 1996;46:583–4. 54. Ensink RJH, Vingerhoets HM, Schmidt CW, et al. Treatment for severe palatoclonus by occlusion of the eustachian tube. Otol Neurotol 2003;24:714–6. 55. Bryce GE, Morrison MD. Botulinum toxin treatment of essential palatal myoclonus tinnitus. J Otolaryngol 1998;27:213–6. 56. Lagueny A, Tison G, Burbaud P, et al. Stimulus-sensitive spinal segmental myoclonus improved with injections of botulinum toxin type A. Mov Disord 1999;14: 182–5. 57. Carnero-Pardo C, Sanchez-Alvarez JC, Gomez-Camello A, et al. Myoclonus associated with thoracodorsal neuropathy. Mov Disord 1998;13(6):971–2.
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Restless Le gs Syndrome William G. Ondo, MD KEYWORDS Restless legs syndrome Genetics Dopamine Iron Treatment
CLINICAL RLS
Restless legs syndrome (RLS) is clinically defined by the presence of 4 criteria: (1) an urge to move the limbs with or without sensations, (2) worsening at rest, (3) improvement with activity, and (4) worsening in the evening or night.1 The diagnosis of RLS is exclusively based on these symptoms. A validated diagnostic phone interview,2 rating scale,3 and quality of life scale4 have all been validated based on these features. The patient subjective descriptions, however, are quite varied and tend to be suggestible and education dependent. The sensation is always unpleasant but not necessarily painful. It is usually deep within the legs and commonly between the knee and ankle. In a study of patients with RLS , the most common terms used, in descending order of frequency, included: ‘‘need to move,’’ ‘‘crawling,’’ ‘‘tingling,’’ ‘‘restless,’’ ‘‘cramping,’’ ‘‘creeping,’’ ‘‘pulling,’’ ‘‘painful,’’ ‘‘electric,’’ ‘‘tension,’’ ‘‘discomfort,’’ and ‘‘itching.’’5 Patients usually deny any ‘‘burning’’ or ‘‘pins and needles’’ sensations, commonly experienced in neuropathies or nerve entrapments, although neuropathic pain and RLS can coexist. The key is to rephrase their description into a question by asking, ‘‘If that makes you want to move your legs, is it better while moving, and are the symptoms worse in the evening/night?’’ Essentially all patients report transient symptomatic improvement by walking, although some use stationary bike riding or kicking. Other therapeutic techniques reported by our patients include rubbing or pressure, stretching, and hot water. All symptom relief strategies increase sensory stimulation to the legs and are generally alerting. Other clinical features typical for RLS include the tendency for symptoms to gradually worsen with age, improvement with dopaminergic treatments, a positive family history of RLS, and periodic limb movements of sleep (PLMS). PERIODIC LIMB MOVEMENTS OF SLEEP
PLMS are defined by the Association of Sleep Disorders as ‘‘periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep.’’ The incidence in the general population increases with age and is reported to occur in as many as 57% of elderly people.6–9 Therefore, PLMS are common in the general population. Department of Neurology, Baylor College of Medicine, 6550 Fannin Drive, Suite 1801, Houston, TX, USA E-mail address:
[email protected] Neurol Clin 27 (2009) 779–799 doi:10.1016/j.ncl.2009.04.007 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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One study, employing a cut-off of 5 PLMS/hour, reported that 81% of patients with RLS showed pathologic PLMS.10 The prevalence increased to 87% if 2 nights were recorded. Although PLMS accompany most cases of RLS, RLS prevalence in the setting of polysomnographically documented PLMS found that only 9 of 53 patients (17.0%) with PLMS complained of RLS symptoms.11 Therefore, most people with RLS have PLMS but many patients with isolated PLMS do not have RLS. The exact relationship between the 2 phenotypes is unclear, but recent genetic studies suggest that they are highly correlated. PLMS can occur simultaneously in both legs, alternate between legs, or occur unilaterally. The duration of movement is typically between 1.5 and 2.5 seconds and varies in intensity from slight extension of the great toe to a triple flexion response. Other tonic and myoclonic patterns are less frequently observed, and arms are involved only in a minority of cases. Patients frequently show a movement periodicity of between 20 and 40 seconds, although wide ranges of frequencies and muscle involvement have been reported. Movements are most pronounced in Stage I and Stage II of sleep, where they are often accompanied by K-complexes and by increases in pulse and blood pressure.12 The K-complexes usually precede the PLMS and may persist even if PLMS are reduced with L-dopa.13 PLMS intensity and frequency lessen as sleep deepens. They may persist during rapid eye movement sleep but both the amplitude and frequency are significantly reduced. PLMS may result in arousals but are not generally associated with insomnia.9,14 RLS IN CHILDREN
RLS in children can be difficult to diagnose.15 Although some children report classic RLS symptoms that meet inclusion criteria, others complain of ‘‘growing pains,’’16,17 and some appear to present with an attention-deficit/hyperactivity disorder (ADHD) phenotype. Kotagal and colleagues18 reported that children with RLS have lesser than expected serum ferritin levels and in most cases appear to inherit the disorder from their mother. The National Institutes of Health (NIH) diagnostic criteria for RLS in children are not as well validated but emphasize supportive criteria such as a family history of RLS, sleep disturbances, and the presence of PLMS, which is much less common in pediatric controls.1 The exact relationship between RLS and ADHD is not known. Children diagnosed with ADHD often have PLMS19–22 and meet some criteria for RLS.19 In children with ADHD the prevalence of having a parent with RLS is greater,23 and children diagnosed with PLMS often have ADHD.24 Dopaminergic treatment of RLS/PLMS in children also improves ADHD symptoms.25 Therefore, there is clearly some association between RLS and ADHD. DIAGNOSTIC EVALUATION OF RLS
In most cases, only a simple evaluation is justified for clinically typical RLS. Serum ferritin, and possibly iron-binding saturation, should be obtained for serum iron deficiency, and electrolytes should be obtained for renal failure. Nerve conduction velocities (NCV) and electromyogram (EMG) may be performed in cases without a family history of RLS, atypical presentations (ie, sensations beginning in the feet or superficial pain), in cases that have a predisposition for neuropathy (ie, diabetes) or when physical symptoms and signs are consistent with peripheral neuropathy. If EMG/NCV abnormalities are found, they should be further evaluated. Polysomnographic evaluation is usually reserved for patients in whom the diagnosis is doubtful, in cases where PLMS are suspected to be severe and result in arousals, or if any other sleep disorder
Restless Legs Syndrome
is suspected. There are several potential diagnostic dilemmas. Akathisia represents an inner sense of restlessness accompanied by an intense desire to move. These patients do not typically complain of limb paresthesia. The restlessness is usually generalized, but may be most prominent in the legs. The condition is usually associated with the use of neuroleptic (dopamine blocking) drugs. Akathisia patients generally have milder sleep complaints and less severe PLMS than is seen in RLS.26 Akathisia tends to be associated with whole-body rocking movements or marching in place, and it may concurrently show mild extrapyramidal features or tardive dyskinesia. Painful legs and moving toes present with neuropathic leg pain associated with persistent, semi-rhythmic toe movements, which cannot easily be reproduced volitionally, and may be only partially suppressed.27 The condition may be associated with peripheral nerve injury or minor leg trauma, but many patients have no identifiable etiology or pathology. This syndrome differs clinically from RLS in that the sensory symptoms are described as painful, are not worsened by immobility, are not necessarily worse at night, and are not improved with movement. Nocturnal leg cramps are a common multifactorial disorder manifested by paroxysmal, disorganized spasms that usually involve the feet or calf muscles. The presentation is quite different from that of RLS, but patients may initially describe their RLS symptoms simply as ‘‘night cramps,’’ which can lead to misdiagnosis if a more extensive history is not taken. Other conditions in the differential diagnosis include body positional discomfort syndrome, where patients simply cannot find a comfortable position to lie in, neuropathic or radicular pain, and generalized anxiety. EPIDEMIOLOGY
Historically, epidemiologic studies of RLS were limited by the subjective nature of the disease, the lack of standardized diagnostic criteria, and the indolent onset of the condition. Ekbom initially estimated a 5% prevalence of RLS in the general population.28 Subsequent general population prevalence surveys varied from 1% to 29%.29–31 The largest epidemiologic study of RLS involved more than 23,000 persons from five countries.32 Similar to smaller reports, 9.6% of all people met the criteria for RLS. In general, northern European countries showed increased prevalence compared with Mediterranean countries. The vast majority of these persons were not previously diagnosed, despite frequently reporting symptoms to their physicians. RLS can occur in all ethnic backgrounds; however, most feel that Caucasians are most affected. While most Caucasian surveys show an approximate 10% prevalence, surveys in Asian populations report much lesser prevalences (Table 1). People of African descent have never been specifically studied, but anecdotally African Americans rarely present with RLS. It is unclear whether this represents a true lesser prevalence, or rather differences in medical sophistication and referral patterns. Women usually have higher RLS rates. GENETICS OF RLS
In 40%–60% of cases, a family history of RLS can be found, although this is often not initially reported by the patient.5 Twin studies also show a very high concordance rate.33,34 Most pedigrees suggest an autosomal dominant (AD) pattern,35 although an autosomal recessive (AR) pattern with a very high carrier rate is possible. To date at least 6 gene linkages have been shown in family studies, 5 risk-factor genes identified through genome-wide association studies, and 1 through candidate gene
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Table 1 Selected epidemiology of restless legs syndrome in the general population since 1995 RLS Diagnostic Criteria
Author, y
N
Population
Location
RLS (%)
Tison et al, 2005181
10,263
IRLSSG interview
Adults
France
8.5
Henning et al, 200432
23,052
NIH written
Adults
Europe/United States
9.6
Garbarino 2560 et al, 2002182
Written
Police shift workers
Genoa, Italy
8.5: shift workers 4.2: day workers
Ohayan and 18,980 Roth, 2002183
ICSD phone interview
15–100
Europe
5.5
Berger et al, 2004184
IRLSSG interview
20–79
Northeast Germany
10.6
IRLSSG interview
65–83
Augsburg, Germany
9.8
4310
Rothdach 369 et al, 2000185 Nichols et al, 2003186
2099
IRLSSG
Adult
Idaho (single PCP)
24.0
Ulfberg et al, 2001187
200
IRLSSG written
Women 18–64
Sweden
11.4
Ulfberg et al, 2001188
4000
IRLSSG written
Men 18–64
Sweden
5.8
Phillips et al, 200031
1803
Single phone question
>18
Kentucky, United 10.0 States
Lavigne et al, 1997189
2019
2 written questions
Adults
Quebec, Canada
10–15
Cho et al, 2008190
5000
Phone interview IRLSSG
18–69
South Korea
3.9
Sevim et al, 2002191
3234
IRLSSG interview Adults, no secondary RLS
Turkey
3.2
Tan et al, 2001192
1000
IRLSSG interview >21
Singapore
0.1
Japan
1.5
Kageyama 3600 female, Single written et al, 2000193 1012 male question
Adults
Abbreviations: ICSD, International Classification of Sleep Disorders; IRLSSG, International Restless Legs Syndrome Study Group diagnostic criteria; NIH, National Institutes of Health RLS diagnostic criteria.
analysis (Table 2). To date, no actual mutation has been identified in individual families. At least 2 of the risk genes are associated with spinal cord development, but none are directly linked to dopamine systems or iron regulation, the 2 areas most associated in RLS pathology. As with other common conditions, the genetics of RLS are complex and probably involve the presence of multiple at-risk genetic alleles. PATHOPHYSIOLOGY OF RLS
Pathologic studies suggest that the pathophysiology of RLS involves central nervous system (CNS) iron homeostatic dysregulation. Cerebrospinal fluid (CSF) ferritin is
Restless Legs Syndrome
Table 2 Genes and linkages associated with RLS Chromosome Gene
Odds Ratio
6p21.2
BTBDP
1.3 (1.04–1.7) Zinc Finger194,195
Comment
2p
MEISI
1.7 (1.4–2.1)
15q
LBXCOR1 1.5 (1.2–1.9)
9p23-24
PTPRD MAO-A NOS1
Homobox gene195 Mitogen-activated protein kinase195
1.4 protein tyrosine phosphatase receptor type delta196 2.0 (1.1–3.8) High activity allele in women only197 0.76 (0.6–0.9) Neuronal nitric oxide synthase-1198
12q22-23
AR French Canadian family199
14q13-21
AD Italian200
9p24.2-22.3
No mutation in PTPRD found, AD, United States201
2q33
South Tyrolean202
20p13
French Canadian, AD203
9p
May be different from US families, German204
16p12.1
AD, French Canadian205
lower in RLS cases,36 and specially sequenced MRI imaging studies show reduced iron stores in the striatum and red nucleus.37,38 Recently, CNS ultrasonography was able to identify RLS based on reduced iron echogenicity in the substantia nigra.39,40 Most importantly, pathologic data in RLS autopsied brains show reduced ferritin staining, iron staining, and increased transferrin stains, but reduced transferrin receptors.41 Researches also show reduced Thy-1 expression, which is regulated by iron levels.42 Substantia nigra dopaminergic cells are not reduced in number, nor are there any markers associated with neurodegenerative diseases, such as tau or alpha-synuclein abnormalities.43,44 The reduced transferrin receptor finding is especially important because globally reduced iron stores would normally upregulate transferrin receptors. Therefore it appears that primary RLS has reduced intracellular iron indices secondary to a perturbation of homeostatic mechanisms that regulate iron influx and/or efflux from the cell. Intracellular iron regulation is very complex; however, subsequent staining of RLS brains has shown reduced levels of iron regulatory protein-type 1.41 This potentiates or inhibits (depending on feedback mechanisms involving iron atoms themselves) the production of ferritin molecules, which are the main iron storage proteins in the CNS and in the periphery, and transferrin receptors, which facilitate intracellular iron transport. CNS dopaminergic systems are also implicated in RLS. Most researchers agree that dopamine agonists (DA) acutely and robustly treat RLS. The normal circadian dopaminergic variation is also augmented in patients with RLS.45 However, dopaminergic brain imaging studies are inconsistent and show modest or no abnormalities.46–49 Dopamine precursor studies show normal or reduced levels, dopamine transporter studies have been normal, and dopamine receptor studies show reduced, normal, or increased activity. It should be noted that these mostly reflect activity in the striatum. There is no pathologic evidence of reduced cells or dopamine itself. If fact, indirect evidence suggests that there is an increased dopamine turnover in RLS.50 There are several potential interactions between iron and dopamine systems. First iron is a cofactor for tyrosine-hydroxylase, which is the rate-limiting step in the production of dopamine. Iron chelation reduces dopamine transporter protein expression and activity in mice.51 However, 3 observations follow. First, human CSF studies have
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failed to show reduced dopaminergic metabolites.52,53 Second, iron is a component of the dopamine type-2 (D2) receptor. Iron deprivation in rats results in a 40% to 60% reduction of D2 postsynaptic striatal but not spinal cord receptors.54–56 The effect in the striatum is quite specific, as other neurotransmitter systems including D1 receptors are not affected. Third, iron is necessary for Thy1 protein regulation. This cell adhesion molecule, which is robustly expressed on dopaminergic neurons, is reduced in brain homogenates in iron-deprived mice57 and in brains of patients with RLS.42 Thy1 regulates vesicular release of monoamines, including dopamine.58 It also stabilizes synapses and suppresses dendritic growth.59 Another puzzle that remains is the identification of a specific anatomy culpable for RLS. The spinal cord and subcortex are implicated in studies of RLS onset after stroke,60 and more specifically, involvement of the seldom studied diencephalospinal dopaminergic tract, originating from the A11–A14 nuclei, might explain some RLS features. It is involved in antinociception, is near circadian control centers, and would explain why legs are involved more than arms. A preliminary animal model with A11 lesions showed increased standing episodes, which improved after the administration of ropinirole, a dopamine agonist.61 Subsequent studies of this model in mice, with and without dietary iron deprivation, also show increased movement, as measured in laser marked cages, in the lesioned animals.62 This hyperkinesis is normalized by D2 agonists such as ropinirole and pramipexole, but not by the D1 agonist SKF. Opioid pathways are implicated by clinical improvement seen with narcotics, and recent pathologic data show reduction of b-endorphin positive cells (37.5%, P 5 .006, effect size 2.16) and met-enkephalin positive cells (26.4%, P 5 .028, effect size 1.58) in 6 patients with RLS compared with 6 controls.63 Dopamine activity was normal in this study. Afferent systems are also implicated.64 Stiasny-Kolster reported that pinprick pain ratings (static hyperalgesis) in patients with RLS were significantly elevated in the lower limb whereas pain to light touch (allodynia 5 dynamic mechanical hyperalgesia) was normal. They felt this type of hyperalgesia was probably mediated by central sensitization to A-delta fiber high-threshold mechanoreceptor input, a hallmark sign of the hyperalgesia type of neuropathic pain. SECONDARY RLS
Despite the appropriate attention given to RLS genetics, between 2% and 6% of the population probably suffer from RLS without any identifiable highly penetrant genetic pattern. Patients without a positive family history are classified as either primary RLS, if no other explanation is found, or secondary RLS, if they concurrently possess a condition known to be associated with RLS. The most common causes of secondary RLS include renal failure, iron deficiency, neuropathy, myelinopathy, pregnancy, multiple sclerosis,65 and possibly Parkinson disease and essential tremor. There is some evidence to support an association of RLS with some genetic ataxias,66–68 fibromyalgia,69–71 and rheumatological diseases.72–75 A variety of other associations are at best tenuous. Finally, several medications are known to exacerbate existing RLS or possibly precipitate RLS themselves. The most notable of these include antihistamines, dopamine antagonist, including many antinausea medications, mirtazapine, and possibly tricyclic antidepressants and serotonergic reuptake inhibitors. Numerous forms of neuropathy, including diabetic, alcoholic, amyloid neuropathy, motor neuron disease, poliomyelitis, and radiculopathy, have been seen at higher than expected frequency in patients presenting with RLS.5,76–86 In contrast, series
Restless Legs Syndrome
evaluating RLS in populations presently with neuropathy have not shown a particularly high prevalence of RLS, usually ranging from 5% to 10%, similar to the general population.82,83 Hatten recently presented data from a neuropathy cohort. They found that a larger percentage of neuropathy patients endorsed RLS on screen questionnaires (18.4% versus 6.1%) but upon interview this narrowed to 12% versus 8% of controls. Specific forms of neuropathy may incur different risks for the development of RLS. Gemignani and colleagues76 reported that 10 of 27 patients (37%) with Charcot-MarieTooth type II (CMT II), an axonal neuropathy, had RLS, whereas RLS was not seen in any of 17 patients with CMT I, a demyelinating neuropathy. The phenotype of neuropathic RLS may be slightly different from that of idiopathic RLS.5,80 In our population, neuropathic RLS symptoms initially presented more acutely and at an older age, and then progressed rapidly. Numerous patients with neuropathic RLS reached maximum symptom intensity within 1 year from the initial symptom onset, which is unusual in idiopathic cases. Neuropathic RLS may also have accompanying neuropathic pain, which is often burning and more superficial. The painful component and the urge to move, however, are seldom differentiated by the patient. The spinal cord is implicated in the pathogenesis of RLS,87 and cases of RLS and PLMS are seen after transient or permanent spinal cord lesions. Traumatic spinal cord lesions,88,89 neoplastic spinal lesions,90 demyelinating or postinfectious lesions,91–93 and syringomyelia94 all can precipitate RLS and PLMS. Spinal cord blocks used for anesthesia also frequently cause or exacerbate RLS.95,96 Hogl and colleagues95 systematically evaluated RLS following spinal anesthesia. Of 161 patients without any history of RLS, 8.7% developed RLS immediately after the procedure. Uremia secondary to renal failure is strongly associated with RLS symptoms. Multiple series report a 20% to 57% prevalence of RLS in renal dialysis patients; however, only a minority of uremic patients volunteer RLS symptoms unless specifically queried.97–114 Numerous risk factors have been identified in individual studies but none consistently. The prevalence of RLS in mild to moderate renal failure that does not require dialysis is unknown. The RLS seen in patients on dialysis is often severe. Compared to idiopathic RLS, series show similar or increased overall severity, increased PLMS, increased wakeful leg movements, and a more rapid progression.111,115 Both RLS and PLMS have also been associated with increased mortality in the dialysis population.112,116,117 Dialysis does not improve RLS. In fact, one study suggested that RLS correlated with greater dialysis frequency.103 However, patients who receive a successful kidney transplant usually experience dramatic improvement in RLS within days to weeks.118–120 The degree of symptom alleviation appears to correlate with improved kidney function. Reduced CNS iron is possibly implicated in all cases of RLS. It is intuitive to suggest that reduced body stores of iron could also result in low CNS intracellular iron and also cause RLS symptoms. A series of reports have associated low serum ferritin levels with RLS.36,37,121–125 Serum ferritin is the best indicator of reduced iron stores and the only serum measure to consistently correlate with RLS. Anemia has not been independently associated with RLS; however, blood donors frequently develop RLS symptoms.123,126 Decreased serum iron stores are only associated with certain demographics of patients with RLS. The authors have reported that serum ferritin is lesser in patients with RLS who lack a family history compared with those with familial RLS.121,127 Earley and colleagues128 have made the same observation but segregated the groups based on age of RLS onset. The patients with an older age of RLS onset had lesser serum
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ferritin levels compared with patients with a younger age of onset. These groups, however, generally represent the same dichotomy as genetic based segregations since there is a very strong correlation between a younger age of onset of RLS and a positive family history. The development of RLS during pregnancy has long been recognized.28,129,130 Manconi and colleagues131 evaluated risk factors for RLS in 606 pregnancies. They reported that 26% of these women suffered from RLS, usually in the last trimester. The authors could find no significant differences in age, pregnancy duration, mode of delivery, tobacco use, the woman’s body mass index, baby weight, or iron/folate supplementation in those with RLS. Hemoglobin, however, was significantly lesser in the RLS group, and plasmatic iron tended to be lesser, compared with those without RLS. Several other studies have also correlated RLS with anemia before132 or during pregnancy.133 RLS and Parkinson disease (PD) both respond to dopaminergic treatments, both show dopaminergic abnormalities on functional imaging,48,134 and both are associated with PLMS.135 However, the pathologies of the 2 dopaminergically treated diseases are very different, and in regard to iron accumulation they are actually quite opposite.44 Several surveys have found a 20% prevalence of RLS in PD populations.121,136–139 In a survey of 303 consecutive patients with PD, the authors found that 20.8% of all patients with PD met the diagnostic criteria for RLS. Only decreased serum ferritin was associated with RLS.121 Asian populations, which have less RLS in general, also have lesser numbers of RLS in their PD populations.140,141 Despite this high number of cases, there are several caveats that tend to lessen its clinical significance. The RLS symptoms in patients with PD are often ephemeral, usually not severe, and can be confused with other PD symptoms such as wearingoff dystonia, akathisia, or internal tremor. They do not correlate with daytime sleepiness, and PD precedes the RLS in most cases. There is no evidence that RLS becomes PD. Essential tremor (ET) is associated with RLS in one study.142 Patients in the ET/RLS group almost always presented with ET, often severe. Interestingly, they had family histories of both, suggesting a common genetic origin. TREATMENT OF RLS
The development of validated rating scales and standardized diagnostic criteria have vastly improved the quality of RLS treatment trials. Although multiple medications have shown outstanding efficacy, all of them provide only symptomatic relief rather than any ‘‘curative’’ effect (Table 3). Therefore, treatment should only be initiated when the benefits are felt to justify any potential side effects and costs. Treatment decisions also need to consider the chronicity and general progressive course of RLS. Over time, both dosing and medication changes are often required to maximize benefit and minimize the risk of tolerance and side effects. DAs are clearly the best investigated and probably most effective treatments for RLS. The improvement is immediate and often very dramatic. No evidence favors any particular DA. Ropinirole,143–145 pramipexole,146–148 and rotigotine patches149,150 are the best studied. Pergolide,143,151–154 bromocriptine,155 apomorphine,156 cabergoline,157 and lisuride158 are also effective. Polysomnogram studies of DA consistently show dramatic improvement in PLMS, and modest or no improvement in other sleep parameters. Adverse events in RLS DA studies are generally milder than DA PD studies, perhaps owing to the lesser dose or differences in the disease state.
Restless Legs Syndrome
Table 3 Medications and doses used for RLS Drug
Amount Per Dose (mg)
Duration of Effect (h)
Comment
Dopaminergics: immediate effect, considered first line therapy L-dopa
100–250
2–6
Approved in Europe, fast onset, can use as needed, highest augmentation rates
Pramipexole
0.125–1
5–12
Approved, commonly used, slower onset but longer duration
Ropinirole
0.25–4
4–8
Approved, slow release preparations available
Pergolide
0.125–1
6–14
Well studied but seldom used because of the risk for cardiac valve fibrosis and other possible ergot AEs
Cabergoline
0.25–2
>24
Long acting but may have same AEs as other ergot DAs
Rotigotine
0.5–6
24
Patch preparation, well studied and effective in RLS
Bromocriptine
5–20
4–6
Rarely used in RLS
Opioids: numerous opioids are used Methadone
2–15
8–12
Latency to benefit
Hydrocodone
5–10
4–10
Faster acting, shorter duration
Alpha-2 delta blockers Gabapentin
300–1200
4–8
May help painful component of RLS
Pregabalin
50–200
6–12
Trials underway but almost no published data
Gabapentin enacarbil
600–12,000
8–16
Gabapentin prodrug with better absorption and pK profile. Well studied and effective
Benzodiazepines: more beneficial for sleep than RLS, can be used in combination with other RLS medications. Clonazepam (0.5–2.0 mg) is traditionally used. Oral iron
>50
?
No specific iron salt is superior, titrate up as tolerated. Ferritin will only modestly increase
IV iron dextran
1g
?
Usually not repeated before 3 months, several day latency to benefit, long-term safety unknown, patients with ‘‘normal’’ serum ferritin equally responsive
Hallucinations and hypotension rarely occur in RLS, and daytime sedation may lessen rather than increase. Nausea remains the most common adverse event. DAs work best if administered 60 to 90 minutes before the onset of symptoms. Based on pharmacokinetics, many people may benefit from more than 1 dose, despite the formal indications, which recommend dosing 1 to 3 hours before bed. The effect is immediate, so titration to the smallest effective dose can be fairly rapid. The dopamine precursor levodopa also effectively treats RLS;159–163 however, several comparative studies have favored DA over levodopa.152,164,165 Levodopa is also felt to have greater potential for augmentation.166 The long-term use of DA for RLS may be more problematic. Although studies up to 1 year have shown that most patients on DA continue to benefit from the medications,167,168 some reports have raised specific concerns about both the development of tolerance and dopaminergic induced augmentation. Augmentation is defined by an earlier phase shift of symptom onset, an increased intensity of symptoms, increased
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anatomic involvement, or less relief with movement.169 Winkelman and colleagues retrospectively assessed augmentation and tolerance in 59 patients treated for RLS with pramipexole for at least 6 months (mean duration 5 21.2 11.4 months). Augmentation developed in 32% (19/59), and tolerance occurred in 46% (27/59) of patients. These two complications were statistically related (P<.05). The only clinical predictors of these complications were previous augmentation or tolerance to Ldopa. The authors evaluated for augmentation in 83 patients with RLS who were initially started on a DA by them. Patients with at least 6 months use of DA were followed up for a mean of 39.2 20.9 months. Efficacy was maintained over time but at the expense of moderate but significant increases in dose (P<.01). Adverse events were frequent but usually mild, and seldom resulted in discontinuation. Augmentation was frequent (48%) but usually modest, and predicted by a positive family history for RLS and especially the lack of any neuropathy on EMG/NCV. The mechanisms behind augmentation are not understood. Opioid medications, also known as narcotics, have long been known to successfully treat RLS. Open-label trials consistently show good initial and long-term results, without difficulty with tolerance, dependence, or addiction.170 There exist, however, only 2 controlled trials that show efficacy.162,171 The author of this review and his team used opioids as second line therapy and reported their experience with methadone (a m-specific opioid agonist) in patients with RLS who have failed DA because of lack of efficacy, adverse events, or severe augmentation.172 Overall, methadone at doses from 5 to 20 mg/d markedly benefits most refractory patients with RLS without augmentation, tolerance, or evidence for dependency. Gabapentin is an antiepileptic with multiple mechanisms of action, including inhibition of the Alpha (delta) subunit of the sodium channel. Garcia-Borreguero and colleagues conducted a 24-patient, 6-week per arm, cross-over study of gabapentin (mean dose 1855 mg/day) or placebo. RLS rating scale, clinical global impression, pain analog scale, and the Pittsburgh sleep quality index all improved on gabapentin. In addition, sleep studies showed significantly reduced PLMS and improved sleep architecture (increased total sleep time, sleep efficiency, and slow wave sleep, and decreased stage 1 sleep). The PLMS did not improve as robustly as seen in DA studies. Solzira (Gabapentin enacarbil) is a novel preparation that is absorbed more effectively.173 Multiple large trials have shown efficacy. Polysomnographic studies showed increased slow wave sleep and moderately improved PLMS. This drug is currently before several regulatory agencies for an RLS indication. Pregabalin (Lyrica) is also undergoing Phase III trials for RLS. Despite their past widespread use, there is little data to support the use of benzodiazepines for RLS. In the opinion of most experts benzodiazepines help facilitate sleep but seldom improve RLS’s cardinal features. These can be used successfully in mild cases of RLS and as adjunct therapy for residual insomnia. Although open-label oral iron supplementation has been reported to improve RLS,174 the only controlled study of oral iron supplementation failed to improve RLS symptoms.175 Oral iron, however, has numerous limitations related to absorption and tolerance. In contrast, the administration of high dose (1 g) intravenous iron can dramatically increase serum ferritin levels. An open-label study of intravenous iron showed robust efficacy.176 Controlled trials of iron dextran with uremic RLS also show efficacy.177 Additional studies with different iron preparations are ongoing. Numerous other agents including other antiepileptic medications, clonidine, baclofen, tramadol, and magnesium, have been reported to help RLS but suffer from limited data and cannot be recommended as either first or second line therapy. Physical measures that increase activity or create a sensory stimulus178 can also improve
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RLS but are often problematic when one desires sleep. Botulinum toxin administration into leg muscles179 and deep brain stimulation into the thalamic ventral intermedial nucleus180 do not help. REFERENCES
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144. Walters AS, Ondo WG, Dreykluft T, et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord 2004;19(12):1414–23. 145. Bogan R, Connolly G, Rederich G. Ropinirole is effective, well tolerated treatment for moderate-to-severe RLS: results of a U.S. study. Mov Disord 2005; 20(Suppl 10):S61. 146. Oertel W, Stiasney-Kolster K. Pramipexole is effective in the treatment of restless legs syndrome (RLS): results of a 6 week, multi-centre, double, and placebo controlled study. Mov Disord 2005;20(Suppl 10):S58. 147. Trenkwalder C, Stiasny-Kolster K, Kupsch A, et al. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord 2006;21(9):1404–10. 148. Partinen M, Hirvonen K, Jama L, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study-the PRELUDE study. Sleep Med 2006;7(5):407–17. 149. Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2008;7(7):595–604. 150. Oertel WH, Benes H, Garcia-Borreguero D, et al. Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe. Sleep Med 2008; 9(3):228–39. 151. Earley CJ, Yaffee JB, Allen RP. Randomized, double-blind, placebo-controlled trial of pergolide in restless legs syndrome. Neurology 1998;51(6):1599–602. 152. Staedt J, Wassmuth F, Ziemann U, et al. Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A doubleblind randomized crossover trial of pergolide versus L-Dopa. J Neural Transm (Budapest) 1997;104(4–5):461–8. 153. Trenkwalder C, Brandenburg U, Hundemer H, et al. A randomized long-term placebo controlled multicenter trial of pergolide in the treatment of restless legs syndrome with central evaluation of polysomnographic data. Neurology 2001;56(Suppl 3):A5. 154. Wetter TC, Stiasny K, Winkelmann J, et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999;52(5): 944–50. 155. Walters AS, Hening WA, Kavey N, et al. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol 1988;24(3):455–8. 156. Reuter I, Ellis CM, Ray Chaudhuri K. Nocturnal subcutaneous apomorphine infusion in Parkinson’s disease and restless legs syndrome. Acta Neurol Scand 1999;100(3):163–7. 157. Happe S, Trenkwalder C. Role of dopamine receptor agonists in the treatment of restless legs syndrome. CNS Drugs 2004;18(1):27–36. 158. Benes H. Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome. Sleep Med 2006;7(1):31–5. 159. Benes H, Kurella B, Kummer J, et al. Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep 1999;22(8):1073–81. 160. Brodeur C, Montplaisir J, Godbout R, et al. Treatment of restless legs syndrome and periodic movements during sleep with L-dopa: a double-blind, controlled study. Neurology 1988;38(12):1845–8.
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161. Collado-Seidel V, Kazenwadel J, Wetter TC, et al. A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms. Neurology 1999;52(2):285–90. 162. Kaplan PW, Allen RP, Buchholz DW, et al. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/ levodopa and propoxyphene. Sleep 1993;16(8):717–23. 163. Saletu M, Anderer P, Hogl B, et al. Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa and sr-L-dopa in restless legs syndrome. J Neural Transm 2003; 110(6):611–26. 164. Trenkwalder C, Benes H, Grote L, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multicenter, randomized, active controlled trial. Mov Disord 2007;22(5):696–703. 165. Pellecchia MT, Vitale C, Sabatini M, et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release. Clin Neuropharmacol 2004;27(4): 178–81. 166. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/ levodopa. Sleep 1996;19(3):205–13. 167. Stiasny K, Wetter TC, Winkelmann J, et al. Long-term effects of pergolide in the treatment of restless legs syndrome. Neurology 2001;56(10):1399–402. 168. Montplaisir J, Denesle R, Petit D. Pramipexole in the treatment of restless legs syndrome: a follow-up study. Eur J Neurol 2000;7(Suppl 1):27–31. 169. Garcia-Borreguero D, Kohnen R, Hogl B, et al. Validation of the Augmentation Severity Rating Scale (ASRS): a multicentric, prospective study with levodopa on restless legs syndrome. Sleep Med 2007;8(5):455–63. 170. Walters AS, Winkelmann J, Trenkwalder C, et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord 2001;16(6):1105–9. 171. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993;16(4):327–32. 172. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord 2005; 20(3):345–8. 173. Merlino G, Serafini A, Young JJ, et al. Gabapentin enacarbil, a gabapentin prodrug for the treatment of the neurological symptoms associated with disorders such as restless legs syndrome. Curr Opin Investig Drugs 2009;10(1):91–102. 174. O’Keeffe ST, Noel J, Lavan JN. Restless legs syndrome in the elderly. Postgrad Med J 1993;69(815):701–3. 175. Davis BJ, Rajput A, Rajput ML, et al. A randomized, double-blind placebocontrolled trial of iron in restless legs syndrome. Eur Neurol 2000;43(2):70–5. 176. Earley CJ, Heckler D, Allen RP. The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 2004;5(3):231–5. 177. Sloand JA, Shelly MA, Feigin A, et al. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis 2004;43(4):663–70. 178. Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest 2009;135(1):74–80. 179. Nahab FB, Peckham EL, Hallett M. Double-blind, placebo-controlled, pilot trial of botulinum toxin A in restless legs syndrome. Neurology 2008;71(12): 950–1.
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180. Ondo W. VIM deep brain stimulation does not improve pre-existing restless legs syndrome in patients with essential tremor. Parkinsonism Relat Disord 2006; 12(2):113–4. 181. Tison F, Crochard A, Leger D, et al. Epidemiology of restless legs syndrome in French adults: a nationwide survey: the INSTANT Study. Neurology 2005;65(2): 239–46. 182. Garbarino S, De Carli F, Nobili L, et al. Sleepiness and sleep disorders in shift workers: a study on a group of italian police officers. Sleep 2002;25(6): 648–53. 183. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002;53(1): 547–54. 184. Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164(2):196–202. 185. Rothdach AJ, Trenkwalder C, Haberstock J, et al. Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology 2000;54(5):1064–8. 186. Nichols DA, Allen RP, Grauke JH, et al. Restless legs syndrome symptoms in primary care: a prevalence study. Arch Intern Med 2003;163(19):2323–9. 187. Ulfberg J, Nystrom B, Carter N, et al. Restless Legs Syndrome among workingaged women. Eur Neurol 2001;46(1):17–9. 188. Ulfberg J, Nystrom B, Carter N, et al. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001;16(6):1159–63. 189. Lavigne GL, Lobbezoo F, Rompre PH, et al. Cigarette smoking as a risk factor or an exacerbating factor for restless legs syndrome and sleep bruxism. Sleep 1997;20(4):290–3. 190. Cho YW, Shin WC, Yun CH, et al. Epidemiology of restless legs syndrome in Korean adults. Sleep 2008;31(2):219–23. 191. Sevim S, Dogu O, Camdeviren H, et al. Unexpectedly low prevalence and unusual characteristics of RLS in Mersin, Turkey. Neurology 2003;61(11): 1562–9. 192. Tan EK, Seah A, See SJ, et al. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001;16(3):577–9. 193. Kageyama T, Kabuto M, Nitta H, et al. Prevalences of periodic limb movementlike and restless legs-like symptoms among Japanese adults. Psychiatry Clin Neurosci 2000;54(3):296–8. 194. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357(7):639–47. 195. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39(8):1000–6. 196. Schormair B, Kemlink D, Roeske D, et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 2008; 40(8):946–8. 197. Desautels A, Turecki G, Montplaisir J, et al. Evidence for a genetic association between monoamine oxidase A and restless legs syndrome. Neurology 2002; 59(2):215–9. 198. Winkelmann J, Lichtner P, Schormair B, et al. Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome. Mov Disord 2008;23(3):350–8.
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199. Desautels A, Turecki G, Montplaisir J, et al. Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity. Arch Neurol 2005;62(4):591–6. 200. Bonati MT, Ferini-Strambi L, Aridon P, et al. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 2003;126(Pt 6):1485–92. 201. Chen S, Ondo WG, Rao S, et al. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004;74(5):876–85. 202. Pichler I, Marroni F, Volpato CB, et al. Linkage analysis identifies a novel locus for restless legs syndrome on chromosome 2q in a South Tyrolean population isolate. Am J Hum Genet 2006;79(4):716–23. 203. Levchenko A, Provost S, Montplaisir JY, et al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology 2006;67(5): 900–1. 204. Lohmann-Hedrich K, Neumann A, Kleensang A, et al. Evidence for linkage of restless legs syndrome to chromosome 9p: are there two distinct loci? Neurology 2008;70(9):686–94. 205. Levchenko A, Montplaisir JY, Asselin G, et al. Autosomal-dominant locus for Restless Legs Syndrome in French-Canadians on chromosome 16p12.1. Mov Disord 2009;24(1):40–50.
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Psychogenic Movement Disorder s Elizabeth L. Peckham, DOa,*, Mark Hallett, MDb KEYWORDS Psychogenic movement disorder Functional movement disorder Conversion Tremor Medically unexplained symptoms Dystonia
Psychogenic movement disorders (PMDs) represent a challenging dilemma for the treating neurologist. The terminology to classify this disorder is confusing and making the diagnosis is difficult. Once the diagnosis has been established, treatment options are limited, and the patient generally does not accept the diagnosis. DEFINITIONS
The definition of PMDs is movement disorders caused by an abnormal psychiatric state, rather than an organic disorder of the nervous system. Psychogenic dystonia has been classified based on the level of certainty by Fahn and Williams.1 This classification is now widely accepted for other types of movements observed in PMDs. Documented Psychogenic
Movements are persistently relieved by psychotherapy or psychological suggestion or with the administration of placebos. If the patient is observed to be symptom free when left alone, this may also be documented as psychogenic; however, this feature is usually indicative of malingering or factitious disorder. Clinically Established Psychogenic
Inconsistent or incongruent with classical dystonia (on examination, the patient is unable to move the limbs but is able to dress herself in daily life). In addition, one or all of the following is highly suggestive: other neurologic signs present that are psychogenic (self-inflicted injuries, false weakness, false sensory findings), an obvious psychiatric disturbance is present, and multiple somatizations are present.
a
Neurology Specialists of Dallas, 7515 Greenville Avenue, Suite 500, Dallas, TX 75231, USA Human Motor Control Section, NINDS NIH, Building 10, Room 7D37, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428, USA * Corresponding author. E-mail address:
[email protected] (E.L. Peckham). b
Neurol Clin 27 (2009) 801–819 doi:10.1016/j.ncl.2009.04.008 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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Probable Psychogenic
Movements are inconsistent or incongruent, but there are no other features (as above) to further support the diagnosis. Movements are consistent with organic dystonia, but there are other features on examination to suggest psychogenicity (self-inflicted injuries, false weakness, false sensory findings). Multiple somatizations are present, but movements are consistent with organic dystonia. Possible Psychogenic
An obvious emotional disturbance is present, but movements are consistent with organic dystonia. Because of high diagnostic certainty, category a and b have been combined to form a category called ‘‘clinically definite.’’2 Shill and Gerber3 expanded this further with a designation of ‘‘clinically proven PMD,’’ which requires remission when the patient is unobserved or with psychotherapy or when there is a premovement Bereitschaftspotential (BP) on electroencephalography (EEG) (for myoclonus only). Additionally, they created further criteria of PMD to include excessive pain or fatigue and previous disease exposure.3 The latter criterion presumably occurs as the nervous system mimics what it has previously seen. Extending the idea of Shill and Gerber that clinical neurophysiologic criteria can be used to secure the diagnosis, we propose that the category of ‘‘clinically proven PMD’’ could include such neurophysiologic tests or that a new category of ‘‘laboratory proven PMD’’ be considered. Alternative terms for PMD are reported in the literature as a ‘‘functional’’4 movement disorder, ‘‘nonorganic’’5 movement disorder, or as part of the spectrum of ‘‘medically unexplained symptoms.’’6 In the psychiatric literature, there are multiple terms that should be discussed as they relate to PMDs. These include conversion disorder, somatization disorder, factitious disorder, and malingering. These terms are classified in the Diagnostic and Statistical Manual of Psychiatric Disorders, Volume IV (DSM IV).7 The first category is somatoform disorders, and these include conversion disorder and somatization disorder. Conversion disorder is likely the most common mechanism of PMDs; it is defined as unexplained sensory or motor deficits that suggest a neurologic or other medical condition. Psychological factors are associated with symptoms. Somatization disorder is defined as a disorder beginning before the age of 30 years and extending over a period of years and consists of multiple conversion symptoms including ‘‘pseudo-neurological,’’ gastrointestinal, pain, and sexual symptoms. Factitious disorders include intentional production of physical or psychological symptoms, where the goal is to assume the ‘‘sick role’’ and external incentives (financial, avoiding legal responsibility) are not present. In malingering, the symptoms can also be physical or psychological, but the individual is consciously aware of external incentives, and when the external incentives are removed, the symptoms resolve. An important distinction between conversion/somatoform disorders and factitious disorders/malingering is that conversion/somatoform disorders are unconsciously produced, whereas factitious disorders/malingering are conscious. PATIENT HISTORY
Although the diagnosis of PMD was originally thought to be one of exclusion,1 there are many characteristics that define PMD as a positive entity (Table 1). When obtaining a neurologic history, it is important to look for these diagnostic features. Although there is no definite prototype PMD patient, most of these patients are women
Psychogenic Movement Disorders
Table 1 Historical characteristics All PMDs
PMD tremor
Unusual combination of rest, postural, and action tremor Absence of finger tremor Inconsistent dystonic movements over time Dystonia as a fixed posture or paroxysmal disorder Incongruous dystonic movements and postures Other movement disorders also present (bizarre gait) Foot dystonia in adult Resting dystonia Contraction of antagonist with apparent action in agonist Painful Inconsistent frequency, amplitude Involving more than 1 body region Remits or improves with distraction Burst length >70 ms on surface EMG Triphasic pattern present on agonist/antagonist muscles Presence of a BP Rest, postural, and action tremor Passive resistance against examiner rather than true rigidity Non-decremental response on rapid alternating movements Effortful response to tasks marked by grimacing, sighing Bizarre response to postural testing, overexaggeration without falling Momentary fluctuation of gait and stance Excessive slowness Psychogenic Rhomberg Uneconomic postures Walking on ice Sudden buckling of knees without falling
PMD dystonia
PMD myoclonus
PMD Parkinsonism
PMD gait
Sudden onset Precipitating event Spontaneous remission Multiple somatizations Litigation or compensation (may suggest malingering)
Data from Refs.1,2,5,8,11,13,20,22,24,37,39,73
(61%–87%), and average age is 44 years (range, 4–73 years).8 In the history, the movements commonly occur as an abrupt onset and can be preceded by physical or emotional trauma. It is important to obtain a detailed psychosocial history, asking questions about stress, physical, emotional, or sexual abuse, substance abuse, and how the movements have affected interpersonal relationships.5 The movements themselves may also stop suddenly or have inconsistency over time.8 Interestingly, PMDs are commonly seen in patients in health care professions or allied health care professionals9 possibly due to the exposure to disease. Litigation or compensation for disability may be a factor in PMDs, and in one study this was found in 11 of 28 (39%) of patients studied;10 such patients would be suspicious for malingering. Finally, underlying psychiatric disturbances are commonly seen in PMDs. The most common underlying psychiatric diagnoses are anxiety, depression, somatization, and conversion disorders.11 Underlying psychiatric diagnoses should be pursued by a psychiatrist who is familiar with PMDs, as this can aid in treatment options. Although it is common to find a coexisting psychiatric diagnosis with PMDs, it is important to note that psychiatric diagnoses are common with organic conditions as well.5
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PHYSICAL EXAMINATION FINDINGS
In general, PMDs are characterized by an inconsistent character of movement (unusual presentation in amplitude, frequency, distribution), and they may increase with attention or decrease with distraction.9 Voluntary movements may appear slow, and patients may seem to struggle and put in more effort than needed to complete the task.11 Often, this is manifest by sighing, grimacing, and using their whole body to do a movement. The movements themselves may appear bizarre and should be incongruous with a known movement disorder.10 Observation is the most important tool for the neurologist looking for inconsistency of movements. However, several physical examination findings on routine neurologic examination may also suggest a psychogenic disorder: false weakness or give way weakness, false sensory loss, sensation that splits the midline, vibratory sense that splits the midline, and pseudo waxy flexibility.12 Several bedside tests that may be helpful in making a diagnosis of a PMD can be performed. First, the Hoover sign12 can be performed to look for psychogenic weakness. Testing is done with the patient laying supine and the heel of the weak leg in the examiner’s hand. When the patient is asked to press the heel into the examiner’s hand, there is no movement. Next, the opposite ‘‘strong’’ leg is flexed at the hip, and with counter pressure on this leg, hip extension is noted on the ‘‘weak’’ heel. An additional bedside test is the coactivation sign.12 During this test, the examiner palpates both agonist and antagonist muscles on strength testing. It may be easier to feel contraction of an antagonist muscle when the agonist muscle is tested (triceps activation when biceps muscle is being tested). On postural testing, bizarre or extreme responses may be present when the patient is pulled backward by the examiner.13 The ‘‘chair test’’ was described by Okun and colleagues14 as a bedside test that may be helpful in patients with a psychogenic gait disorder. Patients are asked to walk 20 to 30 ft forward and backward and then are asked to move a swivel chair the same distance by using their legs. In a study of 9 patients, 8 patients with a psychogenic gait were able to propel the chair forward and backward even though they had great difficulty with walking. These patients were compared with 9 control subjects with nonpsychogenic gait problems, and the control group had difficulty with both tasks. NEUROPHYSIOLOGY TESTING
Neurophysiology testing in PMD is primarily helpful in distinguishing psychogenic tremor and myoclonus from organic forms of these conditions (Table 2). The main limitation with performing neurophysiology testing is that few laboratories in the United States have the capability to perform this technique, and it is time consuming. For psychogenic tremor, surface electromyograph (EMG) is placed over the muscles involved in tremor. Standard muscles used may involve biceps, wrist flexors, thenar, and anterior tibialis muscles bilaterally to record the frequency, amplitude, and duration of tremor.15 The basic protocol for testing patients uses a rest condition (tremor evaluated at rest with hands in the lap), a postural condition (arms are outstretched), a kinetic position (finger to nose testing), weighting conditions (using small wrist weights over the most affected hand), and testing of entrainment (tapping the opposite hand at a certain frequency to see if the tremor adopts that same frequency).16,17 Psychogenic tremor shows fluctuation in amplitude and frequency and disappearance of tremor when the patient is distracted.17 In one study, distractibility was formally tested by having the patient perform serial sevens and with alternate finger tapping while the EMG was recorded.16 When compared with patients who had essential tremor (ET), PMD tremor showed disappearance of the movements when the patient
Psychogenic Movement Disorders
Table 2 Electrophysiology characteristics of psychogenic tremor Tremor Characteristic
PMD
ET
PD
Normal Volunteer (Mimic Tremor)
Amplitude
Variable
Stable
Stable
No data
Frequency
Variable (4–10 Hz)
4–12 Hz
4–6 Hz
No data
Distractible
Yes
No
No
Yes
Weighting
Increased amplitude or stays the same
Amplitude stays the same or decreased
Amplitude stays the same or decreased
No data
Entrainment
Yes, tremor entrains or disappears in many (but not all) cases
No
No
No data
Affected body regions
Fewer affected
Multiple, symmetric
Multiple, asymmetric
No data
Oscillators
Single
Multiple
Multiple
Single
Ballistic movement test
Cessation of tremor or decreased amplitude
No cessation of tremor
No cessation of tremor
Cessation of tremor or decreased amplitude
Data from Refs.15–19,27
was distracted, whereas in ET the movements continued. In addition, in this same study by Kenney and colleagues,16 patients were tested for suggestibility through the instruction that their tremor would decrease if a tuning fork was vibrated on the forehead and that the tremor should increase with hyperventilation. Both of these conditions of suggestibility were also statistically significant when compared with ET. Entrainment is generally a very good test, but there are problems. Entrainment is thought to be specific in patients with PMD; however, entrainment was not significantly different when ET and PMD patients were compared by Kenney and colleagues.16 In another problem with the entrainment study, Zeuner and colleagues17 found that PMD patients were not very good at following the instruction for voluntary tapping, and this can make assessment tricky. For the weighting condition, tremor amplitude will often increase in psychogenic tremor, whereas it normally decreases or stays the same in organic forms of tremor.18 In a study by O’Suilleabhain and colleagues,15 PMD tremor involved fewer limb segments and fewer limbs than those in ET and Parkinson tremor. Further, in organic forms of tremor, there are thought to be multiple oscillators present, resulting in different frequencies of tremor in different limbs. This is in contrast to PMD where there appears to be a single oscillator. A bedside test that can be helpful with the simultaneous use of surface EMG is to have the patient perform a contralateral fast ballistic movement. In Kumru and colleagues,19 this was found to cause cessation of contralateral tremor oscillations or a significant decrease in amplitude when compared with ET and Parkinson’s disease patients who had no change. Psychogenic myoclonus can also be distinguished from organic myoclonus with the help of electrophysiology. Evaluation of the patient is performed in the same way as the evaluation of tremor with surface EMG over the corresponding muscles that
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produce jerks. Organic myoclonus is characterized by burst length of less than 70 ms, and jerks lasting longer than that are suggestive of a psychogenic etiology.20 In addition, if a triphasic pattern of agonist/antagonist muscles is found, this is also suggestive of PMD. An additional technique that can be used to help distinguish organic from psychogenic myoclonus is EEG backaveraging. This technique is performed by backaveraging epochs of EEG and correlating this with the jerks recorded on surface EMG. In most normal subjects, a voluntary movement is preceded electrophysiologically by a premovement potential, the BP.20 In patients with psychogenic myoclonus, there is a BP-like slow EEG shift before the jerk.21 BPs are never recorded in organic involuntary movements. In the absence of a BP, it is not possible to exclude a psychogenic etiology, as the BP can be absent in normal subjects. Although, PMDs are thought to be involuntary, by this measurement, they follow more of a voluntary motor pathway. In addition, with EEG the presence of a large somatosensory potential or a brief cortical correlate of myoclonus is indicative of organic disease.22 WORKUP
The diagnosis of PMDs was originally thought to be one of exclusion.1 However, it is better to make a positive diagnosis based on the defining characteristics as discussed above. There is no standard workup for PMDs, and if suspected, the patient should be evaluated by a specialist with expertise in these conditions. The history and physical examination findings should be the main factors in making this diagnosis, and diagnostic testing should be used primarily to give further support to the underlying clinical suspicion that it is psychogenic. Magnetic resonance imaging can be helpful for excluding an underlying structural or demyelinating lesion. Blood work to include thyroid function, renal and liver function, and evaluation for Wilson’s disease11 may be helpful. Neurophysiology studies to evaluate tremor and myoclonus can aid in the diagnosis as discussed earlier. TYPES OF PMD Psychogenic Tremor
Psychogenic tremor represents the majority of PMD, up to 55%, and is present between 2% and 4% of patients seen in movement disorder clinics.11,23 The majority of cases are women, and, in one large study of PMD, tremor average duration was 4.6 years, and the average age was 43 years ( 14 years).11 Clinical sites affected include the hand (84%), the leg (28%), and generalized body tremor (20%).8 Common clinical characteristics on history that help differentiate it from organic tremors include sudden onset, unusual combination of rest and postural tremor, decrease with distraction, multiple associated somatizations, and spontaneous remission.24,25 As in other PMDs, the course is usually abrupt in onset (73%), followed by either a static course (46%) or fluctuating course (17%).26 The frequency of the tremor is between 4 and 10 Hz,27 and neurophysiology studies as described here may be very helpful in making the diagnosis. Clinically, absence of finger tremor can be a positive diagnostic sign for psychogenic tremor.11 The underlying mechanism is largely unknown but may represent an underlying clonus mechanism in some patients.25 Another clinical manifestation seen in some patients is the coactivation sign, which can be appreciated by passively moving the affected oscillating joint and feeling for cocontraction of antagonist muscles in the affected limb.25 A recent study by Raethjan and colleagues28 suggests 2 possible mechanisms of psychogenic tremor based on an evaluation of 15 patients. Seven patients in the study showed coherent oscillations between the right and left hand, suggesting a voluntary-type mechanism; the other 8 patients
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showed independent oscillators suggestive of a clonus or physiologic tremor mechanism. Psychogenic Dystonia
In most centers, psychogenic dystonia is the second most commonly encountered phenomenon except for one study by Columbia University where it was the most frequent.2 Historically, there are clues that point to a psychogenic etiology, including inconsistent dystonic movements over time, incongruous dystonic movements and postures, dystonia presenting as either a fixed or paroxysmal dystonia, and the presence of other bizarre involuntary movements to include a bizarre gait.1 Additional criteria include foot dystonia in an adult, resting dystonia, and contraction of antagonist with apparent action in agonist muscles,8 but none of these is specific. Organic dystonias should be suspected when there is a gradual onset with activity, and pain is not usually a feature despite contorted postures.9 In addition, there is a ‘‘dystonia-causalgia’’ syndrome described by Bhatia and colleagues,29 in which dystonia is induced by a peripheral injury. There is controversy about this in the literature, but the most recent study from Toronto Western Hospital involving 13 patients suggests a psychogenic etiology based on a suggestion of conversion disorder on the Minnesota Multiphasic Personality Inventory and resolution of most patients’ symptoms with a sodium amytal interview.9 There are no physiologic tests available that readily distinguish psychogenic dystonia from organic dystonia.30 Psychogenic Parkinsonism
The true percentage of psychogenic Parkinsonism is not known, but it is thought to be relatively uncommon, representing only approximately 10% of PMDs.31 Typical features of organic Parkinsonism (decreased blink rate, axial rigidity, hypomimia) are typically absent in psychogenic Parkinsonism.32 Characteristic features in the tremor of psychogenic Parkinsonism include tremor of an abrupt onset that is present at rest and persists with posture and action.9 In accordance with other forms of psychogenic tremor, the tremor of psychogenic Parkinsonism will increase with attention and decrease with distraction and concentration.8 True rigidity and ‘‘cogwheel’’ phenomenon are not present, and, instead, there is passive resistance felt against the examiner. Slowness does not show the true decremental response found in organic Parkinsonism but instead is slow and effortful, often with whole-body movement to try and complete the task.13 On postural stability testing, patients may have bizarre responses including flailing of the arms and reeling backward without falling.8 Electrophysiology studies can be helpful in distinguishing a Parkinson’s psychogenic tremor from other forms of tremor as outlined here. Neuroimaging can be helpful in establishing a diagnosis of psychogenic Parkinsonism. Loss of dopamine nerve function seen in organic Parkinsonism can be measured by decreases in dopamine transporter density or presynaptic dopamine deficiency (I 123 B-CIT) on single positron emission computed tomography (SPECT).31,33 In psychogenic Parkinsonism, these features are absent. Psychogenic Gait
Disorders of gait and balance are commonly seen in psychogenic patients and represent 8% to 10% of all PMDs.34 Psychogenic gait disorders have been described since the late 1800s, and the term astasia-abasia, meaning inability to stand and walk was used together in a paper describing gait disorders by Paul Blocq.35 During World War I, Roussy and Lhermitte further classified ‘‘hysteric gait disorders’’ into several subtypes: astasia-abasia, pseudotabetic, pseudopolyneuritic, tightrope walker, robot,
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habitual limping, choreic, knock-kneed, as on a sticky surface, and as through water.36 At the present time, certain characteristics are evaluated on the physical examination to help define a psychogenic gait disorder. In one study by Lempert and colleagues,37 6 key features were identified in 97% of 37 patients through a videotape analysis. These included momentary fluctuation of gait and stance, excessive slowness, psychogenic Rhomberg, uneconomic postures, walking on ice, and sudden buckling of knees without falls. In another study by Baik and Lang,38 279 videotapes were analyzed, and patients with PMD both with and without gait abnormalities were compared. Of those PMD patients with a gait abnormality, excessive slowness, buckling of the knees, and astasia-abasia were the most common findings. Psychogenic Myoclonus
Myoclonus represents between 8.5% and 19%10,32,39 of all PMDs depending on the center cited. In a study by Monday and Jankovic,39 18 patients were diagnosed with psychogenic myoclonus based on movements that were inconsistent with organic myoclonus and had at least 2 of the following features: decrease in movements with distraction, periods of remission, acute improvement, response to placebo, presence of other psychogenic symptomatology, and evidence of psychopathology by past psychiatric testing or by history. Myoclonus is described as brief, shock-like movements that are caused by muscle contractions arising from the central nervous system.8 In general, the frequency and amplitude varies little over time, the myoclonus remains in 1 body region (except in essential myoclonus), decreases with rest/sleep, worsens with distraction, and rarely remits.24 Features of psychogenic myoclonus included continuously changing pattern, frequency, amplitude, and anatomic distribution.39 Electrophysiology studies can be helpful in the evaluation of psychogenic myoclonus as described in the section on neurophysiology testing. TREATMENT
Treatment begins when the physician has made the diagnosis and is ready to explain PMD to the patient (Fig. 1). This is a crucial first step, as it will directly influence whether the patient is accepting of the diagnosis and is willing to try an approach at treatment or whether he or she continues to seek further medical attention, convinced that there is something else really going on. It is advisable to discuss this diagnosis with the patient after several office visits, where a patient-physician relationship can be developed and after appropriate testing can be performed to help support the diagnosis. Reassurance is very important early on, emphasizing that the main components of the neurologic examination are ‘‘normal’’ and suggesting that the corresponding anatomy is also normal. In our experience, it is important to emphasize to the patient that this is an ‘‘involuntary’’ condition and is most likely the result of malfunctioning neural pathways. We often discuss that the exact cause of what is going on is unknown, but there may be environmental triggers (stress, physical trauma) that have helped precipitate the movements. From there, we usually discuss that there have been treatments found to be helpful and the best approach is to have the neurologist work in conjunction with a psychiatrist who understands PMDs. This is extremely important, as sending a patient to a psychiatrist without this understanding can result in the patient being sent back to you stating that he or she is not psychogenic. This will cause your patient to lose trust and faith in your diagnosis. Medication treatment can be initiated, and other supportive treatments can be added as well (rehabilitation, psychology) depending on the patient and the movements involved. If the patient is young and has a short duration of symptoms, we emphasize these key points stating
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Suspected diagnosis of PMD based on history and exam
Lab work, imaging and electrophysiology studies when appropriate
Discussion of the diagnosis with the patient
Referral to psychiatrist who understands PMD
Options for treatment: Psychotherapy Oral medications Referral to rehabilitation medicine Behavioral modifications Biofeedback Hypnosis Acupuncture? rTMS?
Fig. 1. Algorithm for evaluation and treatment of psychogenic movement disorders.
that these are good prognostic factors. A question often asked by patients is ‘‘What do I tell my friends and family.’’ The best approach to this question is for the patient to tell the family that he or she has a neurologic condition that produces involuntary movements and the cause is not well understood, but they are undergoing medical treatment to try and help the symptoms. We always introduce the term psychogenic; however, we prefer the term functional, as it is more accepted by the patient in general. The term psychogenic has an underlying implication to patients that they are doing this on purpose and it is all in their head. In a study by Stone and colleagues40 102 general neurology patients were asked which term they preferred when given the choice of pseudoseizures, nonepileptic attack disorder, psychogenic seizures, stress-related seizures, or functional seizures and patients felt that the terms stress-related seizures and functional seizures were less offensive and on par with the term tonic-clonic seizure. Large randomized studies in patients with PMD are lacking, and evidence for treatment is largely based on retrospective, case control, and case report studies. Treatment can first be divided into inpatient versus outpatient treatment and further by classification of treatment to include medication, rehabilitation, cognitive behavioral therapies, biofeedback, hypnosis, placebo trials, and acupuncture. Inpatient Treatment
Inpatient treatment is an option used at specialized centers in Canada and England and consists of a team approach. Patients are admitted for weeks to several months and followed by neurologists, psychiatrists, psychologists, physiatrists, and possibly
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therapists trained in alternative types of treatments. By far, the highest success rate is reported for resolution of symptoms with this type of technique. In a case series of 32 patients, 81% reported resolution of symptoms after a hospital stay of 1 week to 6 months.41 The remaining 19% of patients had partial resolution of symptoms. Inpatient treatment is not a feasible option for treatment in the United States due to insurance restrictions, and, thus, few centers in the United States have this capability. In these centers, stay is usually much shorter (1–2 weeks). Because of this, treatment is largely aimed at involving the same physicians and therapists in an outpatient setting.
Outpatient Treatment Oral medications
In a study by Voon and Lang,42 23 patients were identified with PMD, and 15 patients agreed to be treated with antidepressant medications. Of the 15 patients, 10 were diagnosed with primary PMD, and the remaining 5 were diagnosed with PMD and another somatoform disorder. Patients were treated with either paroxetine or citalopram and titrated up to an optimal dose during 4 weeks. Those who did not respond were switched to venlafaxine. Of the primary PMD patients, 80% (8 patients) had marked improvement, and 7 patients had complete remission. None of the 5 patients with PMD and other somatoform disorders improved. Notably, all of the primary PMD patients had concurrent underlying anxiety or depression, whereas only 2 of the 5 (40%) patients with PMD and other somatoform disorders had an underlying psychiatric disorder. Neuroleptic medications have also been reported to be of benefit for patients with conversion disorder. In a study by Rampello and colleagues,43 18 patients were treated—6 with haloperidol and 12 with sulpiride (not available in United States). The sulpiride group showed remarkable improvement in 8 patients, partial improvement in 2 patients, and no improvement in 1 patient. The haloperidol group showed 1 patient with remarkable improvement, 3 with partial improvement, and 2 with no improvement. The mechanism believed to account for improvement was thought to be secondary to the inhibition of the D2 dopamine receptor subtype that induces a large increase in prolactin secretion. Prolactin levels were followed in these patients and were found to be higher in the sulpiride group versus the haloperidol group. There is also a case report of a patient who was treated with risperidone for psychogenic stiff neck.44 The patient was previously tried on antidepressants, other neuroleptics, and antiepileptic medications with no benefit. Initially, she was placed on a combination of sertraline and risperidone, and the symptoms disappeared completely after 6 months of treatment with risperidone alone. Behavioral modification
Shapiro and Teasell45 had a case series of 39 consecutive patients with conversion disorder who were admitted to an inpatient rehabilitation unit for treatment. All patients were told that they had a musculoskeletal problem that could resolve completely if they had an organic etiology. If the patients did not improve after 4 weeks, then they were told that it was a psychiatric condition, and the treatment would be modified to help them improve completely. If they did not improve, then they were given a final diagnosis of conversion disorder, and they were told that they could not improve because of an unconscious need to remain disabled. In 8 of 9 patients with acute conversion disorder (symptoms <2 months), the treatment was successful. In 1 of 28 chronic (>6 months duration) patients, behavioral treatment was successful.
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Psychotherapy of a more standard variety is likely the most common method for psychiatric intervention. Cognitive behavioral therapy is currently the most popular method for dealing with conversion disorders. Physical therapy
A case series of 3 patients were treated in an inpatient setting where patients underwent behavioral modification treatments and shaping techniques for a maximum of 9 days of treatment.46 Specifically, correct patterns of movements were praised, and abnormal movements were ignored. All 3 patients had complete resolution of symptoms.46 In addition, a retrospective study by Speed47 was performed in 10 patients with psychogenic gait. Patients were treated with physical therapy, occupational therapy, and recreational therapy, and psychological interventions were used in appropriate cases. All patients were able to ambulate normally (mean, 11.8 days) before discharge. Biofeedback
There is 1 published abstract report where EMG biofeedback was used as a treatment for psychogenic tremor.48 In this study, 15 patients were trained over several sessions to decrease EMG signals associated with involuntary movements. Treatment was successful in 9 patients (60%). Hypnosis
In a randomized, controlled clinical trial, 44 patients with somatization disorder with motor conversion symptoms and conversion disorder, motor type, were assigned to a control (waiting list) group or an experimental (hypnosis) group in an outpatient setting.49 Patients were told at the beginning that either treatment was equally effective. Treatment consisted of 10 weeks of 1-hour hypnosis sessions, and the experimental group was improved compared with the control group. Improvement was maintained at a 6-month follow-up. Two additional studies used hypnosis in an inpatient setting. In one study, 8 patients with conversion disorder were treated for an average stay of 2 months (range, 1 week–6 months) with hypnosis, and 7 of 8 subjects showed improvement or resolution of symptoms.50 A second study followed 45 patients with a multidisciplinary approach to treatment using a nurse, group therapist, creative therapy therapist, sports therapist, and physiotherapist. Approximately half of these patients were randomized to an additional treatment of hypnotherapy. Both groups had beneficial results, and there was no statistical difference in the group that had the addition of hypnosis. Acupuncture
There is 1 case report that describes a dramatic response to acupuncture in a patient with chronic, treatment-resistant PMD.51 There have been no formal clinical trials or case control series of acupuncture. Transcranial magnetic stimulation
There have been 3 recent clinical reports where transcranial magnetic stimulation (TMS) was used in psychogenic conditions. In a case report in 2009, Chastan and colleagues52 reported using 2 sessions of repetitive TMS (rTMS) in a patient with psychogenic dysphonia. The first session was performed over the left prefrontal cortex with no effect, and the second session, over the right motor cortex with immediate and dramatic improvement. Additionally, in Germany, rTMS was used in 8 patients with psychogenic tremor as a distraction technique.53 In this group, 4 patients responded, 2 showed temporary improvement, and 2 did not respond. The hypothesis
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from this study was that responders to rTMS were more inclined to see the reversibility of the disorder and thus were amenable to psychiatric treatment. Trial of placebo
There is one case report where a patient with psychogenic blepharospasm (not responsive to botulinum toxin) improved through placebo.54 It was suggested that she would have improvement with a placebo medication and that if she did not improve then the cause was psychiatric and she would need to see a psychiatrist. This patient was a minor and it was done with parental consent. At this time, a placebo trial, without informed consent, is considered unethical. PROGNOSIS
Reports are variable in terms of prognosis, but, in general, prognosis for patients with PMDs is poor (Table 3). In one study by Feinstein and colleagues,55 42 patients were sampled by telephone interview after an average follow-up of 3.2 years from diagnosis, and 90% had persistence of involuntary movements. In this study, poor outcome was associated with psychiatric comorbidity of Axis I disorders, long duration of symptoms, and insidious onset of movements. An additional study in patients with functional unilateral sensory or motor weakness at an average of 12.5 years of follow-up from presentation showed the presence of symptoms in 83% of 42 subjects evaluated. One patient in this sample went on to develop multiple sclerosis after being thought to be psychogenic initially. Patients with sensory symptoms had statistically significant better outcomes and reported higher levels of physical functioning, social functioning, and less pain when compared with those with motor symptoms. Lower levels of physical functioning were reported with higher age at onset of symptoms. In a study by Thomas and colleagues,56 228 patients were evaluated by structured telephone interview, and 56% of patients reported improvement in symptoms, 21% reported no change, and 22% were worse after an average duration of 3.4 years’ follow-up. In this study, poor prognostic factors were inconsistent movements, dissatisfaction with the physician, long duration of illness, positive history of smoking, and suggestibility. Good prognostic factors were good physical health, positive social life, patients’ perception of receiving effective treatment by the physician, elimination of a stressor, comorbid diagnosis of anxiety, and attribution of a specific medication.
Table 3 Prognostic indicators Favorable Short duration of symptoms (<1 y) Inconsistency of movements
Poor Chronic symptoms Motor symptoms
Good physical health Positive social life perception Elimination of stressor
Smoking Suggestibility Pending litigation
Patient’s perception of receiving effective treatment Changed marital status
Dissatisfaction with physician
If admitted to hospital, resolution of symptoms on discharge
—
Data from Refs.55,56,58,74
Older age at onset of symptoms
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In a study by McKeon and colleagues,23 53% (33 patients) with electrophysiologically confirmed psychogenic tremor responded to a follow-up questionnaire. After a median follow-up of 3.2 years, 64% of patients rated their disability as moderate severe, 27% had complete resolution of symptoms, and 9% reported mild unchanged symptoms. Of the patients who had resolution of symptoms, in 15% (5 patients) the resolution occurred spontaneously and in 12% (4 patients) it occurred after an intervention (1 with an antidepressant, 1 with psychology/rehabilitation, 1 with hypnotherapy, 1 with behavioral therapy). In a separate study by Crimlisk and colleagues57 of 64 patients with medically unexplained symptoms, 28% showed complete resolution of symptoms, 20% improved, 14% remained unchanged, and 38% worsened after 6 years of follow-up. In this group, 3 patients were misdiagnosed and did have an underlying neurologic disorder including paroxysmal hemidystonia, spinocerebellar ataxia, and myotonic dystrophy. Finally, much higher rates of improvement are reported in a follow-up study by Couprie and colleagues58 in patients who were admitted to the hospital for an inpatient stay for treatment of conversion disorder. In this study, 56% of patients admitted had resolution of symptoms on discharge, and 90% remained resolved at a 4-year follow-up. Two patients (4%) were misdiagnosed—1 with a stroke and 1 with multiple sclerosis. A common concern with diagnosing PMD is that an underlying diagnosis has been missed; however, recent reports as discussed here show a very low percentage of patients with a misdiagnosis. This is in contrast to a previous report by Slater and Glithero59 in 1965 in which more than half of patients diagnosed with ‘‘hysteria’’ were thought to be misdiagnosed. RESEARCH FINDINGS
Research to date has been primarily aimed at patients with conversion disorder. There have been several imaging studies using functional magnetic resonance imaging (fMRI). In 1997, Marshall and colleagues60 studied 1 patient with left-sided paralysis secondary to a conversion disorder. Imaging was studied in 2 conditions: 1 when the patient prepared to move her leg and 2 when she moved the leg. There was activation of cerebral blood flow to the motor and premotor areas of corresponding hemispheres when she prepared to move the left (paralyzed leg), prepared to move the right (normal) leg, and when she moved the right leg. When she attempted to move the left leg, there was absence of blood flow to the right primary motor cortex, and, instead, there was activation of the right orbitofrontal and right anterior cingulate cortex. This suggested to the authors that these 2 areas inhibit prefrontal effects of the willed movement of the right primary cortex. Motor imagery has been an interesting tool in conversion disorder patients. In 2007, de Lange and colleagues61 studied 8 conversion paralysis patients using fMRI as the patients performed tasks of imagined movements with the affected and unaffected hands. Motor imagery of both hands recruited the same areas of the motor cortex; however, motor imagery of the affected hand recruited additional regions including the ventromedial prefrontal cortex and superior temporal cortex. This additional activation was thought to represent difficulty in deactivating these areas of the brain during motor imagery tasks. The authors proposed that their findings represented heightened self-monitoring of subjects with conversion paralysis, and they hypothesized that cognitive-behavioral therapy should therefore be beneficial. In 2008, de Lange62 studied 7 conversion paralysis patients with fMRI, and imagined actions of the affected and unaffected hands were either implicitly or explicitly instructed to the patient. For both of these tasks, the patient had to judge the laterality of a rotated drawing of a right or left hand. The drawings were presented in different directions from 0 to 180 and in
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palmar and dorsal orientations. In the implicit task, patients had to judge as fast and accurately as they could whether the drawing represented a right or left hand. For the explicit task, patients were told to imagine that the hand was their own and imagine moving their hand into the position on screen. They also had to determine whether it was a right or left hand. Implicit imagery yielded larger activation of the ventromedial prefrontal cortex and superior temporal cortex in the affected hand compared with the unaffected hand, but this difference between hands was not present during the explicit task. This suggests that implicit and explicit tasks have a different level of self-monitoring involved, and techniques aimed at using explicit tasks (such as hypnosis) may be a valuable tool for conversion paralysis patients. A study by Stone and colleagues,63 in 2007, compared 4 patients with conversion paralysis manifested as a weak ankle, and 4 normal control subjects using fMRI where subjects were instructed to move the affected limb. The control subjects were instructed to simulate weakness when moving the ankle. Both groups showed reduction in the level of activation in the motor cortex; however, the patient group showed additional activation of the basal ganglia, insula, lingual gyri, and inferior frontal cortex. This suggests that the conversion group were attempting to move with greater mental effort than the control subjects. Research in positron emission topography by Spence and colleagues64 compared 3 subjects with psychogenic paralysis with 4 control subjects who feigned paralysis. Patients with hysteria showed evidence of hypoactivity of the dorsolateral prefrontal cortex (DLPFC), and feigners exhibited hypoactivity of the right anterior prefrontal cortex, which was statistically significant. Although the sample size was small, the suggestion from this was that the left DLPFC is involved in internal choice of action, and thus patients appear to think that they cannot do the task, but actually they cannot ‘‘will’’ the task. A single-photon emission computed tomography (SPECT) study was performed on 7 patients (6 females, 1 male) using 99m EC-TCD who had unilateral loss of motor and/ or sensory loss due to a psychogenic etiology.65 During the study, patients had a SPECT scan performed under three separate conditions: resting condition with the deficit present, with a vibrating tuning fork placed on both hands when the deficit was present, and 2–4 months after the deficit resolved. SPECT imaging showed a decrease in blood flow of the thalamus and basal ganglia contralateral to the deficit in the vibratory condition which normalized on scans performed once the patients’ symptoms resolved. The authors conclude that this provides evidence of abnormalities in the sensorimotor pathways correlating with psychogenic neurological symptoms. Additional research in conversion disorder has been performed by Roelofs and colleagues66 and has addressed the speed of motor initiation times and motor execution times based on timed tasks between 4 patients and 6 control subjects. Motor initiation tasks were statistically slower in patients than in controls, but motor execution times were not statistically different. From this study, an additional study was conducted in control subjects divided into 8 low and 9 highly hypnotizable control subjects.67 It was hypothesized that the highly hypnotizable subjects were similar to conversion disorder patients. All subjects had implicit and explicit motor task instructions while they were hypnotized so that their right arm was paralyzed. For the implicit task, the patients were shown a picture of a drawing of a left or right hand in different directions from 0 to 315 degrees and in palmar or dorsal orientations. They were instructed to say right or left as quickly and accurately as they could when shown the drawing. For the explicit task, patients were again shown the drawing of a right or left hand and were asked to mentally rotate their hands to the direction on screen
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without actually moving the hand and to say ‘‘yes’’ once the task was completed. On the implicit task, there was no significant difference in reaction time. On the explicit task, the reaction time of the highly hypnotizable subjects showed a significant increase per degree of rotation compared with the normal arm. The results suggest a similar mechanism in highly hypnotizable subjects and conversion disorder subjects. Previous research by Roelofs and colleagues68 compared 50 conversion disorder patients with 50 control subjects to evaluate the level of hypnotizability of each group. Conversion patients were significantly more susceptible to hypnotic suggestion than control subjects, and further, there was a significant correlation between the level of hypnotic susceptibility and number of conversion complaints. Finally, a case report in 2008 describes a patient with left sided conversion paralysis who was evaluated by TMS.69 When her symptoms were present, she had a normal, symmetric central conduction time in the upper and lower limbs, an asymmetric corticomotor threshold which was increased in the right hemisphere, and a small motorevoked potential (MEP) over the left abductor hallucis muscle. The abnormal threshold can be explained either by decreased cortical or lower motor neuron (LMN) excitability. In this case, the mean amplitude of the F-waves was symmetric on both sides, thus the cortical asymmetry is most likely explained by decreased cortical excitability. TMS was repeated 1 month after the resolution of the patients’ symptoms and was normal. In addition the MEP of the left abductor hallucis increased 10-fold with resolution of symptoms. The TMS findings of increased corticomotor threshold with preserved LMN excitability corresponding with the patient’s paralysis are thought to represent inhibitory activation over the motor cortex. It is hypothesized that this represents a protective mechanism of the limbic system, but is difficult to draw any definite conclusion based on the findings of one patient. PSYCHOGENIC MOVEMENT DISORDERS IN CHILDREN
PMDs are well characterized in the adult population, but there is little information on children with PMDs. Two recent articles on children with PMD have addressed this issue. In a study by Ferrara and Jankovic,70 medical records from 54 children with PMD were reviewed. This represented 3.1% of all children with movement disorders seen in the Baylor clinic over a 20-year period. Average age of diagnosis was 14.2 years, and there was a female preponderance in those older than 13 years, whereas the ratio of male to female was equal in those patients younger than 12 years. Children at highest risk for development of PMD were adolescent girls, and the youngest patient was 7 years old. The most common phenomenology of movement was tremor, followed by dystonia, myoclonus, gait disorder, convergence spasm, disrupted speech, athetosis, and situational apraxia of eyelid opening. Similar to the adult population, there was an immediate stressor found in 69% of patients. In addition, 52% of patients reported comorbid symptoms of anxiety, depression, or persistent irritability and 6% of patients had suicidal ideation. Of the patients, 91% had associated somatic complaints, such as, headaches, fatigue, abdominal discomfort, numbness, joint pain, blurred vision, and sleep disturbance. Disability was common, and academic performance was affected in 50% of patients; 24% of patients were home schooled due to their PMD. Further, 22% of patients had unnecessary surgeries for their PMD or related symptoms. It was uncommon to find coexistent neurologic disorders in the patients, but psychiatric conditions were common. Over one-third of patients were described as perfectionistic and high achievers. In a similar study by Schwingenschuh and colleagues,71 15 cases of children with PMD were reviewed, and the average age at diagnosis was 12.3 years; the youngest patient was 7 years old. Psychogenic
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dystonia (47%) was the most common manifestation, followed by tremor (40%) and gait disorder (13%). In 40% of patients, a single movement was present, whereas in 60%, multiple movement types were observed. In this study, there was a female preponderance by 4:1. In 80% of cases, the DSM IV diagnosis was conversion disorder, and the remaining 20% of cases were somatization disorder. In this review, 47% of cases recovered fully, 33% recovered substantially, and 20% remained substantially disabled. Good prognostic indicators were a short duration of illness (<1 month), tremor, and an identifiable stressor that could be resolved. Childhood and adult PMDs appear similar in phenomenology and clinical characteristics and both carry a better prognosis with a shorter duration of illness. Similar techniques with a multidisciplinary approach have been used in both groups with some success. SUMMARY
PMD patients have often proven difficult to identify, but well-defined characteristics in the history, examination, and physiologic testing are now making the task easier. However, there is very little research in this area, and evidence for beneficial treatment is lacking. Prognosis is usually poor, and most patients are left with a high level of disability. This is especially unfortunate, because this is one condition in neurology where it should be possible to completely reverse symptoms. This condition is truly a ‘‘crisis for neurology,’’72 and further research should be dedicated to developing an algorithm for effective treatments. REFERENCES
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39. Monday K, Jankovic J. Psychogenic myoclonus. Neurology 1993;43(2):349–52. 40. Stone J, Campbell K, Sharma N, et al. What should we call pseudoseizures? The patient’s perspective. Seizure 2003;12(8):568–72. 41. Rosebush P, Mazurek M. The treatment of conversion disorder. In: Hallett M, editor. Psychogenic movement disorders. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 289–301. 42. Voon V, Lang AE. Antidepressant treatment outcomes of psychogenic movement disorder. J Clin Psychiatry 2005;66(12):1529–34. 43. Rampello L, Raffaele R, Nicoletti G, et al. Hysterical neurosis of the conversion type: therapeutic activity of neuroleptics with different hyperprolactinemic potency. Neuropsychobiology 1996;33(4):186–8. 44. Marazziti D, Dell’Osso B. Effectiveness of risperidone in psychogenic stiff neck. CNS Spectr 2005;10(6):443–4. 45. Shapiro AP, Teasell RW. Behavioural interventions in the rehabilitation of acute v. chronic non-organic (conversion/factitious) motor disorders. Br J Psychiatry 2004;185:140–6. 46. Ness D. Physical therapy management for conversion disorder: case series. J Neurol Phys Ther 2007;31(1):30–9. 47. Speed J. Behavioral management of conversion disorder: retrospective study. Arch Phys Med Rehabil 1996;77(2):147–54. 48. Levy JK, Thomas M. Biofeedback therapy for psychogenic movement disorders. Psychogenic Movement Disorders 2006;343 [abstract]. 49. Moene FC, Spinhoven P, Hoogduin KA, et al. A randomized controlled clinical trial of a hypnosis-based treatment for patients with conversion disorder, motor type. Int J Clin Exp Hypn 2003;51(1):29–50. 50. Moene FC, Hoogduin KA, Van DR. The inpatient treatment of patients suffering from (motor) conversion symptoms: a description of eight cases. Int J Clin Exp Hypn 1998;46(2):171–90. 51. Van Nuenen BF, Wohlgemuth M, Wong Chung RE, et al. Acupuncture for psychogenic movement disorders: treatment or diagnostic tool? Mov Disord 2007;22(9): 1353–5. 52. Chastan N, Parain D, Verin E, et al. Psychogenic aphonia: spectacular recovery after motor cortex transcranial magnetic stimulation. J Neurol Neurosurg Psychiatr 2009;80(1):94. 53. Dafotakis M, Schonfeldt-Lecuona C, Fink GR, et al. [Psychogenic tremor]. Fortschr Neurol Psychiatr 2008;76(11):647–54 [in German]. 54. Lim EC, Ong BK, Seet RC. Is there a place for placebo in management of psychogenic movement disorders? Ann Acad Med Singap 2007;36(3):208–10. 55. Feinstein A, Stergiopoulos V, Fine J, et al. Psychiatric outcome in patients with a psychogenic movement disorder: a prospective study. Neuropsychiatry Neuropsychol Behav Neurol 2001;14(3):169–76. 56. Thomas M, Vuong KD, Jankovic J. Long-term prognosis of patients with psychogenic movement disorders. Parkinsonism Relat Disord 2006;12(6):382–7. 57. Crimlisk HL, Bhatia K, Cope H, et al. Slater revisited: 6 year follow up study of patients with medically unexplained motor symptoms. BMJ 1998;316(7131):582–6. 58. Couprie W, Wijdicks EF, Rooijmans HG, et al. Outcome in conversion disorder: a follow up study. J Neurol Neurosurg Psychiatr 1995;58(6):750–2. 59. Slater ET, Glithero E. A follow-up of patients diagnosed as suffering from ‘‘hysteria’’. J Psychosom Res 1965;9(1):9–13. 60. Marshall JC, Halligan PW, Fink GR, et al. The functional anatomy of a hysterical paralysis. Cognition 1997;64(1):B1–8.
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61. de Lange FP, Roelofs K, Toni I. Increased self-monitoring during imagined movements in conversion paralysis. Neuropsychologia 2007;45(9):2051–8. 62. de Lange FP, Roelofs K, Toni I. Motor imagery: a window into the mechanisms and alterations of the motor system. Cortex 2008;44(5):494–506. 63. Stone J, Zeman A, Simonotto E, et al. FMRI in patients with motor conversion symptoms and controls with simulated weakness. Psychosom Med 2007;69(9): 961–9. 64. Spence SA, Crimlisk HL, Cope H, et al. Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement. Lancet 2000;355(9211):1243–4. 65. Vuilleumier P, Chicherio C, Assal F, et al. Functional neuroanatomical correlates of hysterical sensorimotor loss. Brain 2001;124(Pt 6):1077–90. 66. Roelofs K, Van Galen GP, Keijsers GP, et al. Motor initiation and execution in patients with conversion paralysis. Acta Psychol (Amst) 2002;110(1):21–34. 67. Roelofs K, Hoogduin KA, Keijsers GP. Motor imagery during hypnotic arm paralysis in high and low hypnotizable subjects. Int J Clin Exp Hypn 2002;50(1):51–66. 68. Roelofs K, Hoogduin KA, Keijsers GP, et al. Hypnotic susceptibility in patients with conversion disorder. J Abnorm Psychol 2002;111(2):390–5. 69. Geraldes R, Coelho M, Rosa MM, et al. Abnormal transcranial magnetic stimulation in a patient with presumed psychogenic paralysis. J Neurol Neurosurg Psychiatr 2008;79(12):1412–3. 70. Ferrara J, Jankovic J. Psychogenic movement disorders in children. Mov Disord 2008;23(13):1875–81. 71. Schwingenschuh P, Pont-Sunyer C, Surtees R, et al. Psychogenic movement disorders in children: a report of 15 cases and a review of the literature. Mov Disord 2008;23(13):1882–8. 72. Hallett M. Psychogenic movement disorders: a crisis for neurology. Curr Neurol Neurosci Rep 2006;6(4):269–71. 73. Reuber M, Mitchell AJ, Howlett SJ, et al. Functional symptoms in neurology: questions and answers. J Neurol Neurosurg Psychiatr 2005;76(3):307–14. 74. Stone J, Sharpe M, Rothwell PM, et al. The 12 year prognosis of unilateral functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 2003; 74(5):591–6.
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Peripherally Induce d Movement Disorders Joseph Jankovic, MD KEYWORDS Peripherally-induced Dystonia Tremor Myoclonus Hemifacial spasm Complex regional pain syndrome Botulinum toxin
Peripherally induced movement disorders may be defined as involuntary or abnormal movements triggered by trauma to the cranial or peripheral nerves or roots.1–4 Although patients often recall some history of trauma before the onset of a movement disorder, only anatomically and temporally related injury should be considered relevant. Despite strict criteria, the cause-and-effect relationship may not be always obvious, and the movement disorder may have no direct relationship to the earlier trauma. In some cases where the relationship is not clear, particularly if there is some secondary gain or pending litigation, the cause-effect is decided by the legal system rather than by scientific evidence.5 Furthermore, the issue is often complicated by the coexistence of various psychosocial problems, and some patients may have a predominant or superimposed psychogenic movement disorder.6 It is beyond the scope of this brief review to speculate at length about possible pathophysiologic mechanisms of peripherally induced movement disorders, but individual predisposition and central reorganization in response to the peripheral injury have been considered to play an important role in the pathogenesis of peripherally induced movement disorders.1,7–9 Central plasticity in response to altered peripheral input may result in maladaptive changes, such as neuropathic pain, hyperreflexia, increased muscle tone, and dystonia. The central changes may include functional alterations of excitatory and inhibitory connections, sprouting of new connections, reorganization of somatosensory and motor maps, altered levels of brain chemicals and neurotransmitters, degeneration and atrophy, and many other changes. A variety of neurophysiologic techniques, such as paired-pulse transcranial magnetic stimulation, have been used to study whether preexisting abnormality of motor cortex excitability may predispose some patients to develop peripherally induced movement disorders.9 Functional MRI studies of patients with complex regional pain syndrome (CRPS) have found abnormal activations in regions such as the basal ganglia and parietal lobe which
Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, 6550 Fannin Smith 1801, Houston, TX 77030, USA E-mail address:
[email protected] Neurol Clin 27 (2009) 821–832 doi:10.1016/j.ncl.2009.04.005 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
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may explain some of the CNS-related symptoms in patients with CRPS, including movement disorders and behavioral abnormalities.10 The relationship between peripheral trauma and subsequent movement disorder has been recognized for at least 2 centuries; Gowers drew attention to this phenomenon in his 1888 book.11 During the past quarter century, many series of patients with well-documented, peripherally induced movement disorders have been reported in peer-reviewed publications.12–19 Peripheral trauma has been reported to cause hemifacial spasm, dystonia, tremor, tics, segmental myoclonus, and even parkinsonism (Box 1). Different types of peripheral injury, including direct trauma, crush, laceration, surgery, or burn, may lead to movement. Because of a growing number of reports of immobilization-induced movement disorders, there is concern that immobilization20–22 and constraint-induced therapies proposed for patients with dystonia, although the latter may be effective for poststroke hemiplegic patients,23,24 may actually cause or exacerbate dystonia. In previous reports, the author’s team proposed the following criteria for the diagnosis of peripherally induced movement disorders: (1) the trauma is severe enough to cause local symptoms for at least 2 weeks or requires medical evaluation within 2 weeks after trauma; (2) the initial manifestation of the movement disorder is anatomically related to the site of injury; and (3) the onset of the movement disorder is within days or months (up to 1 year) after the injury.12,14,15,25 It is possible that in some patients, the peripheral injury is merely coincidental and not causative, and alternatively, some patients whose movement disorders are likely causally related to peripheral injury do not fulfill these criteria. Despite these and other limitations, the diagnostic criteria provide a useful framework for research into the mechanisms, clinical features, epidemiology, and treatment of this group of neurologic disorders. The diagnostic criteria do not include many well-recognized features of peripherally induced movement disorders. For example, in many but not all cases, the movement disorder starts locally in the injured region and may later spread to involve adjacent and ipsilateral body parts, eventually crossing over to the contralateral side. Peripherally induced movement disorders are also often associated with pain and other sensory phenomena, including CRPS.26,27 CRPS, a chronic illness associated with
Box 1 Peripherally induced movement disorders Hemifacial spasm Dystonia Tremor Parkinsonism Segmental myoclonus Jumping postamputation stump and other postamputation dyskinesias Tics Hemimasticatory spasm Painful legs (arms) moving toes (fingers) Synkinesis secondary to aberrant regeneration, fasciculations, myokymia Contractures—congenital torticollis, Dupuytren contractures
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various combinations of sensory, motor, and circulatory manifestations, has been categorized by the task force on taxonomy for the International Association for the Study of Pain (IASP) as type 1 (formerly referred to as ‘‘reflex sympathetic dystrophy’’ or RSD), a soft tissue injury associated with spontaneous pain, allodynia, and hyperalgesia not limited to the distribution of a single peripheral nerve, and type 2 (formerly referred to as ‘‘causalgia’’), a nerve injury with sensory symptoms and pain not necessarily limited to the territory of the injured nerve. The IASP criteria, however, have never been validated, and their clinical and scientific value has been questioned by clinicians and pain specialists.28 Furthermore, the frequency of movement disorders in patients with CRPS has not been systematically studied. In one series of 200 patients with CRPS, 43 were thought to have dystonia,29 and in another series of 145 cases, tremor was found in 48% and ‘‘dystonia/myoclonic jerks’’ in 30%.30 In one study, 58 patients, all with CRPS type 1 (and none with CRPS type 2) had abnormal movements characterized as ‘‘muscle spasms leading to dystonic posture’’ (60.4%), ‘‘coarse postural or action tremor’’ (15.5%), ‘‘irregular jerks’’ (8.6%), ‘‘dystonic spasms and irregular jerks’’ (8.6%), ‘‘dystonic spasms and postural tremor’’ (5.2%), and ‘‘episodic generalized choreiform movement’’ (1.7%).31 This article is organized according to the predominant phenomenology. HEMIFACIAL SPASM
Probably the best example of a peripherally induced movement disorder is hemifacial spasm (HFS).32 Characterized by involuntary, unilateral, intermittent, irregular, tonic or clonic contractions of muscles innervated by the ipsilateral facial nerve, hemifacial spasm is slightly more common in women than men, and the Asian population appears to be at a particularly high risk. The mean age at onset of 158 patients evaluated at Baylor College of Medicine Movement Disorders Clinic was 48.5 14.1 years (range, 15–87), and the mean duration of symptoms was 11.4 8.5 (range, 0.5–53) years. The lower lid was the most common site of the initial involvement, followed by cheek and perioral region. Social embarrassment and involuntary eye closure that interfered with vision were the most common complaints. Botulinum toxin type A (BTX-A) injections, used in 110 patients, provided marked to moderate improvement in 95% of patients. Seven of the 25 patients (28%) who had microvascular decompression reported permanent complications, and HFS recurred in 5 patients (20%). Hemifacial spasm has been most frequently attributed to vascular loop compression at the root exit zone of the facial nerve. Among 135 patients with hemifacial spasm evaluated at Baylor College of Medicine Movement Disorders Clinic, we found the following etiologies: (1) 88 (65%) 5 presumably due to vascular compression of the facial nerve; (2) 13 (10%) 5 synkinesis following Bell palsy; (3) 10 (8%) 5 facial nerve injury; (4) 2 5 facial myoclonus caused by encephalitis; (5) 2 5 facial dystonia; (6) 11 (8%) 5 facial tics; (7) 1 5 demyelination; (8) 1 5 vascular insults; (9) 1 5 familial; and (10) 11 (8%) 5 psychogenic hemifacial spasm.33 Synkinetic movement associated with aberrant regeneration following facial nerve palsy is another example of peripherally induced movement disorder, and is often misdiagnosed as hemifacial spasm.34 DYSTONIA
In contrast to action dystonia and mobile dystonic posture, seen typically in patients with primary (idiopathic) dystonia, the posttraumatic, peripherally induced dystonias are often characterized by a fixed posture present at rest (Figs. 1 and 2), limitation of passive range of movement, contracture, absence of sensory tricks (geste antagonistique), and presence of CRPS.1,3,13,16,18,35–37 Abnormal fixed postures, however,
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Fig. 1. Fixed foot dystonia after chronic immobilization with an ankle cast.
are not a consistent finding, and patients with peripherally induced dystonia, with or without CRPS, may exhibit dystonic movements that are clinically indistinguishable from primary dystonia. Past history of ‘‘significant’’ neck trauma, such as a whiplash associated with a motor vehicle accident, is reported by about 10% to 20% of patients presenting to a neurologist with cervical dystonia.36,38–40 Whether such prior trauma is etiologically relevant is not always clear because most patients with cervical dystonia do not have a prior history of trauma and most injuries to the neck do not lead to cervical
Fig. 2. Marked dystonic deformity about 3 months after soft tissue injury to the hand.
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dystonia.41 Furthermore, abnormal head and neck postures sometimes follow neck injury but are not necessarily caused by involuntary dystonic muscle contractions (‘‘pseudodystonia’’). Two variants of posttraumatic cervical dystonia have been differentiated in adults according to the delay between trauma and onset of the movement disorder.36 Acute-onset cervical dystonia, which usually begins immediately or within days after trauma, is frequently associated with local pain immediately after the injury, marked limitation of range of motion, abnormal postures without phasic movements, prominent shoulder elevation with trapezius hypertrophy (Fig. 3), lack of effect of sensory tricks, and no increase with activation. Shoulder elevation may be seen not only in patients with acute neck injury but also in patients with lesions of the accessory nerve or other muscle and nerve injury involving the shoulder.18,37,42 The second type of posttraumatic cervical dystonia usually occurs between 3 and 12 months after neck trauma, and the clinical picture of this delayed-onset dystonia is similar to the phenotype of nontraumatic, idiopathic, cervical dystonia (Fig. 4A, B). One form of posttraumatic cervical dystonia is congenital muscular torticollis.43 This relatively common condition of infancy may present in late childhood or adulthood with contractures due to fibrosis of sternocleidomastoid and other cervical muscles, limited cervical range of motion, pain, and muscular hypertrophy. Early recognition and treatment, including local botulinum toxin injections, may prevent subsequent contractures and other complications. It is not clear whether the ‘‘overuse’’ syndrome, such as seen with repetitive, occupational injuries or in musicians, leads to or is a cause of focal dystonia.19,44,45 About 10% of patients with writer’s cramp report previous hand trauma.46,47 One possible form of peripherally induced dystonia is the recently recognized ‘‘runner’s dystonia.’’33 This form of dystonia is quite unique for several reasons, including the involvement of legs without spread, an uncommon presentation for adult-onset focal dystonia.48 In our series of patients with runner’s dystonia (mean age of 44.6 10.43 years and mean duration of symptoms 7.2 4.44 years) who initially noted dystonia of 1 leg during long-distance running, 2 of 5 had injury to the affected leg within 1 year before the onset of the dystonia, raising the possibility of peripherally induced dystonia. Although neck and limbs have been most frequently reported to be affected by peripherally induced dystonia, there is a growing number of reports of focal dystonia involving other anatomic sites, such as the eyelids and oromandibular muscles. In one series of 264 patients with blepharospasm, ocular lesions preceded the onset of blepharospasm in 12% of cases.49 It is possible that some cases of blepharospasm are peripherally induced as a result of some ocular injury or even chronic irritation associated with dry eyes, which commonly precedes the onset of blepharospasm.50 One of the most common forms of peripherally induced dystonia is oromandibular
Fig. 3. Patient with acute neck injury with spasm in the left trapezius resulting in slight elevation of the ipsilateral shoulder, resolved within 24 hours.
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Fig. 4. Patient with chronic trapezius muscle spasm and hypertrophy associated with ipsilateral shoulder elevation lasting more than 9 months after a motor vehicle accident. (A) Front. (B) Back.
dystonia, associated with trauma to the face, mouth, or jaw, including oral or dental surgery.15,51 In some cases, peripherally induced oromandibular dystonia is not only very disabling, interfering with speech and swallowing, but may also be life-threatening due to respiratory compromise.52,53 Edentulous dyskinesias, occurring particularly in the elderly, may be considered a form of peripherally induced oromandibular dystonia.54 The long-term natural course of peripherally induced dystonia has not been well studied, but complete spontaneous recovery is rare. Fixed contractures often develop, if physical therapy, muscle relaxation treatments, and other therapeutic measures are delayed. Anticholinergics are usually ineffective, but meaningful functional improvement and pain relief may be achieved with botulinum toxin injections.55 If disabling despite optimal medical therapy, surgical intervention such as local peripheral denervation and central ablative or stimulating procedures may be necessary.4,56 Intrathecal baclofen infusion and spinal cord stimulation may also be helpful, although the latter has been used chiefly to alleviate some of the sympathetic symptoms associated with CRPS or RSD.57,58 Although globus pallidus internus deep brain stimulation has been found to be effective in the treatment of primary and some secondary forms of segmental or generalized dystonia, this procedure has not been assessed in the treatment of peripherally induced dystonia.59,60 Because emotional factors often play an important role in peripherally induced dystonia and because issues related to litigation or compensation are often present,16,61 careful psychological evaluation and insight-directed counseling are important elements of the overall management of patients with posttraumatic movement disorders. TREMOR
Phenomenologically, peripherally induced tremors are similar to essential, parkinsonian, dystonic, and other neurologic tremors.14,62 Besides local injury to the limb, whiplash-type neck injury has been associated with arm tremors.63 In our series of peripherally induced tremors, the oscillatory movement was initially restricted to the injured limb, but it spread to other body regions in about half of the patients and in some cases became associated with bradykinesia, rigidity, and other parkinsonian features.14 Although tremor may occur as an isolated symptom, in some cases it is associated with other movement disorders, particularly dystonia, and it may present as dystonic tremor.14,64 Peripherally induced tremors are generally resistant to conventional medical therapy, although botulinum toxin treatment may effectively, albeit transiently, relieve the tremor.
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PARKINSONISM
Peripheral trauma as a causative factor of parkinsonism, while still controversial, was first suggested in the late 19th century.65 The concept received some support from a 1986 report of 3 patients with probable peripherally induced parkinsonism.17 As a result of additional reports of patients in whom parkinsonism was documented to start at or shortly after local limb injury,14 supported by growing animal and other experimental evidence, the notion of peripherally induced parkinsonism is being increasingly accepted.25,66 It is well recognized that shoulder pain, usually wrongly attributed to some orthopedic or arthritic problem, is one of the most common presentations of Parkinson disease, often preceding motor or other parkinsonian signs by several months or years.67 In some of our cases, parkinsonism followed within days or weeks of a well-documented shoulder injury. Rest or postural tremor starting within days or weeks after an injury to the affected hand or foot, followed by progressive rigidity and bradykinesia, which gradually spread beyond the site of the original injury, was the typical presentation of the reported cases.14 In some of these patients, the tremor and subsequent parkinsonism occurred during direct, prospective observation immediately before and following the injury or surgery. Positron emission tomographic studies in a limited number of patients showed decreased (18F)-fluorodopa uptake in the striatum, suggesting that these patients may have had a subclinical form of Parkinson disease. Because levodopa therapy is usually not effective in these patients, although some may improve with surgical therapy,4 it is possible that the peripherally induced parkinsonism is associated with postsynaptic damage, possibly as a result of some central reorganization following altered peripheral input. MISCELLANEOUS PERIPHERALLY INDUCED MOVEMENT DISORDERS
Besides dystonia, tremor, and parkinsonism, a variety of other movement disorders have been reported to occur after peripheral injury.1,4 One of the best examples of peripherally induced movement disorder is a postamputation jumping stump, a form of segmental myoclonus.68 Other forms of segmental myoclonus include jerking movements involving muscles or muscle groups after thoracic, abdominal, or spinal surgery.68,69 Another example is myoclonus of the scapula after long thoracic nerve lesion70 or of the shoulder following neuralgic amyotrophy.71 For example, adult-onset tics, otherwise clinically similar to childhood-onset tics associated with Tourette syndrome, have been reported after recent trauma to the affected body part.72,73 We recently described a case with adult-onset motor tics after peripheral trauma. A 43-year-old man suffered a left shoulder dislocation during a motorcycle accident 21 years ago. Within 2 weeks after the injury, he noticed the gradual onset of involuntary jerking movements of his left shoulder, which were markedly exacerbated after a second left shoulder injury 2 years later. The involuntary movements are phenomenologically identical to tics typically associated with Tourette syndrome, but without the involvement of any other body part and without phonic tics or the typical comorbidities, such as attention deficit or obsessive-compulsive disorder. Other movement disorders that occur after peripheral injury include the syndrome of painful legs and moving toes, segmental myoclonus, stimulus-suppressible peripheral myoclonus, spasms of amputation stumps,68,74 other postamputation movement disorders,75–77 and hemimasticatory spasm.78 There are many other movement disorders of peripheral origin that have variable etiology and phenomenology (see Box 1). In this article, chiefly because of space limitations and lack of evidence-based data, the author has purposefully avoided the discussion of the complex overlap between
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peripherally induced and psychogenic movement disorders. This topic is partly covered in recent reviews on psychogenic movement disorders.6,79–82 One of the main areas of controversies in this regard is CRPS and, specifically, whether some, most, or even all patients with this disorder have a coexistent or primary psychogenic disorder.83,84 In one study, early traumatic experiences were reported in 87% of patients with CRPS-I, and the authors suggested that these ‘‘early traumatic experiences might be a predisposing, although not a necessary factor for the development of CRPS-I-related dystonia.’’85 They concluded, however, that ‘‘Although the psychological profile of the patients with CRPS-I-related dystonia shows some elevations, there does not seem to be a unique disturbed psychological profile on a group level.’’ Thus, although some patients with peripherally induced movement disorders may have behavioral abnormalities and perhaps even primary psychogenic movement disorder, this cannot be generalized to all patients who experience abnormal movement after injury. Further studies are needed to elucidate the peripheral and central mechanisms of this group of movement disorders.
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I ndex Note: Page numbers of article titles are in boldface type. A Acupuncture, for PMDs, 811 Adult-onset tics, 827 Alpha-synuclein, Parkinson disease due to, 585–586 Amantadine, for Parkinson disease, 609, 612 Anticholinergic drugs, for dystonia, 711 Antidopaminergic drugs, for dystonia, 711 Anxiety syndromes, in Parkinson disease, 619 Autophagy, Parkinson disease and, 594 B Behavioral modification, for PMDs, 810–811 Benzodiazepine(s), for dystonia, 711 Biofeedback, for PMDs, 811 Botulinum toxin, for dystonia, 710–711 Bromocriptine, for Parkinson disease, 608, 612 C Cabergoline, for Parkinson disease, 608 Catechol-O-methyl transferase (COMT) inhibitors, for Parkinson disease, 609–611 Cerebellar intention tremor, 683–684 Children PMDs in, 815–816 restless legs syndrome in, 780 Tourette syndrome in comorbidities of, management of, 744–747 management of, 744–747 Chorea(s), 719–736 autoimmune, 729–730 causes of, 719–721, 729 defined, 719 described, 719, 723–724 genetic, 723–729 Sydenham, 724–729. See also Sydenham chorea. vascular, 729–730 Clinically established psychogenic movement disorder, 801 Clozapine, for levodopa-induced dyskinesia in patients with Parkinson disease, 617 Cognitive disorders, in Parkinson disease, 617–618 COMT inhibitors. See Catechol-O-methyl transferase (COMT) inhibitors.
Neurol Clin 27 (2009) 833–842 doi:10.1016/S0733-8619(09)00039-5 neurologic.theclinics.com 0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
834
Index
Constipation, in Parkinson disease, 621 Cortical myoclonus evaluation of, 763–769 clinical neurophysiology methods in, 763 electrophysiologic properties from, 765–767 research methods in, 767–768 pathophysiology of, 762–763 treatment of, 773 Cortical tremor, 688 Cortical-subcortical myoclonus evaluation of, 769–770 treatment of, 773–774 Counseling, for dystonia, 708–710
D Deep brain stimulation, complications of, surgical treatment of movement disorders and, 640–651 Depression, in Parkinson disease, 619 DJ1, Parkinson disease due to, 589–590 Documented psychogenic movement disorder, 801 Dopamine agonists, for Parkinson disease, 612–615 Dopaminergic drugs, for dystonia, 711 Dopa-responsive dystonia, 704–705 Drug(s), tremor due to, 688 Dyskinesia, anti-Parkinson therapy and, 615–617 Dystonia(s), 697–718, 823–826 classification of, 697–698 molecular, 699 clinical diagnosis of, 708–710 counseling for, 708–710 dopa-responsive, 704–705 DYT6, 703 early-onset, described, 698 genetic testing in, 708–710 lubag, 708 primary causes of, 709 described, 697–698 primary torsion, 698–702. See Primary torsion dystonia. psychogenic, 807 secondary, 704 causes of, 706–707 described, 698 surgical treatment of, 664–665 treatment of, 710–712 anticholinergic drugs in, 711 antidopaminergic drugs in, 711 benzodiazepines in, 711 botulinum toxin in, 710–711 described, 710
Index
dopaminergic drugs in, 711 levodopa in, 711 physical therapy in, 712 surgical, 712 tremulous cervical, 686 Dystonia-parkinsonism rapid-onset, 708 x-linked, 708 Dystonia-plus, 704 Dystonic tremor, 686 DYT1 endophenotype, in primary torsion dystonia, 701–702 DYT1 phenotype, in primary torsion dystonia, 701–702 DYT3, 708 DYT5, 704–705 DYT11, 705–708 DYT12, 708 DYT15, 705–708 E Environment, Parkinson disease due to, 592–593 Ergoline dopamine agonists, for Parkinson disease, 608, 612–613 Essential tremor, 680–682 surgical treatment of, 664 F FLASQ-PD, 637–639 Focal tremor, 686 G Gait, psychogenic, 807–808 Genetic(s) in dystonia, 708–710 in Parkinson disease, 584–592 in restless legs syndrome, 781–782 Glucocerebrosidase mutations, Parkinson disease due to, 591 H Hemifacial spasm, 823 Holmes tremor, 684–685 HtrA2/Omi, Parkinson disease due to, 592 Huntington disease, 719–736 causes of, 722–723 clinical features of, 722 described, 719, 722 management of, 723 pathogenesis of, 722–723 Hypnosis, for PMDs, 811 Hypotension, orthostatic, in Parkinson disease, 622
835
836
Index
I Impulse control disorders, in Parkinson disease, 619–620
L Levodopa for dystonia, 711 for Parkinson disease, 611–612 Lisuride, for Parkinson disease, 608, 612 LRRK2, Parkinson disease due to, 590–591 Lubag, 708
M MAO-Bs. See Monoamine oxidase type B inhibitors (MAO-Bs). Monoamine oxidase type B inhibitors (MAO-Bs), for Parkinson disease, 606–610 Movement disorders. See also specific disorders. mechanisms of action in, 634–636 peripherally induced, 821–832 adult-onset tics, 827 described, 821–823 dystonia, 823–826 hemifacial spasm, 823 parkinsonism, 827 Tourette syndrome, 827 tremor, 826 types of, 822 psychogenic, 801–819. See also Psychogenic movement disorders (PMDs). surgical treatment of, 633–677 candidate selection for, 636–637 complications of deep brain stimulation–related, 640–651 studies related to, 642–650 surgical, 641–651 dystonia, 664–665 essential tremor, 664 FLASQ-PD in, 637–639 history of, 633–634 multidisciplinary team in, 636–637 Parkinson’s disease, 651, 664 stimulator placement and programming in, 637, 639, 641 Moyamoya disease, chorea due to, 729 Mutation(s) glucocerebrosidase, Parkinson disease due to, 591 POLG1, Parkinson disease due to, 591–592 Myoclonus, 757–777 characteristics of, 757 clinical classification of, 757–761 cortical. See Cortical myoclonus. cortical-subcortical
Index
evaluation of, 769–770 treatment of, 773–774 defined, 757 evaluation of cortical myoclonus, 763–769 cortical-subcortical myoclonus, 769–770 peripheral myoclonus, 772 segmental myoclonus, 771–772 subcortical-segmental myoclonus, 770–771 peripheral evaluation of, 772 treatment of, 774 psychogenic, 808 segmental evaluation of, 771–772 treatment of, 774 subcortical-suprasegmental evaluation of, 770–771 treatment of, 774 treatment of, 772–774 cortical myoclonus, 773 cortical-subcortical myoclonus, 773–774 described, 772–773 peripheral myoclonus, 774 segmental myoclonus, 774 subcortical-suprasegmental myoclonus, 774 Myoclonus-dystonia, 705–708 N Nonergoline dopamine agonists, for Parkinson disease, 609, 613–614 O ‘‘Obsessive-compulsive behaviors’’ (OCBs), 740 OCBs. See ‘‘Obsessive-compulsive behaviors’’ (OCBs). Orthostatic hypotension, in Parkinson disease, 622 Orthostatic tremor, 687–688 P Palatal tremor, 685–686 Panic attacks, in Parkinson disease, 619 Parkin, Parkinson disease due to, 586–587 Parkinson disease, 583–603 anxiety syndromes in, 619 autophagy and, 594 causes of, 584 environmental factors, 592–593 genetic factors, 584–592 alpha-synuclein, 585–586
837
838
Index
Parkinson (continued) described, 584 DJ1, 589–590 glucocerebrosidase mutations, 591 HtrA2/Omi, 592 LRRK2, 590–591 parkin, 586–587 PINK1, 588–589 POLG1 mutations, 591–592 UCH-L1, 587–588 cognitive disorders in, 617–618 constipation in, 621 depression in, 619 epidemiology of, 583 geographic distribution of, 583 impulse control disorders in, 619–620 incidence of, 583 morphologic abnormalities associated with, 583–584 nonmotor symptoms in, 617–622 orthostatic hypotension in, 622 panic attacks in, 619 pathogenesis of, 593 prevalence of, 583 psychiatric disorders in, 618–619 salivary disturbances in, 622 sleep disorders in, 620–621 treatment of medical, 605–631 amantadine in, 609, 612 bromocriptine in, 608, 612 cabergoline in, 608 COMTs in, 609–611 described, 605–606 dopamine agonists in, 612–615 entacapone in, 609–611 ergoline dopamine agonists in, 608, 612–613 levodopa in, 611–612 lisuride in, 608, 612 MAO-Bs in, 606–610 motor complications of, 615–617 nonergoline dopamine agonists in, 609, 613–614 pergolide in, 608 pramipexole in, 609, 613 rasagiline in, 606–608 ropinirole in, 609, 614 selegiline, orally disintegrating tablets in, 607–610 selegiline in, 607, 608 tolcapone in, 609, 610 surgical, 651, 664 urological dysfunction in, 621–622 Parkinson tremor, 682–683
Index
Parkinsonism, 827 psychogenic, 807 Pergolide, for Parkinson disease, 608 Periodic limb movements of sleep, 779–780 Peripheral myoclonus evaluation of, 772 treatment of, 774 Peripheral nerve pathology, tremor due to, 686 Peripherally induced movement disorders, 821–832. See also specific disorders and Movement disorders, peripherally induced. Physical therapy for dystonia, 712 for PMDs, 811 Physiologic tremor, 679–680 PINK1, Parkinson disease due to, 588–589 Placebo, trial of, for PMDs, 812 PMDs. See Psychogenic movement disorders (PMDs). POLG1 mutations, Parkinson disease due to, 591–592 Possible psychogenic movement disorder, 802 Pramipexole, for Parkinson disease, 609, 613 Primary torsion dystonia, 698–702 DYT1 phenotype and endophenotype in, 701–702 DYT6, 703 early-onset but not DYT1, 702–703 DYT1 and, 698, 700 late-onset focal and segmental, 703–704 structure and function of TorsinA in, 700–701 Primary writing tremor, 686 Probable psychogenic movement disorder, 802 Psychiatric disorders, in Parkinson disease, 618–619 Psychogenic dystonia, 807 Psychogenic gait, 807–808 Psychogenic movement disorders (PMDs), 801–819 clinically established, 801 definitions associated with, 801–802 described, 801 documented, 801 historical characteristics of, 803 in children, 815–816 neurophysiology testing in, 804–806 patient history in, 802–803 physical examination findings in, 804 possible, 802 probable, 802 prognosis of, 812–813 psychogenic dystonia, 807 psychogenic gait, 807–808 psychogenic myoclonus, 808 psychogenic parkinsonism, 807 psychogenic tremor, 806–807
839
840
Index
Psychogenic (continued) research findings in, 813–815 treatment of, 808–812 acupuncture in, 811 behavioral modification in, 810–811 biofeedback in, 811 described, 808–809 hypnosis in, 811 inpatient, 809–810 oral medications in, 810 outpatient, 810–812 physical therapy in, 811 TMS in, 811–812 trial of placebo in, 812 types of, 801–802, 806–808 workup for, 804–806 Psychogenic myoclonus, 808 Psychogenic parkinsonism, 807 Psychogenic tremor, 688–689, 806–807
R Rapid-onset dystonia-parkinsonism (DYT12), 708 Rasagiline, for Parkinson disease, 606–608 Restless legs syndrome, 779–799 clinical, 779 diagnostic evaluation of, 780–781 epidemiology of, 781 genetics of, 781–782 in children, 780 pathophysiology of, 782–784 periodic limb movements of sleep, 779–780 secondary, 784–786 treatment of, 786–789 Ropinirole, for Parkinson disease, 609, 614 Rubral tremor, 684–685
S Salivary disturbances, in Parkinson disease, 622 Secondary restless legs syndrome, 784–786 Segawa disease, 704–705 Segmental myoclonus evaluation of, 771–772 treatment of, 774 Selegiline, for Parkinson disease, 607, 608 Selegiline orally disintegrating tablets, for Parkinson disease, 607–610 Sleep, periodic limb movements of, 779–780 Sleep disorders, in Parkinson disease, 620–621 Spasm(s), hemifacial, 823 Subcortical-suprasegmental myoclonus
Index
evaluation of, 770–771 treatment of, 774 Sydenham chorea, 724–729 causes of, 726–727 clinical features of, 725–726 described, 724–725 management of, 727–729 pathogenesis of, 726–727
T Task-specific tremor, 686 Tic(s), adult-onset, 827 Tic disorders. See also Tourette syndrome. classification of, DSM-IV, 739 diagnosis of, 737–738 pathophysiology of, 741–743 phenomenology of, 737–738 TMS. See Transcranial magnetic stimulation (TMS). Tolcapone, for Parkinson disease, 609, 610 TorsinA, structure and function of, in primary torsion dystonia, 700–701 Tourette syndrome, 737–755, 827. See also Tic disorders. clinical course of, 743–744 comorbidities of, spectrum of, 739–741 diagnosis of, 737–738 features of, 737 history of, 737 in children comorbidities of, management of, 744–747 management of, 744–747 pathophysiology of, 741–743 phenomenology of, 737–738 prognosis of, 743–744 Transcranial magnetic stimulation (TMS), for PMDs, 811–812 Tremor(s), 679–695 cerebellar intention, 683–684 cortical, 688 described, 679 drug-induced, 688 dystonic, 686 essential, 680–682 surgical treatment of, 664 focal, 686 Holmes, 684–685 orthostatic, 687–688 palatal, 685–686 Parkinson, 682–683 peripheral nerve pathology and, 686 physiologic, 679–680 primary writing, 686 psychogenic, 688–689, 806–807
841
842
Index
Tremor(s) (continued) rubral, 684–685 task-specific, 686 Tremulous cervical dystonia, 686 Trial of placebo, for PMDs, 812 U UCH-L1, Parkinson disease due to, 587–588 Urological dysfunction, in Parkinson disease, 621–622 V Vascular choreas, 729–730 X X-linked dystonia-parkinsonism (DYT3), 708