V. Shanker, MD (*) • S. Bressman, MD Department of Neurology , Beth Israel Medical Center, Albert Einstein College of Medicine , New York , NY 10003 , USA e-mail: [email protected]
This chapter contains videos segment which can be found at the URL: http://www.springerimages.com/Suchowersky
Video Segment Content
Phenomenology
Case 1: Dystonic posturing.Left shoulder elevation and posturing of the left arm is highlighted. Case 2: Dystonic tremor.The video shows a 60-year-old woman with a 40 year history of essential tremor who developed a dystonic tremor in the left arm and hand 1 year prior to neurologi-cal examination. The dystonic tremor can be seen with arm extension—the left arm tremor diminishes with repositioning. However, the essential tremor in the right arm persists in all directions. Case 3: Overfl ow dystonia.This video shows a 64-year-old woman with dystonia in the right foot. Dystonic movements in the right foot are activated with rapid alternating movements in the left foot, displaying an overfl ow of movement. Case 4: Overfl ow dystonia.This video shows a 61-year-old man with left arm dystonia. Overfl ow dystonia is seen in the left arm with walking. Case 5: Geste antagoniste.This is a 54-year-old woman with DYT6 dystonia. The video highlights her facial movements. Her oromandibular movements quiet with a sensory trick where she places her fi nger on her upper lip.
Distribution
Case 6: Blepharospasm.This is a 57-year-old woman who developed involuntary eye closing and blinking 2 years prior to the video. She is currently receiving botulinum toxin injections. Case 7: Oral-mandibular dystonia .This is a 77-year-old woman who presented with lip curling and mouth pulling at 64. She developed jaw opening dystonia several years later.
Case 8: Spasmodic dysphonia.This is a 72-year-old woman with onset of vocal dystonia at 45. Right laterocollis and upper face dystonia are seen as well. Case 9: Cervical dystonia: torticollis.The video shows a 65-year-old woman with left torticollis whose symptoms began at 21. The video clip also highlights another example of geste antagoniste; when gen-tly touching her forehead bilaterally, there is reduction of dystonic contractions. Case 10: Cervical dystonia: retrocollis.This is a 35-year-old woman with onset of cervical dystonia at 9. During spontane-ous speech, the patient exhibits severe retrocollis. While reading, a left laterocollis and right torticollis are present. Case 11: Cervical dystonia: anterocollis.This is a 55-year-old man who presented with acute onset of neck stiffness at 48. At onset, he complained he had diffi culty laying his head fl at on the pillow at night. On examination, dystonia is almost fi xed. Case 12: Writer’s cramp.The video shows a 20-year-old woman with dystonia in the right arm activated with writing. Symptoms began at 6 years of age. Case 13: Segmental dystonia: Meige syndrome.This is a 75-year-old man who presented with involuntary movements for 10 years. Examination shows frequent blinking, eye closures when reading, and furrowing of the eyebrows. He has involuntary jaw opening, tongue movements, and lip pursing. Case 14: Multifocal dystonia: hemidystonia.The video shows a 47-year-old woman with left-sided hemidystonia after a hemor-rhagic infarction. Case 15: Generalized dystonia.This is a 31-year-old man with onset of left foot dystonia at 8.5 years that pro-gressed to involve all limbs over 3 years. Trunk and neck dystonia involvement began between the ages of 14 and 16.
Etiology
Case 16: Primary dystonia: DYT1.The video shows a 33-year-old man who developed dystonia in the left leg at 9. Symptoms later generalized. Case 17: Primary dystonia: DYT6.This is a 48-year-old Mennonite man with symptom onset at 7. Dystonia is general-ized with greatest severity in the face, neck, and trunk. Case 18: Secondary dystonia: dopamine responsive dystonia a. Segment A. Pretreatment: This is an 11-year-old girl who presented with bilat-
eral leg dystonia when she was 6 years old. She was initially diagnosed with cerebral palsy. Dystonia now includes the left hand.
b. Segment B. One month posttreatment: She is currently taking Sinemet 25/100 mg tid.
c. Segment C. Ten years post initiation of treatment: Patient continues on a medica-tion regimen of Sinemet 25/100 mg tid.
573 Dystonia
Case 19: Secondary dystonia: myoclonus-dystonia.The video shows a 58-year-old woman who presented with involuntary left head turning at 15 and developed myoclonic jerks at 19. She has a history of multiple suicide attempts and alcoholism. The video shows jerky left torticollis and dystonic involvement of the upper face. Generalized myoclonus is present at rest and action. Case 20: Secondary dystonia: rapid onset dystonia parkinsonism.This is a 30-year-old woman who developed mild dystonia in the left upper extrem-ity at 21. Four years later, she had sudden onset of oro-facial and vocal dystonia which rapidly progressed over 10 days. Symptoms of parkinsonism including cog-wheel rigidity, bradykinesia, and postural instability are seen on examination. She is hyperrefl exic in all extremities. Symptoms have reached a plateau; however, at 28 years of age she developed mild right-sided involvement. She is poorly responsive to all medications. Case 21: Secondary dystonia: psychogenic.This is a 30-year-old woman who developed a sudden onset of involuntary left foot inversion, associated with pain, in the setting of a new family illness. The patient complains of severe pain and slowness in her voluntary movements. The exam did not show any signs of parkinsonism. Video shows periodic episodes of complete foot relaxation. Case 22: Secondary dystonia: psychogenic.This is a 16-year-old girl with a sudden onset of involuntary jaw opening associated with pain. There was a history of remission lasting 10 months. She is able to speak and swallow. Episodes occur randomly without exacerbating factors, and then spon-taneously resolve. She has not responded to previously prescribed oral medication or prior botulinum toxin injections.
Introduction
Dystonia is defi ned as a “syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures” [ 1 ] . Despite the compact defi nition, the range of phenomenology is wide. Variations in both the qual-ity of movements as well as the location of these movements are broad and frequently lead to misdiagnosis, especially when the clinical manifestations are subtle.
There are several common features that distinguish dystonia from other hyperki-nesias. The most important of these is a characteristic directionality, often involving the simultaneous activation of agonist and antagonist muscles. Muscles are typi-cally activated in a consistent fashion producing a recognizable, predictable postur-ing or twisting movement. This process is referred to as patterning . Specifi c activities or positions of the body usually trigger the patterned movements observed in an affected individual [ 2 ] .
The duration of muscle contraction may be prolonged, producing a sustained posture at the peak of movement. Alternatively, the duration may be brief, creating
58 V. Shanker and S. Bressman
the appearance of jerking or tremor. A dystonic tremor has an irregular, directional quality which allows it to be distinguished from a cerebellar or essential tremor [ 3, 4 ] . Dystonic movements or tremors are enhanced when the affected area is posi-tioned against the direction of the pull (i.e., turning the neck to the right in a patient with left torticollis). Likewise, dystonia abates when the affected area is placed in the maximum direction of the pull. This placement is identifi ed as the null point .
Classically, dystonic movements occur during voluntary action and may only be triggered by very specifi c tasks. In some, dystonia remains task specifi c, and for others over time, a range of activities or movements in the affected body region may activate dystonia. The repertoire of movement that induces dystonia in the affected area may extend to activity in remote body parts. This process of inducing dystonia with a movement remote from the involved body region is termed as overfl ow dys-tonia. In more severe cases, dystonia may progress, occurring at rest. Muscular hypertrophy and contractures can occur as well.
Patients are often able to reduce dystonic contractions temporarily with mild sensory input. Sensory tricks vary among individuals and often involve self- stimulation, such as gently touching the back of the head in cervical dystonia. A prop can be used as well, such as placing a toothpick in the mouth with oroman-dibular dystonia [ 5, 6 ] . These “tricks” are a phenomenon referred to as geste antag-oniste . Patients may have multiple sensory tricks. Even the thought of the relieving trick can reduce the dystonic movement [ 7 ] . Devices can be constructed to simulate a sensory trick and provide some amelioration [ 8 ] . Sometimes, voluntary activities can relieve dystonia. This phenomenon is called paradoxical dystonia [ 9 ] and is probably related to that of geste antagoniste. Paradoxical dystonia is most com-monly seen in the facial and oromandibular muscles. One example would be a notable reduction of forced eye closures and grimacing when the patient is speak-ing. The mechanisms underlying the partial benefi t of tricks are not completely understood, but PET scans show that sensory tricks normalize dysfunctional corti-cal glucose metabolism [ 10 ] .
Aside from sensory inputs, there are other circumstances which mitigate symptoms. Dystonia usually disappears in sleep [ 11 ] . Relaxation and hypnosis may quiet symp-toms as well. Conversely, increased emotional and physical stress, as well as fatigue, may exacerbate symptoms.
Despite intense posturing and torsion, pain is not usually a prominent feature. The exception to this is cervical dystonia, which is accompanied by neck and shoul-der pain in 75% of cases [ 12 ] . Pain may be secondary to agitation of posterior cervi-cal pain fi bers during the persistent contraction of neck muscles [ 13 ] . Central levels of pain perception may be involved as well [ 14 ] .
On rare occasions, patients develop continuous unremitting dystonic spasms throughout the entire body. This is referred to as dystonic storm or status dystonicus [ 15, 16 ] . Dystonic storm is usually seen in patients with an established history of generalized dystonia. There is often an identifi able medical illness that serves as the trigger for the storm. This is a neurologic emergency and must be treated in the set-ting of an intensive care unit.
593 Dystonia
Classifi cation
Once the clinical diagnosis of dystonia is made, categorization of the dystonia will help guide the workup. Dystonia may be grouped by one of three categories: (1) age of onset, (2) distribution of symptoms, and (3) etiology.
Age of Onset
Dystonia can begin at any age, from infancy to senescence. The age of symptom onset aids the clinician in predicting the pattern of muscle distribution and in for-mulating a prognosis. Primary dystonia has a bimodal age distribution, with modes at 9 (early-onset) and 45 years of age (late-onset) [ 17 ] . In primary dysto-nia, age of onset is associated with a caudal-to-rostral pattern of disease presenta-tion. Studies of patients with DYT1 and non-DYT1 dystonia demonstrate this relationship [ 18– 20 ] . For example, among DYT1 carriers, the mean age of leg, upper limb, and cervical onset is 8.1, 11.5, and 20.1 years, respectively. Age of onset (and site fi rst affected) is also associated with disease progressions or spread. The earlier the age of onset, the more likely dystonia will progress to involve many body regions. Thus, children usually have onset in a leg or arm and often then progress within 5–10 years to generalized dystonia involving multiple limbs. As one ages, the initial affected area is more likely to be the neck, vocal cords, and other cranial muscles [ 21 ] . Unlike early-onset, those with late-onset dystonia are more likely to have localized disease. Thus, age of onset can be used as a guide-line to predict disease course.
Disease Distribution
Dystonia can be categorized by distribution of disease, a hierarchical scheme describing the extent of body regions affected. There are fi ve categories: focal, seg-mental, hemidystonia, multifocal, and generalized. In focal dystonia, the most com-mon disease distribution, contractions involve a single body region. Some examples include blepharospasm (dystonia of the upper face also frequently including some lower facial contractions), oromandibular dystonia (dystonia of the lower face, jaw, or tongue), spasmodic dysphonia (dystonia of the vocal cords), writer’s cramp (dys-tonia of dominant arm muscles primarily present with writing), and cervical dysto-nia (dystonia of the neck muscles). Additional terminology exists to describe the preferred directional neck pull in cervical dystonia. Torticollis describes lateral turning of the head, laterocollis identifi es head tilting, and head fl exion and exten-sion is labeled as anterocollis and retrocollis, respectively. Similarly, spasmodic
60 V. Shanker and S. Bressman
dysphonia may be depicted as adductor (strangled and strained) or abductor (whispering) dystonia.
When focal dystonia spreads, it usually involves one or more contiguous body regions, termed segmental dystonia . Common segmental distributions include involvement of the facial and oromandibular muscles ( Meige syndrome ), axial muscles (back and trunk), and bibrachial distribution [ 22 ] . Multifocal dystonia defi nes a noncontiguous distribution of affected areas. One example would be involvement of the face, right arm, and left leg. Hemidystonia describes a type of multifocal dystonia involving the ipsilateral arm and leg and almost always implies a secondary dystonia [ 23 ] . Common etiologies include perinatal injury, trauma, and stroke [ 24 ] . Generalized dystonia defi nes a segmental crural distribution (involvement of both legs or one leg and the trunk) plus at least one other body region. This usually includes one or both arms.
Disease Etiology
Categorizing dystonia by etiology is perhaps the best guide for evaluation and treatment. In this fashion, dystonia is labeled as either primary (idiopathic) or secondary (symptomatic).
Primary Dystonia
Primary dystonia has both inclusion and exclusion criteria: (1) dystonia is the only clinical fi nding, except for tremor, that cannot be otherwise explained; (2) there is no other historical information suggestive of an acquired cause (i.e., birth injury, neuro-leptics exposure); (3) diagnostic fi ndings suggestive of secondary forms of dystonia are absent (i.e., elevated ceruloplasmin levels, abnormal MRI); and (4) a trial of low-dose levodopa does not produce dramatic clinical benefi t (as seen in dopa-responsive dystonia (DRD)). There are no additional neurologic abnormalities such as seizures, dementia, abnormal refl exes, weakness, ataxia, and disorders of eye movements or the retina. The presence of these or other neurologic fi ndings is highly suggestive of a secondary dystonia. Primary dystonia can be subcategorized into familial and spo-radic forms. There is a presumed genetic contribution in both groups, although the source is more easily identifi ed in familial cases. There are several primary dystonias, although only DYT1 and DYT6 have identifi ed genes to date.
DYT1 dystonia is also known as Oppenheim’s dystonia or dystonia musculorum deformans. It has autosomal dominant inheritance with reduced penetrance esti-mated at 30–40% [ 25 ] . The DYT1 gene is located on chromosome 9q34.1, and the only disease mutation is a deletion of one of a pair of GAG triplets, coding for glu-tamic acid. The protein coded by DYT1 is called torsinA, and it is localized to the cytoplasm of neurons. TorsinA is a novel member of a superfamily of ATPases
613 Dystonia
associated with a variety of cellular activities (AAA + ). These proteins typically possess Mg 2+ -dependent ATPase activity and form six-membered homomeric ring structures. This superfamily of chaperone proteins mediate conformational changes in target proteins and perform a variety of functions, including degradation of dena-tured proteins, membrane traffi cking, vesicle fusion and organelle movement, cytoskeletal dynamics, and correct folding of nascent proteins. Although the func-tion of torsinA and disease-causing mechanisms of the mutant protein are as yet not fully known, there is accruing evidence that the mutation causes a relative loss of normal function; this may include disrupting normal membrane traffi cking, stress responses, and dopamine release [ 26– 28 ] .
The reduced penetrance of the DYT1 gene mutation suggests gene expression is affected by environmental and/or genetic infl uences. A genetic modifi er, a variant in the DYT1 coding sequence for residue 216, has a protective effect when the H (his-tadine) allele is in trans with the GAG deletion. Nonmanifesting carriers have an increased frequency of this 216H allele, reducing penetrance from 30 to 3%. The protective variant is uncommon, representing no more than 20% of carriers [ 29 ] .
The DYT1 mutation carrier frequency in the Ashkenazi Jewish population is estimated to range from 1:1,000 to 1:3,000 (which, assuming a penetrance of 30%, translates into a disease frequency of 1:3,000–1:9,000). This is about sixfold higher than the carrier frequency in the general population, which was found to be 1:12,000 [ 30 ] . The higher frequency in Ashkenazi Jews is thought to be due to a founder mutation that was introduced into the population over 350 years ago [ 31 ] . Genetic testing for the GAG deletion is commercially available.
Clinically, DYT1 has an early onset with a mean age of 12.5 years. The limbs are almost always affected fi rst, starting equally in an arm (mean age of onset, 15 years old) or leg (mean age of onset, 9 years old). Rarely symptoms begin in cervical or cranial muscles [ 32 ] . The majority of DYT1 patients progress to generalized or multifocal dystonia within the fi rst 5 years since symptom onset. A signifi cant minority, about 25%, are restricted to a focal body region, usually writer’s cramp. Unusual phenotypes have included a dystonic storm as well as jerky, clonic dystonia responsive to alcohol [ 33, 34 ] . There are several other primary dystonias described in the literature. These are not as well understood as DYT1.
DYT6 is a primary dystonia with autosomal dominant inheritance and a reduced penetrance approximated at 60%. Although it was initially identifi ed in three related Amish Mennonite kindreds, it is now known to be more widely distributed outside of this population. DYT6 is mapped to chromosome 8p21–q22 [ 35, 36 ] . Two muta-tions in THAP1, the gene that encodes for THAP1 (thanatos-associated protein [THAP] domain-containing apoptosis-associated protein 1), are identifi ed as the cause of DYT6 [ 37, 38 ] . THAP1 is a member of a family of sequence-specifi c cel-lular factors that are DNA-binding. These factors function as nuclear proapoptic proteins and regulate endothelial cell proliferation. A proposed disease mechanism is that DYT6 mutations disrupt DNA binding and produce transcriptional dysregu-lation. Median age of symptom onset is 13 years old; however, later onset may occur. Unlike DYT1, the usual site of onset involves cranial, cervical, or brachial muscles; also, unlike DYT1, speech is often affected.
62 V. Shanker and S. Bressman
DTY13 is an early-onset dystonia with an unknown genetic cause. Its locus on chromosome 1p36 was identifi ed in an Italian family with autosomal dominant inheritance and reduced penetrance. Dystonia primarily involves craniocervical–brachial muscles. There is a large range in reported age of onset. Distribution is usually focal or segmental. Most of the family members affected also had jerky myoclonic-like dystonic movements in the neck or shoulders [ 39 ] .
DYT17, an autosomal recessive early-onset dystonia, was reported in three members of a large consanguineous Lebanese Shiite family. A novel locus on chromosome 20p11.22–q13.12 was identifi ed; the region of interest is 16 cM. Disease onset was in the teens, and the affected individuals had prominent laryngeal and cervical dystonia [ 40 ] .
DYT7 is a late-onset primary torsion dystonia linked to chromosome 18p. It was identifi ed in a German family with adult-onset dystonia, primarily torticollis [ 41, 42 ] . Age of onset ranged between 28 and 70 years old. All family members maintained a focal distribution over a mean follow-up period of 9 years. Families clinically similar to the DYT7 family reported have not been linked to chromosome 18, suggesting the existence of other late-onset primary torsion dystonias yet to be identifi ed [ 43 ] .
Secondary Dystonia
Secondary dystonia includes a host of etiologies—monogenic, environmental, and complex (see Table 3.1 )—with pathology often involving the basal ganglia. Inherited secondary dystonias are often divided into two groups: (1) nondegenerative or “dysto-nia plus” and (2) degenerative. The nondegenerative “dystonia-plus” syndrome includes three subtypes: (1) dopa-responsive dystonia (DRD, DYT5), (2) myoclonus-dystonia (DYT11, DYT15), and (3) rapid-onset dystonia-parkinsonism (DYT12).
DRD is most commonly due to heterozygous mutations in the gene for GTP cyclohydrolase (GCH1) on chromosome 14q22 [ 44 ] . GCH1 is essential for tetrahy-drobiopterin (BH4) synthesis. BH4 is a cofactor of tyrosine hydroxylase which converts tyrosine to levodopa [ 45 ] . Another rare cause of DRD has an autosomal recessive pattern of inheritance. In this form, mutations in the gene coding for tyrosine hydroxylase produce a dopamine-defi cient state [ 46, 47 ] . DRD usually manifests in childhood. There is a mean age of onset of 6 years and a female to male predomi-nance of 3:2 [ 48 ] . Dystonia usually fi rst affects the foot or legs, producing a gait disturbance which may mimic spastic paraplegia. Parents may report that their chil-dren appear to walk on their tiptoes. Characteristically, symptoms worsen later in the day and improve after sleep [ 49 ] . Other features include hyperrefl exia and par-kinsonism, especially bradykinesia or postural instability. The key diagnostic fea-ture is a dramatic and sustained response to very low dosages of levodopa.
Myoclonus-dystonia is a dystonia-plus subtype dominated by myoclonic jerks with dystonia generally occurring as a mild secondary phenomenon, although rarely, dystonia is the only feature [ 50, 51 ] . A common cause of myoclonus-dystonia, especially familial myoclonus-dystonia, is mutations in the gene coding for epsilon-sarcoglycan on chromosome 7q21 [ 52 ] . This gene is imprinted so that most affected inherit through their fathers and not their mothers. Symptoms usually start in
childhood or early adolescence. Age of onset is younger in girls than boys (5 vs. 8 years old); girls are more likely to present with leg onset, which is a dystonic manifes-tation [ 53 ] . Myoclonic jerks are the primary feature and commonly involve the proxi-mal arms, trunk, neck, face, and to a lesser extent the legs and distal arms. Overfl ow myoclonus is often prominent, and dystonia (especially cervical and brachial dysto-nia) is usually a less prominent feature. Parkinsonian features such as rest tremor, postural instability, and decreased arm swing may be seen as well; a subset of these patients is levodopa responsive [ 53 ] . Symptoms are alcohol responsive, and alcohol dependence is associated with the disease. Other psychiatric disorders may co-occur with myoclonus-dystonia. Obsessive-compulsive disorder appears to be a distinct expression of myoclonus-dystonia due to mutations in the epsilon-sarcoglycan gene [ 54 ] . The disease usually progresses for a variable time, from months to years, and then plateaus. A similar disease picture is linked to chromosome 18q11.
Rapid-onset dystonia-parkinsonism (RDP) is the third dystonia-plus subtype. It has an autosomal dominant pattern of inheritance, and onset is in childhood or early adulthood. This rare condition is due to heterozygous mutations in the gene coding for the Na + /K + -ATPase a 3 on chromosome 19q13 [ 55 ] . Often there is a fam-ily history, but new mutations have been described. As the name suggests, symp-toms of dystonia and parkinsonism develop quickly, usually over hours to days, and then plateau. Alternatively, there may be mild signs at onset, which later rapidly worsen. Proposed diagnostic criteria for RDP include (1) abrupt onset of dystonia with features of parkinsonism over minutes to days, (2) a rostrocaudal gradient of involvement (face > arm > leg), and (3) prominent bulbar features, including risus sardonicus. Recommended suggestive features of disease include (1) minimal or lack of tremor at onset, (2) occasional mild limb dystonia prior to the onset of RDP, (3) triggers associated with the abrupt onset, (4) rare “second onset” or abrupt wors-ening of symptoms later in life, (5) symptom stabilization in a month after onset, and (6) minimal improvement of symptoms with the exception of limited improve-ment of gait in a few patients. As suggested by the criteria, symptoms respond mini-mally to medical treatments including levodopa and dopamine agonists [ 56– 58 ] .
The heterodegenerative dystonias encompass many inherited neurological conditions that are associated with neurodegeneration. For most of these disorders, dystonia is usually one component of a complex of neurologic abnormalities. There is an extensive list of diseases that fall in this category.
Aside from monogenic conditions, dystonia may be a feature of disorders in which the causes are complex or unknown. The most common disorder in this class is Parkinson’s disease; dystonia may be its presenting sign (e.g., toe fl exion, foot inver-sion, writer’s cramp), or it may appear later in the course of disease especially in the setting of levodopa therapy. Dystonia may also be a prominent feature of the parkin-sonisms, such as progressive supranuclear palsy, multiple system atrophy, and cortical basal ganglionic degeneration. Psychological etiologies are commonly considered causes of secondary dystonia. Certain features of the history and exam are suggestive of psychogenic dystonia. A history of somatic complaints, a psychiatric disorder, and employment in the health fi elds are more commonly seen in psychogenic cases. When taking a history, the clinician should look for sources of secondary gain. Other com-mon features include abrupt onset, sudden remission, paroxysmal episodes, and fi xed
653 Dystonia
posturing at onset. On examination, nonpatterned movements, movements that change character over time, improvement of symptoms with distraction, excessive move-ments on startle, and response to placebo are more consistent with a psychogenic dystonia [ 59 ] . Clinicians should also look for inconsistent patterns of weakness or sensory defi cits, signs of self-infl icted injury, and additional movements not congru-ous with a known movement disorder, such as deliberate slowness or bizarre gait.
Diagnostic Workup
The initial step in diagnosing the cause of dystonia is through a careful history. Historical features such as birth history, exposure to neuroleptics and other dop-amine-blocking medications, and family history are useful in distinguishing sec-ondary from primary dystonia. Neurologic examination may be expanded to incorporate activities, such as handwriting or playing a musical instrument, which will produce clinically consistent movements. The remainder of the examination, including slit lamp, should be normal if primary dystonia is suspected. Unusual features of dystonia, such as rest dystonia or a body distribution that is not expected for the age onset (e.g., a child with blepharospasm or an older adult with new-onset leg dystonia), as well as other neurologic abnormalities, are suggestive of a second-ary etiology. If the history and physical examination reveal only dystonia and are not suggestive of a secondary source, a primary dystonia is considered fi rst.
Primary Dystonia
Genetic testing for the DYT1 GAG deletion is available in university-based molecu-lar diagnostic or commercial laboratories if primary dystonia is suspected [ 60 ] . If DYT1 testing is offered, patients and their families should be referred to a genetic clinic for further discussion, as recommended in published referral guidelines [ 61, 62 ] . One option is to refer all patients with disease onset prior to age 26 as this identifi es 100% of clinically ascertained carriers. If a relative is affected with early-onset dystonia, testing may be considered regardless of age of onset. Commercial testing is available for the DYT6 mutations as well and could be considered for patients with early-onset dystonia and prominent cranial involvement.
Secondary Dystonia
The evaluation of secondary dystonias rests on two considerations: (a) a differen-tial that is formulated based on clinical examination, history, and imaging and (b) the need to prioritize dystonias that have timely or specifi c treatments. Thus, uppermost in most clinicians’ minds is fi rst ensuring conditions such as Wilson’s disease, DRD, mass lesions, or psychogenic dystonia are detected. The order in
66 V. Shanker and S. Bressman
which these etiologies are evaluated will depend on their likelihood based on the information gathered from the examination, history, and imaging. Imaging, in par-ticular MRI, is used to detect structural changes associated with secondary dysto-nias such as vascular malformations, tumors, or strokes [ 63, 64 ] . It also may detect brain pathology associated with metabolic disorders. For example, in Wilson’s dis-ease, changes in the putamen, thalamus, and brainstem classically produce the “face-of-the-giant panda sign” on imaging [ 65 ] . Pantothenate kinase-associated neurodegeneration (PKAN) causes a pallidal hypointensity with a relative hyperin-tensity in the anteromedial globus pallidus on T2 weighted imaging. The resulting image appears as the “eye-of-the-tiger” sign [ 66 ] . Caudate atrophy suggests Huntington’s disease or neuroacanthocytosis. Diffuse white matter changes on imaging are suggestive of a leukodystrophy.
Depending on the results of the MRI along with clinical and historical informa-tion, a further diagnostic plan can be tailored. One important diagnosis that is easily screened for and for which the MRI is unrevealing is DRD. A daily dose of 1/2 tablet of 25/100 carbidopa–levodopa, increasing every several days by 1/2 tablet to 2–3 tablets/day, is recommended. Usually, there will be a signifi cant response at that very low dose, but occasionally, higher doses are required. Levodopa trials have high sensitivity but are not fully specifi c as other conditions may show improvement with levodopa therapy, although usually it is much less complete. Genetic testing for GCH1 mutations is also available and is more specifi c, although there are only a few laboratories that perform the screening. Also, conventional sequencing of GCH1 coding regions detects mutations in only an estimated 50–60% of cases, missing large heterozygous deletions that require more comprehensive analysis. Finally, even using the most rigorous screening, mutations are not detected in an estimated 20% of typical DRD cases and other mutations (GCH1 regulatory genes, other disease genes) are suspected. Thus, other confi rmatory tests may be used including CSF analysis for biopterin metabolites and phenylalanine loading which assess the ability to convert phenylalanine to tyrosine, a biopterin dependent reaction.
Aside from DRD, genetic testing can be useful for many other secondary dystonias including those suspected to have a spinocerebellar ataxia, Huntington’s disease, mitochondrial cytopathy, myoclonus-dystonia, or juvenile PD due to parkin muta-tions [ 67– 72 ] . A helpful website to both obtain clinical and genetic testing informa-tion is www.geneclinics.org .
Wilson’s disease (WD) is a therapeutically important condition and needs to be considered as it is a treatable condition and early intervention has a signifi cant infl u-ence on prognosis. Previously, it was said that anyone with onset of dystonia and/or tremor prior to the age of 50 should be tested for WD, but more recent reports have suggested that the age should be extended upward to 70. WD is an autosomal reces-sive disease caused by mutations in the gene coding for the ATPase ATP7B. ATP7B resides in hepatocytes in the trans-Golgi network, transporting copper into the secre-tory pathway for incorporation into apoceruloplasmin and excretion into the bile. Mutations of the gene result in impaired traffi cking of copper in and through the hepatocytes. Consequently, copper accumulates in the organs, fi rst in the liver and later in other organs such as the brain. Routine screening for Wilson’s begins with a slit lamp examination to look for Kayser–Fleischer rings, golden or greenish-brown
copper deposits that form at the upper and lower poles of the limbus, the junction between cornea and sclera, on the inner surface of the cornea in Descemet’s mem-branes. Serum ceruplasmin is low. However, serology will miss 10% of affected patients. A 24-h urine copper is a more sensitive test and is abnormal if there is more than 100 m g of copper in the urine. If the diagnosis of Wilson’s is still suspected and not fully supported by the above testing, the gold standard is a quantitative copper analysis via percutaneous liver biopsy [ 73 ] .
Treatment
Aside from a limited group of secondary dystonias that have specifi c etiologically based treatments (e.g., WD, DRD; see below), the treatment for dystonia is empiric and based on reducing dystonia severity. Treatment options include supportive ther-apy, medications, chemodenervation, and surgical intervention. Treatment strategy is dependent on localization, symptom severity, and impact of dystonia on quality of life (QOL). Patient education on available treatments begins in the clinician’s offi ce but is often supplemented with information from outside resources. One excellent resource is the World Education and Awareness of Movement Disorders (WE MOVE) organization. WE MOVE has a patient-friendly educational website with links to additional resources ( http://www.wemove.org ). The Dystonia Medical Research Foundation also has a website ( http://www.dystonia-foundation.org ) with patient information and links to dystonia support groups. Referral to a medical genetics clinic, when applicable, is advisable as well. How the patient perceives the quality of his or her life may infl uence the perception of disease [ 74 ] . Referrals to a psychiatrist, psychologist, or support group are sometimes helpful, as comorbid psychiatric diagnoses often complicate management.
Physical Therapy and Assisting Devices
Physical therapy and supportive devices are the least invasive mode of therapy, but only a small number of studies have investigated their effi cacy. Orthopedic devices may help maintain posture and avoid contractures. Specially fi tted shoes or braces may assist walking and posture maintenance. In some cases, devices developed to simulate a sensory trick provide an overall reduction in dystonic movements (i.e., a brace that rests against the back of the head in a patient with retrocollis). In small studies, patients using hand orthoses developed for writer’s cramp or tremor showed substantial improvement in handwriting samples. The use of these devices may serve as an alternative or adjunct to medications or chemodenervation in patients with focal hand dystonia predominantly affecting handwriting [ 75, 76 ] .
Both sensory and motor modulating therapies have emerged and shown some promise in dystonia therapy. Constraint-induced movement therapy has had some success in focal hand dystonia [ 77 ] . Small trials have studied the effectiveness of
constraining nonaffected digits to improve motor skills. A group of ten musicians with focal hand dystonia underwent an 8-day period requiring them to perform repetitive exercises with their dystonic fi ngers up to 2.5 h a day [ 78 ] . Exercises with splinting were then performed 1 h a day for 6 months. Final assessment after 6 months showed signifi cant improvement on measurements of dexterity in all par-ticipants, and half were able to return to normal or almost-normal digit range during musical performance. After 23 months of training, all were able to continue or resume professional playing.
Conversely, another approach is to splint the dystonic fi ngers to decrease abnormal overfl ow not involved in a task. A study trained ten patients with focal hand dystonia over a 4–12-week period to perform hand exercises while their dystonic fi ngers were splinted [ 79 ] . Clinically signifi cant improvement was seen on dystonia rating scales and via handwriting analysis. Long-term use of constraint therapy is unknown and has raised some concerns as case reports of patients with extended immobilization or cast-ing have described exacerbation or spread of the dystonia [ 80 ] .
Sensory training is another approach tested in focal hand dystonia. This method is based on the theory that some dystonia patients have disordered sensory percep-tion. In a small trial, researchers taught ten patients with focal hand dystonia to read Braille with the affected hand [ 81 ] . After 8 weeks of daily training, the majority of patients improved in their dystonia rating scales and writing speed. A follow-up study of three self-selected participants who were agreeable to a continued training program reported that all three continued to maintain or improve their skills initially rated at the 2-month mark [ 82 ] .
In one small case series, musicians with focal hand dystonia were taught to per-form attended, goal-oriented, rewarded activities with increasing complexity [ 83 ] . Activities were performed under supervision 1.5–2 h a week and were reinforced with 1 h home rehearsals. Manipulated objects were covered with rough surfaces to reduce excessive gripping and to control hand shaping. Subjects also mentally rehearsed normal task performance. After training, testing of motor control, sensory discrimination, musculoskeletal performance, and physical independence improved. Somatosensory evoked potentials increased in amplitude and in area of hand representation.
Transcranial magnetic stimulation (TMS) is a neurophysiologic approach that helps normalize the abnormally enhanced cortical excitability observed in dystonia. Siebner and colleagues reported a temporary improvement in handwriting and reduction of handwriting pressure in a subgroup of patients receiving TMS [ 84 ] . Transcutaneous electrical stimulation (TENS) is a noninvasive method of sensory nerve stimulation that has also been examined. A randomized placebo-controlled study utilizing TENS in writer’s cramp reported signifi cant improvement of symp-toms after 2 weeks of TENS treatment. Effects persisted for 3 weeks [ 85 ] .
Medication Therapy
There are only a few large randomized, controlled trials to guide the clinician in the use of oral therapies. However, clinical experience has demonstrated that many
693 Dystonia
patients improve with one or more medications. Many of the recommendations made are guided by small studies and clinical experience. A list of commonly used medications with recommended starting doses are listed in Table 3.2 .
Dopaminergic Medications
Detecting DRD is paramount in the clinician’s approach to therapy. Therefore, levodopa should be offered to everyone who presents with early-onset dystonia. Additionally, a small percentage of patients with primary and other secondary dys-tonias will obtain some benefi t, even if failing anticholinergic treatment [ 86– 88 ] . Non-DRD patients may require higher average daily doses of levodopa (given as levodopa–carbidopa) than those with DRD to detect symptomatic benefit. As described above, DRD patients usually respond to dosages of 300 mg or less of levodopa. Less commonly, patients will require higher doses, up to 900 mg a day. A common side effect is nausea, and additional carbidopa may be needed. Mild dyskinesias may occur on initial treatment, especially if there is a rapid escalation of dose. On the other hand, DRD patients sustain an excellent long-term response to levodopa without the fl uctuations or dyskinesias observed in Parkinson’s disease.
Anticholinergic Medications
Trihexyphenidyl (Artane) can produce symptomatic benefi t in both primary and secondary dystonias and is often considered fi rst-line therapy in children who do not have DRD [ 89– 91 ] . Side effects include central (confusion, memory impairment, drowsiness, hallucinations) as well as peripheral (abdominal cramps, urinary retention) anticholinergic effects. Because of the side effect profi le, the medication is started at low dose. One suggestion is to begin with a 2-mg tablet at bedtime and slowly titrate upward weekly by 2–2.5 mg, usually with tid dosing. Titration is based on benefi t and side effects. Some patients will benefi t and tolerate up to 100 mg a day. Children tend to tolerate the medication at higher doses than adults. Pyridostigmine (Mestinon), 30–120 mg/day, can be taken with trihexyphenidyl to offset the periph-eral anticholinergic side effects.
Dopamine-depleting drugs, such as reserpine and tetrabenazine, are useful alterna-tives for dystonia treatment, especially in tardive dystonia [ 92 ] . Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Except for use in tardive dystonia, dopamine depleters are usually considered second-line agents because of their common side effects, including parkinsonism, drowsiness, and depression. Side effects are reversible with cessation of medication. Several case reports and small studies have reported the benefi t of dopamine receptor blockers in dystonia treatment [ 93– 95 ] . Trials using clozapine, a D4 receptor blocker, may provide mod-erate benefi t in patients with focal, segmental, and generalized dystonia and have demonstrated utility in tardive dystonia [ 96– 98 ] . Patients taking clozapine require frequent monitoring because of the risk of developing agranulocytosis. Trials using risperdone, a D2 dopamine receptor blocker with a high affi nity for 5HT2 receptors, are benefi cial in a variety of dystonias [ 99, 100 ] . However, dopamine receptor-blocking medications carry numerous complications including the development of tardive dyskinesias, parkinsonism, and sedation.
GABAergic Drugs
Benzodiazepines (diazepam, lorazepam, clonazepam) are another class of medica-tions benefi cial in dystonia. Of these, clonazepam (Klonopin) is commonly used because of its longer duration of action. Studies suggest it is especially useful in blepharospasm and myoclonus-dystonia [ 101, 102 ] and it is often considered fi rst-line medication in adults. Dosing starts at 0.5 mg qhs and is increased slowly as needed. The usual dose range is between 1 and 4 mg/day. The main side effects are drowsi-ness, confusion, and agitation. To avoid withdrawal, all benzodiazepines should be slowly tapered.
Muscle relaxants, such as oral baclofen (Lioresal), are another treatment alterna-tive. Baclofen is a GABA-B agonist. One retrospective study found substantial improvement, especially in gait, in 30% of 31 children and adolescents with pri-mary dystonia [ 103 ] . Another small study found sustained improvement in 7 of 16 children with primary dystonia [ 104 ] . Data on adult response to baclofen is less impressive. A retrospective study of 60 adults with cranial dystonia found that only 18% responded [ 103 ] . Isolated reports have suggested oral baclofen may be particu-larly helpful in the treatment of tardive dystonia, dystonia in Parkinson’s disease, and glutaric acidemia [ 105– 107 ] . Baclofen is usually initiated at a dose of 5–10 mg/day and titrated over several weeks to 30 mg/day. Further increases are made, slowly titrating benefi t against side effects. Daily dosing ranges from 40 to 120 mg/day in divided doses. Drowsiness is the most common side effect. Respiratory and cardio-vascular depression can occur at high doses. Other muscle relaxants such as cyclobenzaprine (Flexeril), metaxalone (Skelaxin), and tizanidine (Zanafl ex) may be helpful, but reports on these medications for dystonia treatment are limited.
713 Dystonia
In the late 1980s, intrathecal baclofen (ITB) administration was introduced as an alternative to oral dosing. Intrathecal delivery provides a continuous slow infusion of medication from a pump to a catheter placed into the subarachnoid space. Studies regarding the success of ITB in the treatment of dystonia are mixed [ 108 ] . A follow-up of fourteen patients with primary or secondary dystonia receiving ITB reported that only two patients had unequivocal clinical benefi t, although fi ve had improved ratings on dystonia scales [ 109 ] . In this study, etiology of dystonia did not predict ITB effi cacy, although other studies suggest patients with secondary dystonia may be more likely to benefi t. In a study of 77 patients with generalized dystonia, the majority with cerebral palsy, 92% had sustained improvement during a median fol-low-up of 29 months [ 110 ] . A more recent study by Albright and colleagues sug-gested that in children with secondary generalized dystonia, ITB improves ease of care and comfort level in 85% and improves function in 33% [ 111 ] . There are sev-eral complications associated with ITB, including infections, catheter malfunctions, and cerebrospinal fl uid leaks.
Other Pharmacologic Agents
Many different antiepileptic drugs have been investigated for dystonia treatment. Carbamazepine is effi cacious in the treatment of paroxysmal kinesigenic chore-oathetosis, a condition characterized by episodic dystonia induced by sudden move-ment, anxiety, or stress [ 112 ] . However, its effi cacy in other forms of dystonia is unclear [ 113, 114 ] . Case reports have reported benefi t of levetiracetam for focal and generalized dystonia [ 115, 116 ] , topiramate for segmental dystonia [ 117 ] , and val-proate for focal dystonia and myoclonus-dystonia [ 118– 120 ] .
Sodium oxybate (Xyrem) is the sodium salt of gamma hydroxybutyrate (GHB) and recently has been approved for treatment of narcolepsy. It has also been used in patients with myoclonus-dystonia [ 121 ] . Frucht et al. [ 122 ] reported two myoclonus-dystonia patients who experienced greater than 50% improvement from baseline after an 8-week trial. Maintenance doses ranged from 5 to 7.5 g daily, divided into bid or tid doses.
Pharmacologic Treatment in Special Circumstances
Wilson’s Disease
Penicillamine, a copper chelator that increases the urinary excretion of copper, has been the standard of treatment for many years in North America and is still com-monly used in a number of other countries. Worsening of symptoms may be seen after initiation of penicillamine therapy which may be transient or permanent. Other side effects include urticaria and nephritis. Trientine is another copper chelator more recently introduced, and reports suggest there may be some transient worsening of symptoms after drug initiation. Little is known about the long-term outcomes or
72 V. Shanker and S. Bressman
complications of trientine. Oral zinc therapy works by reducing absorption of copper in the intestines. It is used in presymptomatic patients as well as for maintenance therapy. Tetrathiomolybdate, a medication which blocks copper absorption, is currently under investigation as fi rst-line treatment (along with zinc) for WD patients with neurologic symptoms.
Drug-Induced Dystonia
Acute dystonic reactions are one of the most common complications of dopamine receptor-blocking drugs. Typically, mild reactions will respond to a dose of oral anticholinergic medication. However, occasionally, dystonic reaction can be more serious including severe opisthotonus, generalized rigidity, autonomic changes, and oculogyria with tonic eye deviation [ 123– 125 ] .
Severe acute dystonic reactions usually follow exposure to neuroleptics that block D2 receptors and can be terminated with IV treatment of diphenhydramine (25 or 50 mg), benztropine (1 or 2 mg), or biperiden (2 mg) [ 126 ] . Both anticholinergics and clonazepam have been used for maintenance therapy, when needed [ 127 ] .
Tardive dystonia is another complication of dopamine-blocking drugs and is usu-ally seen after long-term use. Although only a small percentage of patients on chronic dopamine-blocking agents develop dystonia, those who do develop tardive dystonia are often moderately to severely disabled. If possible, a fi rst approach is to wean the patient off the offending drug, although this only rarely induces a remis-sion. As discussed above, dopamine-depleting agents such as tetrabenzine may be more benefi cial than other oral medications. Atypical antipsychotics may improve symptoms as well. Nonpharmacologic strategies (see below) such as botulinum toxin for focal disease or surgical intervention may be employed if needed.
Dystonic Storm
Dystonic storm, a rare entity, must be cared for in an intensive care setting as hyper-thermia, fl uid loss, and respiratory compromise may occur. Oral medications such as valium, trihexyphenidyl, baclofen, tetrabenazine, pimozide, and valproic acid can be tried, although dystonic storm is often resistant to these medications [ 128 ] . Sedation and paralysis are sometimes necessary. Dalvi et al. suggested a role for ITB in the treatment of dystonic storm [ 129 ] . When all medication options fail, deep brain stimulation (DBS) may be considered.
Chemodenervation
Botulinum neurotoxin (BoNT) has revolutionized the treatment of dystonia since its introduction into clinical practice in the late 1980s. There are seven BoNT serotypes;
733 Dystonia
however, only types A and B are approved. There are three available formulations of BoNT A—onabotulinum toxin (BOTOX), abobotulinum toxin (DYSPORT), and incobotulinum toxin (XEOMIN). BoNT injections produce transient local weak-ness by interfering with release of acetylcholine into the neuromuscular junction. Normally, release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane. The syn-aptic fusion complex is a set of SNARE proteins (including VAMP, SNAP-25, and syntaxin). BoNT enters the neuron by endocytosis where it then cleaves specifi c sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release.
Botulinum toxin is most benefi cial for segmental and focal dystonia, especially cervical dystonia, blepharospasm, adductor spasmodic dysphonia, and jaw-closing oromandibular dystonia. In these cases, it is considered fi rst-line management because of the low side effect profi le. Most patients experience some benefi t within the fi rst 7–10 days after injection. Maximum benefi t is usually reached after 2–4 weeks and then persists for 12 weeks, although signifi cant benefi t can last for many months. Thus, injections are administered approximately every 3–4 months.
The use of botulinum toxin in cervical dystonia has been studied more than any of the other focal dystonias. The fi rst report of botulinum toxin in cervical dystonia described 12 patients who received up to 200 U of serotype A under electromyog-raphy (EMG) guidance [ 130 ] . Ninety-two percent received benefi t that persisted from 4 to 8 weeks, with 25% experiencing some transient neck weakness. This was followed by a placebo double-blind study of 21 patients who received signifi cant benefi t from toxin injection [ 131 ] . Researchers compared the effi cacy and side effect profi le of serotypes A and B in 139 patients with cervical dystonia [ 132 ] . Improvement on the TWSTRS dystonia rating scale did not signifi cantly differ between the two groups during assessment at 4 weeks. Of those who experienced clinical response with the botulinum toxin treatment, there was a modestly longer duration of action in the A serotype (14 vs. 12 weeks). Botulinum B serotype was signifi cantly more likely to produce symptoms of dry mouth and dysphagia.
Blepharospasm was the fi rst focal dystonia treated with botulinum toxin [ 133 ] . A review of 55 open-label studies, totaling over 2,500 patients, reported that approx-imately 90% have moderate or marked improvement [ 134 ] . A typical starting dose of botulinum toxin is 25 U per eye. Diplopia from diffusion into the inferior oblique, ptosis from weakening of the levator palpabrae, and tearing can occur.
Spasmodic dysphonia responds well to BoNT; however, there is a dearth of ran-domized controlled studies [ 135 ] . Breathiness, hoarseness, and swallowing diffi cul-ties are the potential side effects. Unilateral injections may minimize side effects but have a shorter duration of effi cacy compared to bilateral injections [ 136– 138 ] .
Recent practice parameters recommend botulinum toxin treatment as an option for upper limb dystonia and state it should be a consideration for focal lower limb dystonia. EMG guidance is recommended in these cases. The goal is to identify the most active muscles. Techniques such as eliciting “mirror dystonia” may be useful in distinguishing true dystonic movements from movements of compensation.
74 V. Shanker and S. Bressman
Women and patients with wrist fl exion dystonia may have the best response [ 139 ] . Musicians with task-specifi c dystonia may benefi t as well [ 140 ] .
Other forms of dystonia may also benefi t from botulinum toxin injections. Oromandibular dystonia responds poorly to oral medications, and botulinum toxin injections are often attempted early in the disease course. A case report compared the use of botulinum toxin in jaw-closing and jaw-opening idiopathic oroman-dibular dystonia. Treatment of jaw closure trended toward a signifi cant improve-ment. The masseter muscle is the target of injection in jaw closure dystonia. The medial ptyergoid and temporalis muscles may be targeted as well. Jaw opening involves several muscles including the pterygoid, mylohyoid, digastric, geniohyoid, and platysma [ 141 ] .
In a small percentage of patients, there is a decreased injection response that occurs secondary to the formation of neutralizing antibodies. The preparation of Botox currently used was introduced into the United States in 1997 and is estimated to have a failure rate secondary to antibodies of less than 1% [ 142 ] . Causes that may increase the likelihood of antibody development include shorter dosing intervals, lon-ger duration of treatment, higher dosing, and treatment with older preparation of the A toxin [ 143 ] . If the development of antibodies is suspected, a small amount of toxin (i.e., 20 U of Botox) can be injected into the one side of the frontalis muscle. If asym-metric weakness does not develop in 1–2 weeks, antibody formation is likely.
EMG may help the clinician identify active muscles, improving the accuracy of injections. For this reason, EMG is especially helpful during limb injections [ 144 ] . Several studies have suggested that EMG is also useful in cervical dystonia, improv-ing accuracy and reducing complications [ 145, 146 ] . A randomized, prospective study by Comella and colleagues reported that although the percentage of patients with benefi t was similar among the EMG-guided and EMG-unguided groups, the magnitude of improvement was increased in the group whose injections were EMG-guided [ 147 ] . Patients with retrocollis, head tilt, and shoulder elevation showed additional benefi t.
Surgical Intervention
Prior to the availability and success of botulinum toxin, peripheral denervation procedures were considered in cases when medication failed. When performed for cervical dystonia, the preferred peripheral procedure is an extradural sectioning of the posterior rami, which allows better selection of the involved muscles than intra-dural sectioning of the anterior cervical roots. Anterior resection cannot be per-formed at levels equal to C4 or below due to the risk of damaging the phrenic nerve. A review of 168 patients receiving peripheral denervation over an 8-year period reported moderate to excellent improvement in head position in 77% and moderate to marked improvement in pain in 81% of patients [ 148 ] . Complications of this procedure include local numbness, neck and shoulder weakness, and rarely dysphagia. Myectomy of periorbital muscles and cervical muscles are occasionally performed
753 Dystonia
as a surgical alternative in patients with blepharospasm and cervical dystonia, respectively [ 149, 150 ] . The surgery may be performed alone or in conjunction with selective denervation.
With improved surgical techniques and a greater understanding of the mecha-nisms producing dystonia, the past years have seen an emergence of intracranial surgery for dystonia treatment. Neuroablative surgery, targeting the thalamus or the globus pallidus, was one popular surgical approach which has more recently fallen out of favor. Several studies showed signifi cant benefi ts of ventrolateral cryothala-motomy in dystonia patients [ 151, 152 ] . Later studies suggested that pallidotomies may be more benefi cial than thalamotomies [ 153 ] . The main disadvantages of abla-tive procedures are the irreversibility of the procedure and the risk of debilitating complications such as dysarthria.
DBS, a procedure initially developed for chronic pain treatments, has emerged as the primary surgical alternative for dystonia. Compared to ablative procedures, the factors which make DBS more desirable include the ability to adjust stimulation settings over time and the potential reversibility of the procedure. DBS leads may be placed bilaterally with minimal morbidity compared to bilateral ablation.
The benefi ts of DBS—particularly on primary generalized dystonia, both DYT1 and non-DYT1—are widely reported. Kupsch and colleagues reported the fi rst study of GPi DBS to include a sham stimulation group [ 154 ] . Forty patients with primary segmental or generalized dystonia received implantation of electrodes in the posteroventrolateral portion of the bilateral internal globus pallidi and were then randomized into real and sham stimulation groups. Three months after surgery, the treatment group had signifi cant motor improvement compared to the sham group. After the 3-month evaluation, the sham group received neurostimulation as well, and all patients were reexamined after 6 months. In the entire cohort, there was substantial improvement in movement scores, level of disability, QOL rating scales, and depression scores. Five patients were able to completely discontinue their medi-cation, and twenty patients were able to decrease their medication doses an average of 30%. Twenty-two adverse events were reported, including one lead dislodgement and four infections near the stimulator site. Other adverse effects were mostly attributable to stimulator setting, and most improved with readjustment of the settings. Dysarthria was reported in 12% of patients and was the most common complication.
A prospective multicenter study of bilateral globus pallidus interna (GPi) DBS in a group of 22 patients with primary generalized dystonia [ 155 ] showed signifi cant improvement at 12 months (mean >50%) in dystonia symptoms and disability scores. A 3-year follow-up found that the patients maintained benefi ts they had achieved in mood, QOL scores, and medication reductions during the fi rst year of follow-up [ 156 ] . Patients had signifi cantly improved motor scores for upper and lower limbs at year three compared to year one. Several patients in the study had DYT1; however, gene status did not predict treatment response. Another case series of primary generalized patients followed surgical patients up to 8 years after DBS surgery also reported sustained improvement of symptoms [ 157 ] .
Recent studies of DBS in primary dystonia suggest that patients with shorter disease course may have better outcomes [ 158 ] . Additionally, patients with primary
76 V. Shanker and S. Bressman
dystonia may respond better to stimulation at 60 Hz [ 159 ] . Affected DYT6 carriers may receive benefi t from GPi stimulation, but cranial symptoms appear to be less responsive than limb symptoms [ 160 ] .
GPi DBS also has proven effi cacy in cervical dystonia [ 161, 162 ] . A long-term follow-up of 10 cervical dystonia patients who received bilateral DBS showed a sustained improvement in symptoms on all subscale scores of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) [ 163 ] . Unlike the primary dysto-nias, cervical dystonia may respond best to stimulation at high frequencies [ 164 ] .
The role of DBS in nonprimary dystonia is under study. Both GPi and ventral inter-mediate thalamic nucleus (VIM) stimulation can provide symptom relief in myoclonus-dystonia [ 165, 166 ] . A comparison of the two approaches suggests that while both approaches are effective, GPi stimulation may have fewer side effects [ 167 ] .
DBS has had modest success in other forms of secondary dystonia, including tardive dystonia [ 168– 170 ] and PKAN [ 171 ] . A study of six patients with PKAN with GPi DBS reported long-lasting improvement in painful spasms, dystonia, and functional anatomy [ 172 ] . The role of DBS in other forms of secondary dystonias such as posthypoxic and posttraumatic injury is still unknown [ 173 ] .
Over the past 20 years, the introduction of new therapies, especially botulinum toxin and DBS, has greatly expanded treatment options. As our knowledge of the genetics and pathophysiology of dystonia grows, there is hope for the development of more targeted treatments, including prevention.
References
1. Fahn S. Concept and classifi cation of dystonia. Adv Neurol. 1988;50:1–8. 2. Svetel M, Ivanovic N, Marinkovic J, Jovic J, Dragasevic N, Kostic VS. Characteristics of
dystonic movements in primary and symptomatic dystonias. J Neurol Neurosurg Psychiatry. 2004;75:329–30.
3. Jankovic J, Fahn S. Physiologic and pathologic tremors. Diagnosis, mechanism, and manage-ment. Ann Int Med. 1980;93:460–5.
4. Fahn S. Clinical variants of idiopathic torsion dystonia. J Neurol Neurosurg Psychiatry. 1989;52(Suppl):96–100.
5. Blunt SB, Fuller G, Kennard C, Brooks D. Orolingual dystonia with tip of the tongue geste. Mov Disord. 1994;9:466.
6. Muller J, Wissel T, Masuhr F, Ebersbach G, Wenning GK, Poewe W. Clinical characteristics of the geste antagoniste in cervical dystonia. J Neurol. 2001;248:478–82.
7. Greene PE, Bressman S. Exteroceptive and interoceptive stimuli in dystonia. Mov Disord. 1998;13:549–51.
8. Krack P, Schneider S, Deuschl G. Geste device in tardive dystonia with retrocollis and opist-hotonic posturing. Mov Disord. 1998;13:155–7.
9. Jedynak CP, Bonnet AM, Agid Y. Tremor and idiopathic dystonia. Mov Disord. 1991;6:230–6. 10. Naumann M, Magyar-Lehmann S, Reiners K, Erbguth F, Leenders KL. Sensory tricks in
cervical dystonia: perceptual dysbalance of parietal cortex modulates frontal motor program-ming. Ann Neurol. 2000;47:322–8.
11. Fish DR, Sawyers D, Allen PJ, Blackie JD, Lees AJ, Marsden CD. The effect of sleep on the dyskinetic movements of Parkinson’s disease, Gilles de La Tourette syndrome, Huntington’s disease, and torsion dystonia. Arch Neurol. 1991;48:210–4.
13. Greene P, Kang U, Fahn S, Moskowitz C, Flaster E. Double-blind, placebo controlled trial of botu-linum toxin injection for the treatment of spasmodic torticollis. Neurology. 1990;40:1213–8.
14. Kutvonen O, Dastidar P, Nurmikko T. Pain in spasmodic torticollis. Pain. 1997;69:279–86. 15. Dalvi A, Ford B, Fahn S. Dystonic storms. Mov Disord. 1998;13:611–2. 16. Manji H, Howard RS, Miller DH, et al. Status dystonicus: the syndrome and its management.
Brain. 1998;121:243–52. 17. Bressman SB, de Leon D, Brin MF, et al. Idiopathic torsion dystonia among Ashkenazi Jews:
evidence for autosomal dominant inheritance. Ann Neurol. 1989;26:612–20. 18. Bressman SB, de Leon D, Kramer PL, Ozelius LJ, et al. Dystonia in Ashkenazi Jews: clinical
characterization of a founder mutation. Ann Neurol. 1994;36:771–7. 19. Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines for diagnos-
tic testing. Neurology. 2000;54:1746–53. 20. O’Riordan S, Raymond D, Lynch T, et al. Age at onset as a factor in determining the pheno-
type of primary torsion dystonia. Neurology. 2004;63:1423–6. 21. Greene P, Kang UJ, Fahn S. Spread of symptoms in idiopathic torsion dystonia. Mov Disord.
1995;10:143–52. 22. Tolosa E, Marti MJ. Blepharospasm-oromandibular dystonia syndrome (Meige’s syndrome):
clinical aspects. Adv Neurol. 1988;49:73–84. 23. Marsden CD, Obeso JA, Zarranz JJ, Lang AE. The anatomical basis of symptomatic hemidy-
stonia. Brain. 1985;108:463–83. 24. Chuang C, Fahn S, Frucht SJ. The natural history and treatment of acquired hemidystonia: report
of 33 cases and review of the literature. J Neurol Neurosurg Psychiatry. 2002;72:59–67. 25. Pauls DL, Korczyn AD. Complex segregation analysis of dystonia pedigrees suggests auto-
an ATP-binding protein. Nat Genet. 1997;17:40–8. 27. Goodchild RE, Dauer WT. Mislocalization to the nuclear envelope: an effect of the dystonia
torsinA mutation. Proc Natl Acad Sci USA. 2004;101:847–52. 28. Breakfi eld XO, Kamm C, Hanson PL. Torsin A: movement at many levels. Neuron.
2001;31:9–12. 29. Risch NJ, Bressman SB, Senthil G, et al. Intragenic Cis and Trans modifi cation of genetic
susceptibility in DYT1 torsion dystonia. Am J Hum Genet. 2007;80:1188–93. 30. 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.
31. Risch N, de Leon D, Ozelius LJ, et al. Genetics analysis of idiopathic torsion dystonia in Ashkenzi Jews and their recent descent from a small founder population. Nat Genet. 1995;9:152–9.
32. Bressman SB, de Leon D, Kramer PL, et al. Dystonia in Ashkenazi Jews: clinical character-ization of a founder mutation. Ann Neurol. 1994;36:771–7.
33. Opal P, Tintner R, Jankovic J, et al. Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm. Mov Disord. 2002;17:339–4534.
34. Kabeakci K, Hedrich K, Leung JC. Mutations in DYT1: extension of the phenotypic and mutational spectrum. Neurology. 2004;62:395–400.
35. Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromo-some 8 in two Mennonite families. Ann Neurol. 1997;42:670–3.
36. Klein C, Breakefi eld XO, Ozelius LJ. Genetics of primary dystonia. Semin Neurol. 1999;19:271–80.
37. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsi-ble for DYT6 primary torsion dystonia. Nat Genet. 2009;41:286–8.
78 V. Shanker and S. Bressman
38. Djarmati A, Schneider S, Lohmann K, et al. Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol. 2009;8:447–52.
40. 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.
41. Leube B, Rudnicki D, Ratzlaff T, Kessler KR, Benecke R, Auburger G. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, auto-somal dominant inheritance and purely focal distribution. Hum Mol Genet. 1996;5:1673–7.
42. Leube B, Hendgen T, Kessler KR, Knapp M, Benecke R, Auburger G. Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p. Ann Neurol. 1997;42:111–4.
43. Jarman P, Valente EM, Leube B, et al. Primary torsion dystonia: the search for genes is not over. J Neurol Neurosurg Psychiatry. 1999;67:395–7.
44. Nygaard TG, Wilhelmsen KC, Risch NJ, et al. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nat Genet. 1993;5:386–91.
45. Ichinose H, Ohye T, Takahashi E-I, et al. Hereditary progressive dystonia with marked diur-nal fl uctuations caused by mutations in GTP cylcohydrolase I gene. Nat Genet. 1994;8:236–42.
46. Knappskog PM, Flatmark T, Mallet J, Ludecke B, Bartholome K. Recessively inherited L-DOPA-responsive caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum Mol Genet. 1995;4:1209–12.
47. Ludecke B, Dworniczak B, Bartholome K. A point mutation in the tyrosine hydroxylase gene associated with Segawa’s syndrome. Hum Genet. 1995;95:123–5.
48. Furukawa Y, Lang AE, Trugman JM, et al. Gender-related penetrance and de nova GTOP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology. 1998;50:1015–20.
49. Hyland K, Surtees RA, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxyclase defi -ciency: Clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology. 1992;42:1980–8.
50. Gasser T. Inherited myoclonus-dystonia syndrome. Adv Neurol. 1998;44:126–8. 51. Kyllerman M, Forsgren L, Sanner G, Holmgren G, Wahlstrom J, Druge U. Alcohol respon-
sive myoclonic-dystonia in a large family. Dominant inheritance and phenotypic variation. Mov Disord. 1990;5:270–9.
52. Zimprich A, Grabowski M, Amsus F. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat Genet. 2001;29:66–9.
53. Raymond D, Saunders-Pullman R, de Carvalho Aguiar P, et al. Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with epsilon-sarcoglycan mutations. Mov Disord. 2008;23:588–92.
54. Hess CW, Raymond D, de Carvalho Aguiar P, et al. Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers. Neurology. 2007;68:522–4.
55. de Carvalho Aquiar P, Sweadner KJ, Penniston JT, et al. Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron. 2004;43:169–75.
56. Pittock SJ, Joyce C, O’Keane V, et al. Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred. Neurology. 2000;55:991–5.
58. Brashear A, Dobyns W, de Carvalho Aguiar P, et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain. 2007;130:828–35.
59. Fahn S, Williams DT. Psychogenic dystonia. Adv Neurol. 1988;50:431–55. 60. Klein C, Friedman J, Bressman S, et al. Genetic testing for early-onset torsion dystonia
(DYT1): introduction of a simple screening method, experiences from testing a large patient cohort, and ethical issues. Genet Test. 1999;3:323–8.
793 Dystonia
61. Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines for diagnos-tic testing. Neurology. 2000;54:1746–53.
62. Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diagnosis and treatment on primary (idiopathic) dystonia and dystonia plus syndromes report of an EFNS/MDS-ES task force. Eur J Neurol. 2006;13:433–44.
63. Rutledge JN, Hilal SK, Silver AJ, Defendini R, Fahn S. Magnetic resonance imaging of dys-tonic states. Adv Neurol. 1988;50:265–75.
64. Meunier S, Lehericy S, Garnero L, Vidailhet M. Lessons from brain mapping. Neuroscientist. 2003;9:76–81.
65. Jacobs DA, Markowitz CE, Liebeskind DS, Galetta SJ. The “double panda sign” in Wilson’s disease. Neurology. 2003;61:969.
66. Hayfl ick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Eng J Med. 2003;348:33–40.
67. Valente EM, Edwards MJ, Mir P, et al. The epsilon-sarcoglycan gene in myoclonic syn-dromes. Neurology. 2005;64:737–9.
68. Steinberger D, Korinthenberg R, Topka H, Berghauser M, Wedde R, Muller U. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. Neurology. 2000;55:1735–7.
69. Furukawa Y. Update on dopa-responsive dystonia: locus heterogeneity and biochemical fea-tures. Adv Neurol. 2004;94:127–38.
70. Furukawa Y, Guttman M, Sparagana SP, et al. Dopa-responsive dystonia due to a large dele-tion in the GTP cyclohydrolase I gene. Ann Neurol. 2000;47:517–20.
71. Robinson R, McCarthy GT, Bandmann O, Dobbie M, Surtees R, Wood NW. GTP cyclohy-drolase defi ciency; intramfamilial variation in clinical phenotype including levodopa respon-siveness. J Neurol Neurosurg Psychiatry. 1999;66:86–9.
72. Khan NL, Graham E, Critchley P, et al. Parkin disease: a phenotypic study of a large case series. Brain. 2003;126:1279–92.
73. Comella CL. Dystonia and related movement disorders. Continuum. 2004;10:106. 74. Ben-Schlomo Y, Camfi eld L, Warner T. What are the determinants of quality of life in people
with cervical dystonia? J Neurol Neurosurg Psychiatry. 2002;72:608–14. 75. Espay AJ, Hung SW, Sanger TD, Moro E, Fox SH, Lang AE. A writing device improves
writing in primary writing tremor. Neurology. 2005;64:1648–50. 76. Tas N, Karantas GK, Sepici V. Hand orthosis as a writing aid in writer’s cramp. Mov Disord.
2001;16:1185–9. 77. Candia V, Elbert T, Altenmüller E, Rau H, Schafer T, Taub E. Constraint-induced movement
therapy for focal hand dystonia in musicians. Lancet. 1999;53:42. 78. Taub E, Uswatte G, Pidikiti R. Constraint-induced movement therapy: a new family of
techniques with broad application to physical rehabilitation–a clinical review. J Rehabil Res Dev. 1999;36:237–51.
79. Zeuner KE, Shill HA, Sohn YH, et al. Motor training as treatment in focal hand dystonia. Mov Disord. 2005;20:335–41.
80. Jankovic J. Can peripheral trauma induce dystonia and other movement disorders? Yes! Mov Disord. 2001;16:7–12.
81. Zeuner KE, Bara-Jimenez W, Noguchi PS, Goldstein SR, Dambrosia JM, Hallett M. Sensory training for patients with focal hand dystonia. Ann Neurol. 2002;51:593–8.
82. Zeuner KE, Hallett M. Sensory training as treatment for focal hand dystonia: a one year fol-low-up. Mov Disord. 2003;18:1044–7.
83. Byl N, Nagajaran S, McKenzie A. Effect of sensory discrimination training on structure and function in patients with focal hand dystonia: a case series. Arch Phys Med Rehabil. 2003;84:1504–14.
84. Siebner HR, Tormos JM, Ceballos-Baumann AO, et al. Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer’s cramp. Neurology. 1999;52:529–37.
85. Tinazzi M, Farina S, Bhatia K, et al. TENS for the treatment of writer’s cramp dystonia: a randomized placebo-controlled study. Neurology. 2005;64:1946–8.
80 V. Shanker and S. Bressman
86. Schneider SA, Mohire MD, Trender-Gerhard I, et al. Familial dopa-responsive cervical dystonia. Neurology. 2006;66:599–601.
87. Hunt AL, Giladi N, Bressman S, et al. L-dopa treatment in idiopathic torsion dystonia. Neurology. 1991;41 suppl 1:293.
88. Greene PE, 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.
89. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high dosage trihexyphenidyl. Neurology. 1986;36:160–4.
90. Burke RE, Fahn S. Double-blind evaluation of trihexyphenidyl in dystonia. Adv Neurol. 1983;37:189–92.
91. Jarman PR, Bandmann O, Marsden CD, Wood NW. GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs. J Neurol Neurosurg Psychiatry. 1997;63:304–8.
92. Jankovic J, Beach J. Long-term effects of tetrabenzaine in hyperkinetic movement disorders. Neurology. 1997;48:358–62.
93. Marsden CD, Marion MH, Quinn N. The treatment of severe dystonia in children and adults. J Neurol Neurosurg Psychiatry. 1984;47:1166–73.
94. Harel D, Giladi N. Amelioration of severe torsion dystonia with perphenazine. Isr J Med Sci. 1990;26:590–2.
95. Defazio G, Lamberti P, Lepore V, Livrea P, Ferrari E. Facial dystonia: clinical features, prog-nosis and pharmacology in 31 patients. Ital J Neurol Sci. 1989;10:553–60.
96. Karp BI, Goldstein SR, Chen R, Samii A, Bara-Jimenez W, Hallett M. An open trial of clozapine for dystonia. An open trial of clozapine for dystonia. Mov Disord. 1999;14:652–7.
97. Hanagasi HA, Bilgic B, Gurvit H, Emre M. Clozapine treatment in oromandibular dystonia. Clin Neuropharmacol. 2004;27:84–6.
98. Sieche A, Giedke H. Treatment of primary crainial dystonia (Meige’s syndrome) with clozap-ine. J Clin Psychiatry. 2000;61:949.
99. Bai YM, Yu SC, Chen JY, Lin CY, Chou P, Lin CC. Risperidone for pre-existing severe tar-dive dyskinesia: a 48-week prospective follow-up study. Int Clin Psychoparamacol. 2005;20:79–85.
100. Grassi E, Latorraca S, Piacentini S. Risperidone in idiopathic and symptomatic dystonia: preliminary experience. Neurol Sci. 2000;21:121–3.
101. Asmus F, Zimprich A, Tezenas Du Montcel S, et al. Myoclonus-dystonia syndrome:episilon-sarcoglycan mutations and phenotype. Ann Neurol. 2002;52:489–92.
102. Merikangas JR, Reynolds CF. Blepharospasm: successful treatment with clonazepam. Ann Neurol. 1979;5:401–2.
103. Greene P. Baclofen in the treatment of dystonia. Clin Neuropharmacol. 1992;15:276–88. 104. Greene PE, Fahn S. Baclofen in the treatment of idiopathic dystonia in children. Mov Disord.
1992;7:48–52. 105. Rosse RB, Allen A, Lux WE. Baclofen treatment in a patient with tardive dystonia. J Clin
Psychiatry. 1986;47:474–5. 106. Lees AJ, Shaw KM, Stern GM. Baclofen in Parkinson’s disease. J Neurol Neurosurg
Psychiatry. 1978;41:707–8. 107. Awaad Y, Shamato H, Chugani H. Hemidystonia improved by baclofen and PET scan fi nd-
ings in a patient with glutaric aciduria type I. J Child Neurol. 1996;11:167–9. 108. Ford B, Greene P, Louis E, Pertzinger G, et al. Use of intrathecal baclofen in the treatment of
112. Bhatia KP. The paroxysmal dyskinesias. J Neurol. 1999;246:149–55. 113. Greene PE, Shale H, Fahn S. Analysis of open-label trials of torsion dystonia using high dos-
ages of antihcholinergics and other drugs. Mov Disorders. 1988;3:46–60. 114. Nygaard TG, Marsden CD, Fahn S. Dopa-responsive dystonia: long-term treatment response
and prognosis. Neurology. 1991;41:174–81. 115. Tarsy D, Ryan RK, Ro SI. An open-label trial of levetiracetam for treatment of cervical dys-
tonia. Mov Disord. 2006;21:734–5. 116. Sullivan KL, Hauser RA, Louis ED, Chari G, Zesiewicz TA. Levetiracetam for the treatment
of generalized dystonia. Parkinsonims Relat Disord. 2005;11:469–71. 117. Papapetropoulos S, Singer C. Improvement of cervico-trunco-brachial segmental dystonia
with topiramate. J Neurol. 2006;253:535–6. 118. Sandyk R. Benefi cial effect of sodium valproate and baclofen in spasmodic torticollis. A case
report. S Afr Med J. 1984;65:62–3. 119. Sandyk R. Blepharospasm-successful treatment with baclofen and sodium valproate. A case
report. S Afr Med J. 1983;64:955–6. 120. Pueschel SM, Friedman JH, Shetty T. myoclonic-dystonia. Childs Nerv Syst. 1992;8:61–6. 121. Priori A, Bertolasi L, Pesenti A, Cappellari A, Barbieri S. Gamma-hydroxybutyric acid for
alcohol-sensitive myoclonus with dystonia. Neurology. 2000;54:1706. 122. Frucht SJ, Bordelon Y, Houghton WH, Reardan D. A pilot tolerability and effi cacy trial of
sodium oxybate in ethanol-responsive movement disorders. Mov Disord. 2005;20:1330–7. 123. Frucht S, Fahn S. Movement disorder emergencies-adult and children. In: American Academy
of Neurology 56th Annual Meeting; April 24–May 1, 2004, 2DS-003-1–33. 124. Sacks OW, Kohl M. L-dopa and oculogyric crises. Lancet. 1970;2:215–6. 125. Sachdev P. Tardive and chronically recurrent oculogyric crises. Mov Disord. 1993;8:93–7. 126. Fitzgerald PM, Jankovic J. Tardive oculogyric crises. Neurology. 1989;39:1434–7. 127. Horiguchi J, Inami Y. Effect of clonazepam on neuroleptics-induced oculogyric crisis. Acta
practical management problem. Clin Neuropharm. 1994;17:344–7. 129. Dalvi A, Fahn S, Ford B. Intrathecal baclofen in the treatment of dystonic storm. Mov Diosrd.
1998;13:611–2. 130. Tsui JK, Eisen A, Mak E, Carruthers J, Scott A, Calne DB. A pilot study on the use of botu-
linum toxin in spasmodic torticollis. Can J Neurol Sci. 1985;12:314–6. 131. Tsui JK, Eisen A, Stoessl AJ, Calne S, Calne DB. Double-blind study of botulinum toxin in
spasmodic torticollis. Lancet. 1986;2:245–7. 132. Comella CL, Jankovic J, Shannon KM, Tsui J, et al. Comparison of botulinum toxin sero-
types A and B for the treatment of cervical dystonia. Neurology. 2005;65:1423–9. 133. Scott AB, Kennedy RA, Stubbs HA. Botulinum A toxin injection as a treatment for blephar-
ospasm. Arch Ophthalmol. 1985;103:347–50. 134. Jost WH, Kohl A. Botulinum toxin: evidence-based medicine criteria in blepharospasm and
hemifacial spasm. J Neurol. 2001;248(Suppl):21–4. 135. Watts C, Nye C, Whurr R. Botulinum toxin for treating spasmodic dysphonia (laryngeal
dystonia): a systematic Cochrane review. Clin Rehabil. 2006;20:112–22. 136. Bielamowicz S, Stager SV, Badillo A, Godlewski A. Unilateral versus bilateral injections of
botulinum toxin in patients with adductor spasmodic dysphonia. J Voice. 2002;16:117–23. 137. Koriwchak MJ, Netterville JL, Snowden T, Courey M, Ossoff RH. Alternating unilateral
botulinum toxin type A (BOTOX) injections for spasmodic dysphonia. Laryngoscope. 1996;106:1476–81.
138. Maloney AP, Morrison MD. A comparison of the effi cacy of unilateral versus bilateral botu-linum toxin injections in the treatment of adductor spasmodic dysphonia. J Otolaryngol. 1994;23:160–4.
139. Karp BI, Cole RA, Cohen LG, Grill S, Lou JS, Hallett M. Long-term botulinum toxin treat-ment of focal hand dystonia. Neurology. 1994;44:70–6.
82 V. Shanker and S. Bressman
140. Schuele S, Jabusch HC, Lederman RJ, Altenmuller F. Botulinum toxin injections in the treat-ment of musician’s dystonia. Neurology. 2005;64:341–3.
141. Bhidayasiri R, Cardoso F, Truong DD. Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations. Eur J Neurol. 2006;13 Suppl 1:21–9.
142. Jankovic J, Vuong KD, Ahsan J. Comparison of effi cacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology. 2003;60:1186–8.
143. Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology. 2005;65:1423–9.
144. Molloy FM, Shill HA, Kaelin-Lang A, Karp BI. Accuracy of muscle localization without EMG: implications for treatment of limb dystonia. Neurology. 2003;58:805–7.
145. Dressler D, Hallett M. Immunological aspects of Botox, Dysport, and Myobloc/NeuroBloc. Eur J Neurol. 2006;13:11–5.
146. Lee LH, Chang WN, Chang CS. The fi nding and evaluation of EMG-guided BOTOX injec-tion in cervical dystonia. Acta Neurol Taiwan. 2004;13:71–6.
147. Comella CL, Buchman AS, Tanner CM, Brown-Toms NC, Goetz CG. Botulinum toxin injec-tion for spasmodic torticollis: increased magnitude of benefi t with electromyographic assis-tance. Neurology. 1992;42:878–82.
148. Cohen-Gadol AA, Ahlskog JE, Matsumoto JY, Swenson MA, et al. Selective peripheral den-ervation for the treatment of intractable spasmodic torticollis experience with 168 patients at the Mayo Clinic. J Neurosurg. 2003;98:1247–54.
149. Mauriello Jr JA, Keswani R, Franklin M. Long-term enhancement of botulinum toxin injec-tions by upper-lid surgery in 14 patients with facial dyskinesias. Arch Otolaryngol Head Neck Surg. 1999;125:627–31.
150. Krauss JK, Koller R, Burgunder JM. Partial myotomy/myectomy of the trapezius muscle with an asleep-awake-asleep anesthetic technique for treatment of cervical dystonia. Technical note. J Neurosurg. 1999;91:889–91.
151. Cooper IS. 20-Year follow-up study of the neurosurgical treatment of dystonia musculorum deformans. Adv Neurol. 1976;14:423–52.
152. Andrew J, Fowler CJ, Harrison MJ. Stereotaxic thalamotomy in 55 cases of dystonia. Brain. 1983;106:981–1000.
153. Yosher D, Hamilton WJ, Ondo W, Jankovic J, Grossman RJ. Comparison of thalamotomy and pallidotomy for the treatment of dystonia. Neurosurgery. 2001;48:818–26.
154. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Eng J Med. 2006;355:1978–90.
155. Vidailhet M, Vercueil L, Houeto J, et al. Bilateral deep-brain stimulation of the globus palli-dus in primary generalized dystonia. N Engl J Med. 2005;352:459–67.
156. Vildilhet M, Vercueil L, Houeto JL, et al. Bilateral, pallidal, deep-brain stimulation in primary generalized dystonia: a prospective 3 year follow-up study. Lancet Neurol. 2007;6:223–9.
157. Isaias IU, Alterman RL, Tagliati M. Deep brain stimulation for primary generalized dystonia: long-term outcomes. Arch Neurol. 2009;66:465–70.
158. 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.
159. Alterman R, Miravite J, Weisz D, et al. Sixty hertz pallidal deep brain stimulation for primary torsion dystonia. Neurology. 2007;69:681–8.
160. Groen JL, Ritz K, Contarino MF, et al. DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Mov Disord. 2010;25:2420–7.
161. Krauss JK. Deep brain stimulation for cervical dystonia. J Neurol Neurosurg Psychiatry. 2003;74:1598.
162. Jeong SG, Lee MK, Kang JY, et al. Pallidal deep brain stimulation in primary cervical dysto-nia with phasic type: clinical outcome and postoperative course. J Korean Neurosurg Soc. 2009;46:346–50.
163. Cacciola F, Farah JO, Eldridge PR, et al. Bilateral deep brain stimulation for cervical dystonia: long-term outcome in a series of 10 patients. Neurosurgery. 2010;67:957–63.
833 Dystonia
164. 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;15:506–12.
165. Kurtis MM, San Luciano M, Qiping Y, et al. Clinical and neurophysiological improvement of SGCE myoclonus-dystonia with GPi deep brain stimulation. Clin Neurol Neurosurg. 2010;12:149–52.
166. Trottenberg T, Meissner W, Kabus C, et al. Neurostimulation of the ventral intermediate thalamic nucleus in inherited myoclonus-dystonia syndrome. Mov Disord. 2001;16:769–71.
167. Gruber D, Kühn AA, Schoenecker T, et al. Pallidal and thalamic deep brain stimulation in myoclonus-dystonia. Mov Disord. 2010;25:177–1743.
168. Capelle HH, Blahak C, Scharder C, et al. Chronic deep brain stimulation in patients with tardive dystonia without a history of major psychosis. Mov Disord. 2010;25:1477–81.
169. Chang EF, Schrock LE, Starr PA, Ostrem JL. Long-term benefi t sustained after bilateral pal-lidal deep brain stimulation in patients with refractory tardive dystonia. Stereotact Funct Neurosurg. 2010;88:304–10.
170. Gruber D, Trottenberg T, Kivi A, et al. Long-term effects of pallidal deep brain stimulation in tardive dystonia. Neurology. 2009;73:53–8.
171. Krause M, Fogel W, Tronnier V, et al. Long-term benefi t to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration. Mov Disord. 2006;21:2255–7.
172. Castelnau P, Cif L, Vaente EM, Vayssiere N, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol. 2005;57:738–41.
173. Vidaihet M, Yelnik J, Lagrange C, et al. Bilateral pallidal deep brain stimulation for the treat-ment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study. Lancet Neurol. 2009;8:709–17.
