Therapeutic Challenges in Dystonia

Therapeutic Challengesin Dystonia

Ninith Kartha, MD

KEYWORDS

� Dystonia � Therapy � Botulinum toxin � Deep brain stimulation

Dystonia is a disorder of involuntary sustained muscle contractions, often involvinga rotatory or torsional component, occurring in a consistent and predictable mannerand resulting in abnormal postures.1 Dystonia can resemble myoclonus when thecontractions are short and rapid, or tremor when the contractions are repetitive andrhythmic.2 It can affect an individual body region or multiple body regions and canspread from one to adjacent regions or generalize during the course of the disorder.At onset, it may occur only with action of the involved body part, but with progression,it may occur with movement of adjacent body parts (overflow) and then at rest.Dystonia can result in fixed postures and finally permanent contractures if untreated.

The pathophysiologic interactions that produce dystonia are complex and not wellunderstood. A unique clinical feature of dystonia, the geste antagoniste or sensorytrick, in which light touch to an affected region reduces the severity of symptoms,helps point toward one likely mechanism, that of impaired sensorimotor integrationand processing of sensory input.3 Studies also implicate loss of inhibition at multiplelevels of the nervous system, leading to the co-contraction of agonist and antagonistmuscles.4 The use of transcranial magnetic stimulation has implicated abnormalcortical motor excitability as a factor.5 Abnormal basal ganglia output is suggestedby the success of therapies, such as pallidotomy and deep brain stimulation of theglobus pallidus, in treating some forms of dystonia and the response to dopaminergictherapy seen in the dopa responsive dystonias.6

CLASSIFICATION

Simply diagnosing dystonia is usually insufficient to determine therapy because this isa symptom of several disorders that can vary in associated features, clinical course,and prognosis. It is common to classify dystonia by age of onset, distribution ofinvolvement, or etiology.1 The commonly accepted dividing age between early-onsetand late-onset dystonia is 26 years. Individuals with early-onset dystonia are morelikely to carry a mutation in the DYT1 gene locus, which causes primary torsion dys-tonia, and are more likely to have lower-limb onset with subsequent generalization.7

Department of Neurology, Loyola University Medical Center, 2160 South First Avenue, Room2700, Maywood, IL 60153, USAE-mail address: [email protected]

Neurol Clin 28 (2010) 927–940doi:10.1016/j.ncl.2010.03.020 neurologic.theclinics.com0733-8619/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

mailto:[email protected]

http://neurologic.theclinics.com

Kartha928

Cases of late-onset dystonia are more likely to be sporadic, involve the cranial regionsor upper limbs, and remain focal or segmental.8

In classifying by distribution of body involvement, dystonia can be focal in which onebody region is involved, segmental in which two or more contiguous regions areaffected, multifocal involving two or more noncontiguous regions, or generalized inwhich one leg, the trunk, and one other region are affected or both legs and one otherregion.9 Hemidystonia, in which an ipsilateral arm and leg are affected, is typicallyassociated with structural lesions or neurodegenerative disorders.10,11

Classification by etiology divides most causes of dystonia into primary andsecondary disorders. Dystonia can also be seen as a feature of another neurologicdisorder (ie, tics or the paroxysmal dyskinesias, and pseudo-dystonia). In the primarydisorders, dystonia, which may be associated with tremor, is the only sign. The clinicalhistory, laboratory, and imaging studies should not suggest any secondary causes. Ofthe 17 genetic forms of dystonia that have been identified to date, DYT1, DYT2, DYT4,DYT6, DYT7, DYT13, and DYT17 are associated with primary dystonias. The mostprevalent of these is the mutation at the DYT1 gene locus causing Oppenheim dysto-nia, an autosomal dominant disorder, which accounts for 90% of early-onset dystoniain the Ashkenazi Jewish population and 40% to 65% of early-onset cases in the non-Jewish population.7,12 Although typically manifesting as an early-onset disorder withgeneralized distribution, cases have been identified with onset as late as 64 years ofage and there is wide phenotypic variability with approximately 35% remaining focalor segmental. Gene penetrance is only about 30%, thus many carriers remainasymptomatic.7,13

Although some of the non-DYT1 primary torsion dystonias have been associatedwith predominantly focal or segmental manifestations, the majority of focal andsegmental primary dystonias in adulthood are sporadic in onset or at least have noidentified genetic basis. The most common late-onset focal dystonia is cervical dys-tonia, which affects the shoulder and neck muscles.14–17 Abnormal movements canlead to head rotation (torticollis); lateral flexion (laterocollis); forward flexion (anterocol-lis); extension (retrocollis); or any combination of these. Pain is a common feature.Other forms of late-onset focal dystonia include blepharospasm, which involves theperiocular muscles; oromandibular dystonia, which affects the lower facial, mastica-tory, lingual or pharyngeal muscles; laryngeal dystonia (or spasmodic dysphonia),which affects the vocal cords; and limb dystonia. When upper and lower facial involve-ment is present, the term Meige syndrome is often applied.18 A specialized form offocal dystonia is the task-specific or occupational dystonia. The most common ofthese is writer’s cramp, which affects the dominant hand and initially manifests onlywith the act of writing, though later in the course additional activities of the handcan become affected and persistent abnormal postures can develop.19 Althoughmost commonly associated with a limb, task-specific dystonia can also affect otherbody regions, for example the oral musculature in some musicians (embouchuredystonia).20

The secondary dystonias include dystonia plus syndromes, heredodegenerativedisorders, dystonia associated with parkinsonism and acquired causes. Dystoniaplus syndromes are non-degenerative disorders in which accompanying symptoms,such as ataxia, myoclonus, or parkinsonism, may be present. Of the identified geneticforms of dystonia, the mutations associated with DYT5, DYT11, DYT12, DYT14, DYT15,and DYT 16 lead to dystonia-plus disorders. The most well-known example is dopa-responsive dystonia (DYT5, DYT 14). This disorder is typically a childhood-onsetdisorder associated with parkinsonism, diurnal fluctuation, and a remarkableresponse to low doses of levodopa.21,22 DYT12 is associated with rapid-onset

Therapeutic Challenges in Dystonia 929

dystonia-parkinsonism, however, individuals with this disorder have little to noresponse to levodopa.23 In DYT11 and DYT15 (which are associated with myoc-lonus-dystonia), myoclonus, which is typically the most prominent symptom, mayrespond to alcohol.24–26

In addition to the dopa-responsive dystonias, dystonia associated with parkin-sonism can be seen in degenerative disorders, such as Parkinson disease andthe Parkinson-plus syndromes. In some individuals, the dystonia may be respon-sive to levodopa or may be a side effect of levodopa. Medication side effect isa common cause of acquired dystonia and symptoms may improve with with-drawal of the offending agent, though in some cases, dystonia may persist orworsen after withdrawal, as can occur with tardive dystonias associated withseveral neuroleptic and antiemetic agents. A listing of the various heredodegener-ative disorders associated with dystonia and acquired causes of dystonia isbeyond the scope of this article other than to say that where indicated, a thoroughevaluation, including laboratory testing and brain imaging, should be performed forunderlying etiologies for which treatment may be available (ie, Wilson’s disease).This type of evaluation and levodopa challenge is recommended for all early-onsetcases of dystonia and any atypical presentations of adult-onset dystonia, but maynot be required in all cases of adult-onset focal dystonia that involve the cranial orupper-limb musculature.

THERAPY

Once the diagnosis of primary dystonia is made, treatment is geared toward symp-tomatic relief. In some individuals who have mild disease or who are averse to medicaltherapy, counseling and monitoring of symptoms may be sufficient. In approximately9% to 12% of patients with adult-onset focal dystonia, particularly cervical dystonia,symptoms may spontaneously remit, though this tends to be temporary.8,27 The deci-sion to treat is often influenced by age, distribution of involvement, level of disability,pain related to muscle contractions, and psychosocial impact. The selection of agentmay also be guided by tolerance for particular therapeutic regimens and side effects.For example, elderly patients may not be able to tolerate the potential side effects ofanticholinergic medications, whereas some individuals may have difficulty keeping 3-to 4-month appointments for repeat botulinum toxin injections.

Physical and occupational therapy may have a role in the primary treatment of dys-tonia or in supplementing pharmacologic therapy. The use of specialized braces orhandwriting devices may mimic a sensory trick and help some individuals with cervicaldystonia or writer’s cramp, whereas painful spasms may respond to stretching andrange of motion exercises.28,29 Sensory training and limb-immobilization techniqueshave been used but have unclear benefit. Many patients with mild writer’s crampreport a response to simple maneuvers, such as using a thicker pen or other ergo-nomic changes. Physical therapy may also play a role in preventing contractures.However, there are no large-scale or blinded studies ascertaining the benefits of thesetherapies.

Pharmacologic Agents

There are also no evidence-based oral therapies for dystonia though small orunblinded trials have shown efficacy for several agents, including anticholinergicmedications, dopamine blocking and depleting agents, baclofen, and benzodiaze-pines. Oral medications can be used in isolation, in combination, or as adjunctivetreatment in individuals treated with botulinum toxin or surgical therapies (Table 1).

Table 1Common therapeutic options for dystonia

Therapeutic Agent Indication

Levodopa Dopa-responsive dystonia (trial in all early-onsetdystonia)

Trihexyphenidyl Generalized and segmentalAll focal/task-specific

Tetrabenazine Generalized and segmentalCervical

Baclofen (oral) Generalized and segmentalOromandibularCervical

Clonazepam Generalized and segmentalBlepharospasmCervical

Intrathecal baclofen Dystonia associated with spasticity

Botulinum toxin All focal dystonias

Peripheral denervation/myectomy BlepharospasmCervical

Deep brain stimulation ofglobus pallidus interna

Generalized and segmentalCervical

Kartha930

Botulinum toxin is now the treatment of choice for most cranial and cervical dystoniaand may be considered in writer’s cramp.30

LevodopaIndividuals with dopa-responsive dystonia typically respond to low doses of levodopa.Treatment can be started with carbidopa-levodopa 10/100 to 25/100 or even partialdoses, though in some cases up to 1000 mg/day of levodopa may be required.28

There may be significant improvement or sometimes resolution of symptoms andthe benefit is typically long-lasting without the development of levodopa-inducedmotor fluctuations or dyskinesias, therefore trials of other dopaminergic drugs shouldnot be required.31 Levodopa is rarely useful in other types of dystonia but should beattempted in all cases of early-onset dystonia.

Anticholinergic agentsEvidence-based data supporting the use of anticholinergic therapy in dystonia isgenerally lacking. Trihexyphenidyl has been shown in two class III studies to be supe-rior to placebo in the long-term management of childhood-onset generalized andsegmental dystonia.30,32,33 Open label trials have shown benefit of anticholinergicagents in adult onset focal dystonia,34,35 and a retrospective analysis of subjectswith early-onset and late-onset dystonia treated with slowly titrated doses of anticho-linergic therapy showed benefit in 50% of individuals with adult-onset cervical dysto-nia.36 However, a small crossover study showed no difference betweenanticholinergic therapy and placebo in cranial dystonia.37 Nevertheless, anticholiner-gics are often used as a first-line agent in adult-onset focal dystonia, particularlycervical and task-specific dystonias, and in levodopa-unresponsive early-onset dys-tonia. A major limiting factor in the efficacy of these medications may be the side-effect profile, which includes cognitive slowing and memory loss, sedation, blurryvision, dry mouth, and urinary retention. It is particularly poorly tolerated in individualsover 70 years of age, although it is generally well tolerated in young patients. It is


recommended to start at low doses, 1 mg (or half-tablet) in the case of trihexyphenidyl,and slowly titrate. Some patients may require up to 60 to 100 mg/day.28 Other anticho-linergic medications that have been used for dystonia include diphenhydramine andbenztropine, though the evidence to support this is even less well documented.

Antidopaminergic agentsThe most effective antidopaminergic drugs are those that deplete dopamine, such astetrabenazine, because these drugs typically do not lead to the development of tardivedyskinesias. Tetrabenazine was recently approved by the US Food and Drug Admin-istration (FDA) for use in the treatment of chorea associated with Huntington disease.However, it has been shown in a small placebo-controlled trial to benefit patients withprimary dystonia.38 A long-term retrospective follow-up study showed markedimprovement of symptoms in 63% of subjects with idiopathic dystonia at initialfollow-up and maintained in 45% of subjects at 29 to 31 months.39 There was nosignificant difference between the subset populations of subjects with cranial,cervical, or generalized dystonia though the sample size was small. Subjects with tar-dive dystonia actually showed the most robust response, with 89% showing markedimprovement at initial visit and 85% maintaining this improvement at last follow-up.The most common side effects were drowsiness, parkinsonism, depression,insomnia, nervousness/anxiety, and akathisia. Tetrabenazine has also been shownto induce a rare, acute dystonic reaction.40 Although it has now been approved foruse in the United States with the trade name Xenazine, it is not readily available inpharmacies and must be ordered through the manufacturer. Dosages typically startat 25 mg/day and can be titrated up to 200 mg/day as tolerated. Another dopaminedepletion reserpine has also been used, although evidence is lacking.

Dopamine blocking agents are generally discouraged for use in dystonia because ofthe frequent development of tardive dyskinesias. Class IV studies have shown symp-tomatic benefit with haloperidol, pimozide, and risperidone, however, these are rarelyused.41,42 Clozapine was shown to be effective in a small open-label trial but also israrely used because of side effects, including agranulocytosis.43

Other agentsBaclofen, a g-aminobutyric acid receptor agonist, may be effective in some individualswith oromandibular dystonia and is typically used as a second-line oral agent if trihex-yphenidyl has failed.36 Doses can be titrated up to 80 mg/day. Less information ispresent to support the use of other oral muscle relaxants, such as tizanidine or cyclo-benzaprine. Intrathecal baclofen has been effective in individual cases.44,45 Moststudies involve small populations and generally have been geared toward childrenwith generalized dystonia or secondary dystonia caused by cerebral palsy or othercauses. It seems to be more effective in treating dystonia associated with pain andspasticity and could be considered in patients who have failed anticholinergic thera-pies or botulinum toxin.46 It may also be effective in some individuals with dystonicstorm.47,48 Doses required to treat dystonia are generally higher than those used totreat spasticity alone, and the side effects include constipation or loss of bowel andbladder control, loss of axial motor control, drowsiness, infection, and catheterbreakage or disconnection.49,50

Clonazepam may be effective as a primary treatment, especially in cases of bleph-arospasm or myoclonus dystonia.36,51 An analysis of open-label trials evaluating theuse of clonazepam showed improvement in 23% of subjects with blepharospasmand 21% of those with cervical dystonia.52 It may be most effective as an adjunctivetherapy to help reduce pain and anxiety-related exacerbation in focal dystonias

Kartha932

treated with botulinum toxin. Dose titration is commonly limited by sedation. Otherbenzodiazepines used less commonly include diazepam and lorazepam.

Isolated case studies and small clinical trials have looked at the usefulness of severalother agents, including anticonvulsants. A double-blind trial of valproic acid for Meigesyndrome suggested possible benefit but the sample size was small.53 Carbamazepineand phenytoin may be effective for treatment of paroxysmal kinesigenic dyskinesia.54

Levetiracetam showed some symptomatic improvement of Meige syndrome and gener-alized dystonia in isolated case studies,55,56 but subsequent small open-label studies insubjects with cervical, segmental, and generalized dystonia showed no benefit.57,58

Other agents that have shown benefit in small trials or case studies but for which thereis no evidence-based support include morphine sulfate, lithium, and mexiletine.

Botulinum toxinSince the approval by the FDA of botulinum toxin for the treatment of blepharospasmin 1989 and cervical dystonia in 2000, it has quickly become the treatment of choicefor most focal dystonias. This popularity is in part because of the widely perceivedconcept that the effect of toxin, which acts by inhibiting the release of acetylcholineinto the neuromuscular junction, does not spread to distant sites. Clinical experiencehas shown relative lack of systemic side effects in comparison to oral agents.However, the expansion of therapeutic applications for botulinum toxin in recentyears has led to increased adverse event reporting, with the FDA announcing reportsof events occurring after administration of toxin that seem to be related to actions atremote sites, including respiratory distress, swallowing problems, and generalizedweakness.59 Consequently, this has led to a reinvestigation of the mechanism ofaction of botulinum toxin and its possible effect on remote sites. Studies on animalmodels have shown that toxin effect may act directly at local and distant peripheralnerve terminals and may have indirect effects on the central nervous system.60 Theclinical implications of these studies is not clear, and it is not known if the adverseevents reported are attributable to treatment; however, in the meantime while inves-tigations continue, the FDA has required that botulinum toxin products be labeledwith a black box warning of the risk for possible botulism-like symptoms associatedwith systemic spread and that physicians distribute a medication guide to patientsoutlining these possible side effects.61 Current FDA-approved uses of botulinumtoxin include blepharospasm for botulinum toxin type A (BoNTA Botox) and cervicaldystonia for Botox, botulinum toxin type B (BoNTB, Myobloc), and since 2009,another botulinum toxin type A (BontA, Dysport). Treatment of other forms of dysto-nia is off-label.

In cervical dystonia, several open-label and controlled trials have reportedimprovement in involuntary movements and pain in up to 90% of subjectstreated.62,63 Potential side effects include dysphagia, neck weakness, voicechanges, dry mouth, and pain at injection sites. A placebo-controlled, double-blindstudy of Botox involving 55 subjects with cervical dystonia, followed for 12 weeksand using doses from 140 to 165 units, showed significant improvement in functionalcapacity, head turning, and pain.64 This study was followed by several other class Istudies that showed similar benefit in BoNTA and BoNT B.65 A double-blind,placebo-controlled study looking at various doses of Myobloc (2500, 5000, and10,000 units) in 109 subjects found all doses more effective than placebo with upto 77% improvement in the largest dose group.66 Another dosing study involvingDysport compared three doses (250, 500, and 1000 units) to placebo in 75 subjectsand showed 25% to 30% benefit in the two larger dose groups, however, the largestdose group was associated with more side effects of neck weakness and laryngeal


involvement.67 A direct comparison of Botox and Myobloc in 139 subjects ina randomized, double-blind, parallel-group study showed similar benefit in theToronto western spasmodic torticollis rating scale (TWSTRS) at 4 weeks but slightlylonger duration of effect in subjects treated with BoNTA compared with BoNT B(14 vs 12.1 weeks).68 Dysphagia and dry mouth were less common in BoNTA andseverity of constipation greater with BoNTB.

In the case of blepharospasm, few double-blind, placebo-controlled studies havebeen performed to study the effects of botulinum toxin, and the authors of oneCochrane review concluded there were no high-quality, randomized, controlledstudies to support its use.69 However, Botox has been shown to be effective in smallplacebo-controlled trials and open-label studies. A double-blind study of 12 subjectsshowed no response to placebo and 72% response in a dystonia rating score toBotox.62 Results of additional studies have influenced recommendations regardingpreferred sites of injection and areas to avoid. Potential side effects include dry eye,ptosis, and diplopia. A retrospective comparison study of 25 subjects using pretarsaland preseptal techniques showed that pretarsal sites of injection provided betterbenefit (97% vs 90%) and duration of benefit (11.4 vs 8.2 weeks) with less subjectshaving side effect of ptosis (13% vs 16%).70 Findings of other studies confirm thesuperiority of pretarsal sites of injection.71 One frequent cause of lack of efficacy isthe misdiagnosis of blepharospasm in patients who have apraxia of eyelid openingor the concurrent presence of both entities.71

There are two class I randomized, double-blind, placebo-controlled studiesshowing the effectiveness of BoNTA in writer’s cramp.72 In one study, 40 subjectswere enrolled with 70% of the Botox-treated group reporting benefit warrantingcontinuation of treatment past the 1-year duration of the study. However, a largeplacebo effect was seen with 31.6% of the placebo-treated arm also reportingimprovement.73 The only reported side effects were weakness involving the injectedmuscles and pain at injections sites. There is one class I study showing benefit ofBoNTA in spasmodic dysphonia.74 This study only involved subjects with adductor-type spasmodic dysphonia and used visual-perceptual, clinician assessed auditory-perceptual, and self-assessed perceptual measures to show effectiveness.75 Thereare no class I studies looking at botulinum toxin in oromandibular dystonia. However,several case reports and small group studies have shown benefit in oromandibulardystonia and Meige syndrome. A case report of four subjects with oromandibular dys-tonia involving the lateral pterygoid muscles showed reduction in spontaneous elec-tromyographic activity after botulinum toxin injection with reduction of severity andrelated dysfunction at 3 to 9 months.76

Because of the lack of extensive evidence in oromandibular dystonia, botulinumtoxin is typically second-line therapy after oral medication; however, it is often first-line therapy in the other focal dystonias. Patients report long-lasting improvement inquality of life and despite the concerns noted at the beginning of this section, botu-linum toxin is safe and effective.77,78 The development of neutralizing antibody-medi-ated resistance to Botox has declined with the introduction of a formulation thatcontains much lower levels of neurotoxin protein.79 Onset of improvement typicallyoccurs after 1 to 14 days of injection with improvement lasting 3 to 4 months. Dosagesrequired vary depending on the muscles being injected and are not interchangeablebetween serotypes and brands.

Surgical Therapy

Surgical therapies are generally reserved for the most severe and refractory cases ofdystonia and include peripheral denervation and myectomy in cervical dystonia and

Kartha934

deep brain stimulation of the globus pallidus internus (GPi) for generalized, cervical.and other focal and segmental dystonias.

Peripheral denervation and myectomyTreatment of cervical dystonia with peripheral surgeries has significantly decreasedsince the advent of botulinum toxin. It is reserved now primarily for non-responders.The procedures that have been used include posterior ramisectomy with or withoutmyectomy, anterior cervical rhizotomy, and microvascular decompression of thespinal accessory nerve. There are no controlled studies establishing efficacy orcomparing techniques. In recent years, posterior ramisectomy has become themost commonly performed procedure because of the case studies performed by Ber-trand and colleagues80 that reported good success rates by selectively denervatingdystonically active muscles.81 A retrospective case study found moderate to excellentimprovement in head position in 77% of 162 subjects at 3 months after selectivedenervation based on a clinician-based rating scale.82 A prospective case studyshowed that 68% of 31 subjects followed 12 months after selective denervation hadfunctionally relevant improvement of TWSTRS scores.83 However, only a third wereable to reduce oral medication doses and about half chose to continue botulinum toxininjections. Most common side effects were dysesthesias in the denervated posteriorcervical segments and mild dysphagia. Complications also included incomplete rein-nervation, particularly of the sternocleidomastoid muscle, and three subjects devel-oped dystonic activity in muscles that were previously unaffected. Primarynonresponders to botulinum toxin did not fare as well as secondary nonresponders,possibly reflecting more restricted head movements and fixed postures. Head tremoralso did not respond, possibly because of more widespread muscular activity. Thisfinding prompted the authors to suggest that head tremor and severe restriction ofhead movements were relative contraindications to surgery.83

Peripheral surgeries for other focal dystonias, such as upper eyelid orbicularis oculimyectomy for blepharospasm or recurrent laryngeal nerve sectioning for spasmodicdysphonia, have fallen out of favor because of its replacement by botulinum toxintherapy but may still be an option for severe refractory cases.

Deep brain stimulationAlthough thalamotomy and pallidotomy have been effective therapies, deep brainstimulation (DBS) of the GPi has become the surgical treatment of choice becauseof lower complication rates and ability to modify stimulation parameters. It is possiblethat GPi DBS improves dystonia by disrupting abnormal outflow activity though theexact mechanism of effect is unknown.84 In a prospective study of 22 subjects withprimary generalized dystonia, there was a mean decrease of 51% in the Burke-Fahn-Marsden Dystonia Scale (BFMS) score at month 12.85 Seven subjects withphasic, hyperkinetic movements preoperatively had greater than 75% improvementin BFMS score at 1 year. In some subjects, maximum benefit was not achieved until3 to 6 months. A 3-year follow-up study of the same subjects showed that benefitwas maintained with mean improvement in the movement score of 58%. Improvementin quality of life measured by the Short Form-36 (SF-36) questionnaire that wasobserved at 1 year was also maintained.86 Several studies have looked at factorsthat may predict outcome in patients with generalized dystonia treated with GPiDBS. These studies suggest that duration of disease has a negative influence onoutcome,87 whereas DYT1 positive gene status predicts better improvement.85,88,89

Subjects with phasic dystonia also seem to benefit more than those with toniccontractions.85


Another double-blind study included a 3-month, sham-controlled phase and lookedat subjects with primary generalized and segmental dystonia. Of 40 subjects, itincluded 16 with segmental dystonia affecting the neck and either cranial or upperlimb and trunk musculature.90 The BFMS score improved by a mean of 15.8 pointsin the neurostimulated group compared with 1.6 points in the sham-stimulated group,corresponding to a 37.5% reduction in disability in the treated group compared with8.3% in the sham group. In the open-label extension, the BFMS score in the originalsham-stimulated group improved by a mean of 12 points. There was no significantdifference in improvement between the generalized and segmental groups at 6months.87 A prospective study of 10 subjects with segmental dystonia, includingthe neck, showed a mean improvement in BFMS score of 60% at 1.5 year follow-up. There was a corresponding 51% improvement in quality-of-life score (SF-36).91

Another study showed that 11 subjects with segmental dystonia not only maintainedmean reduction in BFMS score at long-term follow up but actually had better outcomeat 3 years compared with 6 months (61% mean reduction vs 38%).92

Several studies have also shown benefit of GPi DBS in cervical dystonia.93–95 Aprospective, single-blind, multicenter study of bilateral GPi DBS in 10 subjects withmedication-resistant cervical dystonia showed significant improvements in TWSTRSseverity, disability, and pain scores at 12 months.96 Although primary generalized,segmental, and cervical dystonia are the three best indications for GPi DBS at thistime, small case studies have shown promising results for other indications, such astardive dystonia97 and dystonia- choreoathetosis cerebral palsy.98

SUMMARY

Dystonia is a heterogeneous disorder with varying clinical presentations and etiolo-gies. Although there are several options for management, the challenge of treatingpatients with dystonia is in selecting the appropriate therapy or combination of thera-pies to maximize relief and function. Proper diagnosis and classification is essential inmaking appropriate management decisions and providing appropriate counseling,and quality of life is increasingly being recognized as an important factor in selectingtherapies. Comorbidities, such as cognitive dysfunction and depression, should alsobe addressed and although general guidelines exist, treatment choices should betailored to individual patients.

REFERENCES

1. Fahn S. Concept and classification of dystonia. Adv Neurol 1988;50:1–8.2. Jedynak CP, Bennet AM, Agid Y. Tremor and idiopathic dystonia. Mov Disord

1991;6:230–6.3. Trost M. Dystonia update. Curr Opin Neurol 2003;16:495–500.4. Berardelli A, Rothwell JC, Hallett M, et al. The pathophysiology of primary dysto-

nia. Brain 1998;121:1195–212.5. Ikoma K, Samii A, Mercuri B, et al. Abnormal cortical motor excitability in dysto-

nia. Neurology 1996;46:1371–6.6. Lozano AM, Kumar R, Gross RE, et al. Globus pallidus internus pallidotomy for

generalized dystonia. Mov Disord 1997;12:865–70.7. Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines

for diagnostic testing. Neurology 2000;54:1746–52.8. Greene P, Kang UJ, Fahn S. Spread of symptoms in idiopathic torsion dystonia.

Mov Disord 1995;10:143–52.

Kartha936

9. Bressman SB. Dystonia genotypes, phenotypes and classification. Adv Neurol2004;94:101–7.

10. Pettigrew LC, Jankovic J. Hemidystonia: a report of 22 patients and a review ofthe literature. J Neurol Neurosurg Psychiatr 1985;48:650–7.

11. Marsden CD, Obeso JA, Zarranz JJ, et al. The anatomical basis of symptomatichemidystonia. Brain 1985;108(Pt 2):463–83.

12. Bressman SB, de Leon D, Brin MF, et al. Idiopathic torsion dystonia amongAshkenazi Jews: evidence for autosomal dominant inheritance. Ann Neurol1989;26:612–20.

13. Opal P, Tintner R, Jankovic J, et al. Intrafamilial phenotypic variability of the DYT1dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm. MovDisord 2002;17:339–45.

14. Nutt JG, Muenter MD, Aronson A, et al. Epidemiology of focal and generalizeddystonia in Rochester, MN. Mov Disord 1988;3:188–94.

15. Warner T, Camfield L, Marsden CD, et al. A prevalence study of primary dystoniain eight European countries. J Neurol 2000;247:787–92.

16. Nakashima K, Kusumi M, Inoue Y, et al. Prevalence of focal dystonias in thewestern area of Tottori prefecture in Japan. Mov Disord 1995;10:440–3.

17. Dung Le K, Niulsen B, Dietrichs E. Prevalence of primary focal and segmentaldystonia in Oslo. Neurology 2003;61:1294–6.

18. Tolosa E, Marti MJ. Blepharospasm-oromandibular dystonia syndrome (Meige’ssyndrome): clinical aspects. Adv Neurol 1988;49:73–84.

19. Sheehy MP, Marsden CD. Writer’s cramp: a focal dystonia. Brain 1982;105:462–80.

20. Frucht SJ, Fahn S, Greene PE, et al. The natural history of embouchure dystonia.Mov Disord 2001;16:899–906.

21. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia withmarked diurnal fluctuation caused by mutations in the GTP cyclohydrolase Igene. Nat Genet 1994;8:236–42.

22. Ludecke B, Dworniczak B, Bartholome K. A point mutation in the tyrosine hydrox-ylase gene associated with Segawa’s syndrome. Hum Genet 1995;95:123–5.

23. Brashear A, Dobyns WB, de Carvalho Aguiar P, et al. The phenotypic spectrum ofrapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A# gene.Brain 2007;130:828–35.

24. Nygaard TG, Raymond D, Chen C, et al. Localization of a gene for myoclonus-dystonia on chromosome 7q. Neurology 2001;56:1213–6.

25. Han F, Racacho L, Lang AE, et al. Refinement of the DYT15 locus in myoclonus-dystonia. Mov Disord 2007;22:888–92.

26. Saunders-Pullman R, Shriberg J, Heiman G, et al. Myoclonus dystonia: possibleassociation with obsessive-compulsive disorder and alcohol dependence.Neurology 2002;58:242–5.

27. Friedman A, Fahn S. Spontaneous remissions in spasmodic torticollis. Neurology1986;36:398–400.

28. Jankovic J. Treatment of dystonia. Lancet Neurol 2006;5:864–72.29. Tassorelli C, Mancini F, Balloni L, et al. Botulinum toxin and neuromotor rehabili-

tation: an integrated approach to idiopathic cervical dystonia. Mov Disord2006;21:2240–3.

30. Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diag-nosis and treatment of primary (idiopathic) dystonia and dystonia plussyndromes: report of an EFNS/MDS-ES Task Force. Eur J Neurol 2006;13:433–44.


31. Nygaard TG, Marsden CD, Fahn S. Dopa-responsive dystonia: long-term treat-ment response and prognosis. Neurology 1991;41:174–81.

32. Burke RE, Fahn S. Double-blind evaluation of trihexyphenidyl in dystonia. AdvNeurol 1983;37:189–92.

33. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind prospective trialof high-dosage trihexyphenidyl in dystonia. Neurology 1986;36:160–4.

34. Lang AE. High dose anticholinergic therapy in adult dystonia. Can J Neurol Sci1986;13:42–6.

35. Fahn S. High dosage anticholinergic therapy in dystonia. Neurology 1983;33:1255–61.

36. Greene P, Shale H, Fahn S. Experience with high dosages of anticholinergic andother drugs in the treatment of torsion dystonia. Adv Neurol 1988;50:547–56.

37. Nutt JG, Hammerstad JP, deGarmo P, et al. Cranial dystonia: double-blind cross-over study of anticholinergics. Neurology 1984;34:215–7.

38. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine:a double-blind crossover study. Ann Neurol 1982;11:41–7.

39. Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic move-ment disorders. Neurology 1997;48:358–62.

40. Burke RE, Reches A, Traub MM, et al. Tetrabenazine induces acute dystonicreactions. Ann Neurol 1985;17:200–2.

41. Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and othercure options. Eur J Neurol 2004;11:361–70.

42. Lang AE. Dopamine agonists and antagonists in the treatment of idiopathic dys-tonia. Adv Neurol 1988;50:561–70.

43. Karp BI, Goldstein SR, Chen R, et al. An open trial of clozapine for dystonia. MovDisord 1999;14:652–7.

44. Narayan RK, Loubser PG, Jankovic J, et al. Intrathecal baclofen for intractableaxial dystonia. Neurology 1991;41:1141–2.

45. Walker RH, Danisi FO, Swope DM, et al. Intrathecal baclofen for dystonia: bene-fits and complications during six years of experience. Mov Disord 2000;15:1242–7.

46. Ford B, Greene PE, Louis ED, et al. Intrathecal baclofen in the treatment ofpatients with dystonia. Arch Neurol 1996;53:1241–6.

47. Dalvi A, Fahn S, Ford B. Intrathecal baclofen in the treatment of dystonic storm.Mov Disord 1998;13:611–2.

48. Mariotti P, Fasano A, Contarino F, et al. Management of status dystonicus: ourexperience and review of the literature. Mov Disord 2007;22:963–8.

49. Woon K, Tsegaye M, Vloeberghs MH. The role of intrathecal baclofen in themanagement of primary and secondary dystonia in children. Br J Neurosurg2007;21:355–8.

50. Albright AL, Barry MJ, Shafron DH, et al. Intrathecal baclofen for generalized dys-tonia. Dev Med Child Neurol 2001;43:652–7.

51. Asmus F, Zimprich A, Tezenas Du Montel S, et al. Myoclonus-dystoniasyndrome: epsilon-sarcoglycan mutations and phenotype. Ann Neurol 2002;52:489–92.

52. Greene P, Shale H, Fahn S. Analysis of open-label trials in torsion dystonia usinghigh dosage of anticholinergics and other drugs. Mov Disord 1988;3:46–60.

53. Snoeck JW, van Weerden TW, Teelken AW, et al. Meige syndrome: double-blindcrossover study of sodium valproate. J Neurol Neurosurg Psychiatr 1987;50:1522–5.

Kartha938

54. Lotze T, Jankovic J. Paroxysmal kinesigenic dyskinesias. Semin Pediatr Neurol2003;10:68–79.

55. Zesiewicz TA, Louis ED, Sullivan KL, et al. Substantial improvement in a Meige’ssyndrome patient with levetiracetam treatment. Mov Disord 2004;19:1518–21.

56. Sullivan KL, Hauser RA, Louis ED, et al. Levetiracetam for the treatment of gener-alized dystonia. Parkinsonism Relat Disord 2005;11:460–71.

57. Tarsy D, Ryan RK, Ro SI. An open-label trial of levetiracetam for treatment ofcervical dystonia. Mov Disord 2006;21:734–5.

58. Hering S, Wenning GK, Seppi K, et al. An open trial of levetiracetam forsegmental and generalized dystonia. Mov Disord 2007;22:1649–51.

59. Kuehn B. Studies, reports say botulinum toxin may have effects beyond injectionsite. JAMA 2008;299:2261–2.

60. Curra A, Berardelli A. Do the unintended actions of botulinum toxin at distant siteshave clinical implications? Neurology 2009;72:1095–9.

61. Kuehn B. FDA requires black box warnings on labeling for botulinum toxin prod-ucts. JAMA 2009;301:2316.

62. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology 1987;37:616–23.

63. Jankovic J. Dystonia: medical therapy and botulinum toxin. Adv Neurol 2004;94:275–86.

64. Greene P, Kang U, Fahn S, et al. Double-blind, placebo-controlled trial of botu-linum toxin injections for the treatment of spasmodic torticollis. Neurology 1990;40:1213–8.

65. Comella CL. The treatment of cervical dystonia with botulinum toxins. J NeuralTransm 2008;115:579–83.

66. Lew MF, Adornato BT, Duane DD, et al. Botulinum toxin type B: a double-blind,placebo-controlled safety and efficacy study in cervical dystonia. Neurology1997;49:701–7.

67. Poewe W, Schelosky L, Kleedorfer B, et al. What is the optimal dose of botulinumtoxin type A? Results of a double blind, placebo controlled, dose ranging studyusing Dysport. German Study Group. J Neurol Neurosurg Psychiatr 1998;64:13–7.

68. Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin sero-types A and B for the treatment of cervical dystonia. Neurology 2005;65:1423–9.

69. Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy forblepharospasm. Cochrane Database Syst Rev 2005;1:CD004900.

70. Cakmur R, Ozturk V, Uzunel F, et al. Comparison of preseptall and pretarsall injec-tions of botulinum toxin in the treatment of blepharospasm and hemifacial spasm.J Neurol 2002;249:64–8.

71. Kenney C, Jankovic J. Botulinum toxin in the treatment of blepharospasm andhemifacial spasm. J Neural Transm 2008;115:585–91.

72. Dashtipour K, Pender RA. Evidence for the effectiveness of botulinum toxin forwriter’s cramp. J Neural Transm 2008;115:653–6.

73. Kruisdijk JJ, Koelman JH, Ongerboer de Vesser BW, et al. Botulinum toxin forwriter’s cramp: a randomized, placebo-controlled trial and 1 year follow-up.J Neurol Neurosurg Psychiatr 2007;78:264–70.

74. Watts CR, Truong DD, Nye C. Evidence for the effectiveness of botulinum toxin forspasmodic dysphonia from high quality research designs. J Neural Transm 2008;115:625–30.

75. Truong D, Rontal M, Rolnick M, et al. Double-blind controlled study of botulinumtoxin in adductor spasmodic dysphonia. Laryngoscope 1991;101:630–4.


76. Moller E, Bakke M, Dalager T, et al. Oromandibular dystonia involving the lateralpterygoid muscles: four cases with different complexity. Mov Disord 2007;22:785–90.

77. Jankovic J, Esquenazi A, Fehling D, et al. Evidence-based review of patient re-ported outcomes with botulinum toxin type A. Clin Neuropharmacol 2004;27:234–44.

78. Mejia NI, Vuong KD, Jankovic J. Long-term botulinum toxin efficacy, safety andimmunogenicity. Mov Disord 2005;20:592–7.

79. Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and immunogenicity oforiginal versus current botulinum toxin in cervical dystonia. Neurology 2003;60:1186–8.

80. Bertrand CM, Molina-Negro P, Bouvier G, et al. Observations and analysis ofresults in 131 cases of spasmodic torticollis after peripheral denervation. ApplNeurophysiol 1987;50:319–23.

81. Bertrand CM. Selective peripheral denervation for spasmodic torticollis: surgicaltechniques, results and observations in 260 cases. Surg Neurol 1993;40:96–103.

82. Cohen-Gadol AA, Ashklog JE, Matsumoto J, et al. Selective peripheral denerva-tion for the treatment of intractable spasmodic torticollis: experience with 168patients at the Mayo Clinic. J Neurosurg 2001;98:1247–54.

83. Munchau A, Palmer JD, Dressler D. Prospective study of selective peripheraldenervation for botulinum-toxin resistant patients with cervical dystonia. Brain2001;123:769–83.

84. Vitek JL. Mechanisms of deep brain stimulation: excitation or inhibition. Mov Dis-ord 2002;17(Suppl 3):S69–72.

85. Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain stimulation of theglobus pallidus in primary generalized dystonia. N Engl J Med 2005;352:459–67.

86. Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral, pallidal, deep-brain stimulationin primary generalized dystonia: a prospective 3 year follow-up study. LancetNeurol 2007;6:223–9.

87. Yianni J, Bain PG, Gregory RP, et al. Post-operative progress of dystonia patientsfollowing globus pallidus internus deep brain stimulation. Eur J Neurol 2003;10:239–47.

88. Coubes P, Cif L, El Fertit H, et al. Electrical stimulation of the globus pallidusinternus in patients with primary generalized dystonia: long-term results.J Neurosurg 2004;101:189–94.

89. Alterman AL, Snyder BJ. Deep brain stimulation for torsion dystonia. Acta Neuro-chir Suppl 2007;97:191–9.

90. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primarygeneralized or segmental dystonia. N Engl J Med 2006;355:1978–90.

91. Blahak C, Wohrle JC, Capelle HH, et al. Health-related quality of life in segmentaldystonia is improved by bilateral pallidal stimulation. J Neurol 2008;255:178–82.

92. Sensi M, Cavallo M, Quatrale R, et al. Pallidal stimulation for segmental dystonia:long term follow up of 11 consecutive patients. Mov Disord 2009;24:1829–35.

93. Krauss JK, Pohle T, Weber S, et al. Bilateral stimulation of globus pallidus internusfor treatment of cervical dystonia. Lancet 1999;354:837–8.

94. Parkin S, Aziz T, Gregory R, et al. Bilateral globus pallidus stimulation for the treat-ment of spasmodic torticollis. Mov Disord 2001;16:489–93.

95. Eltahawy HA, Saint-Cyr J, Poon YY, et al. Pallidal deep brain stimulation incervical dystonia: clinical outcome in 4 cases. Can J Neurol Sci 2004;31:328–32.

96. Kiss ZHT, Doig-Beyaert K, Eliasziw M, et al. The Canadian multicentre study ofdeep brain stimulation for cervical dystonia. Brain 2007;130:2879–86.

Kartha940

97. Gruber D, Trottenberg T, Kivi A, et al. Long-term effects of pallidal deep brainstimulation in tardive dystonia. Neurology 2009;73:53–8.

98. Vidailhet M, Yelnick J, Lagrange C, et al. Bilateral pallidal deep brain stimulationof patients with dystonia-choreoathetosis cerebral palsy: a prospective pilotstudy. Lancet 2009;8:709–17.

Documents

Therapeutic Challenges in Dystonia