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Treatment of dystonia
Introduction
Despite paucity of knowledge about the cause and pathogenesis of dystonic disorders, the symptomatic treatment of dystonia has markedly improved, particularly since the introduction of botulinum toxin (BoNT). In most cases of dystonia, the treatment is merely symptomatic, designed to improve posture and function and relieve associated pain. In rare patients, however, dystonia can be so severe that it can produce not only abnormal postures and disabling dystonic movements, sometimes compromising respiration, but also muscle breakdown and life-threatening hyperthermia, rhabdomyolysis, and myoglobinuria. In such cases of dystonic storm or status dystonicus, proper therapeutic intervention can be life-saving ( ; , ; ; ; ).
With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed and clinical trials must be appropriately designed to assess the safety and efficacy of the therapeutic intervention ( ). The assessment of various therapeutic interventions in dystonia is problematic for the following reasons: (1) Dystonia and its effects on function are difficult to quantitate, and thus most trials use crude clinical rating scales, many of which have not been properly evaluated or validated; (2) dystonia is a syndrome with different causes, anatomic distributions, and heterogeneous clinical manifestations producing variable disability; (3) some patients, perhaps up to 15%, may have spontaneous, albeit transient, remissions; (4) many studies have used dosages that may have been insufficient or too short a duration to provide benefit; (5) the vast majority of therapeutic trials in dystonia are not double-blind, placebo-controlled; and (6) most studies, have small sample sizes ( ).
The selection of a particular choice of therapy is guided largely by personal clinical experience and by empirical trials ( ; , , , , , ; ; ) ( Table 12.1 ). An evidence-based review concluded that except for BTX in cervical dystonia and high-dose trihexyphenidyl in young patients with segmental and generalized dystonia (level A, class I-II), none of the methods of pharmacologic intervention have been confirmed as being effective according to evidence-based criteria ( ). The patient’s age, the anatomic distribution of dystonia, and the potential risk for adverse effects are also important determinants of choice of therapy. The identification of a specific cause of dystonia, such as drug-induced dystonias or Wilson disease ( ), may lead to a treatment that is targeted to the particular cause. It is therefore prudent to search for identifiable causes of dystonia, particularly when some atypical features are present. The diagnostic approach to patients with dystonia is based on being aware of the multiple causes of torsion dystonia, which are covered in Chapter 11 and in other reviews ( ; ; ; ).
Table 12.1
Medical therapy of dystonia
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Physical rehabilitation for dystonia
A variety of rehabilitation interventions have been proposed for focal dystonia. These include motor training, which has been applied mostly to task-specific dystonia, including writer’s cramp and musician’s dystonia. Although benefit has been shown in several studies, these are small studies with a low level of evidence ( ). Other approaches have included constraint therapy, sensory reorganization, and biofeedback. The limitations of studies of these various techniques included small sample sizes, lack of validated outcome measures, and lack of appropriate control conditions. A recent randomized study compared specialized versus standard neck physiotherapy in 110 cervical dystonia patients using a blinded rater assessment of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) as the primary outcome. This study demonstrated that both inverventions were effective after 4 weeks, but there was no difference between the two approaches. Further, given that all patients received an intervention, the outcome could have been secondary to placebo effects ( ). Although rehabilitation techniques have not been demonstrated to directly affect the severity of dystonia, this intervention may be a useful adjunct to other treatments, including BTX injections, to prevent contractures and improve range of motion ( ).
Fitted braces designed primarily to improve posture and prevent contractures have been used. Although braces are often poorly tolerated, particularly by children, they may be used in some cases as a substitute for a sensory trick. For example, some patients with cervical dystonia are able to construct neck-head braces that seem to provide sensory input by touching certain portions of the neck or head in a fashion similar to the patient’s own sensory trick, thus enabling the patient to maintain a desirable head position. However, many patients with cervical dystonia who have used rigid braces in an attempt to control neck movements find that these are painful and rarely lead to symptom relief.
Various hand devices have been developed in an attempt to help patients with writer’s cramp use their hands more effectively and comfortably ( ; ). In one small study of five professional musicians with focal dystonia, Candia and colleagues (1999) reported success with immobilization by splints of one or more of the digits other than the dystonic finger followed by intensive repetitive exercises of the dystonia finger. It is not clear, however, whether this “constrained-induced” therapy provides lasting benefits. In one study of eight patients with idiopathic occupational focal dystonia of the upper limb, immobilization with a splint for 4 to 5 weeks resulted in a significant improvement at a 24-week follow-up visit, based on the Arm Dystonia Disability Scale (0 = normal; 3 = marked difficulty in playing) and the Tubiana and Champagne Score (0 = unable to play; 5 = returns to concert performances) and was considered marked in four and moderate in three, and the initial improvement disappeared in one ( ). The splint was applied for 24 hours every day except for 10 minutes once a week when it was removed for brief local hygiene. Immediately on full removal of the splint, all patients reported marked clumsiness and weakness, which resolved in 4 weeks. There was also some local subcutaneous and joint edema and pain in the immobilized joint, and nail growth stopped; none of the patients developed contractures. Although the mechanisms of action of immobilization is unknown, the authors have postulated that removing all motor and sensory input to a limb might allow the cortical map to “reset” to the previous normal topography. One major concern about immobilization of a limb, particularly a dystonic limb, is that such immobilization can actually increase the risk for exacerbating or even precipitating dystonia, as has been well demonstrated in dystonia after casting or other peripheral causes of dystonia ( ). In one study of 21 patients with writer’s cramp, after 4 weeks of immobilization, “retraining” for 8 weeks using drawing and writing exercises was associated with significant improvement related to baseline as assessed by the Writer’s Cramp Rating Scale ( ). A variation of the immobilization therapy, constraint-induced movement therapy, has been used successfully in rehabilitation of patients after stroke and other brain insults, and the observed benefit has been attributed to cortical reorganization ( ; ; ; ; ; ).
Another technique, using a repetitive task during regional anesthesia of a weak arm in patients after a stroke, was also associated with improved hand function ( ). Some patients find various muscle relaxation techniques and sensory feedback therapy useful adjuncts to medical or surgical treatments. Some patients with dystonia have impaired sensory perception; therefore, it has been postulated that sensory training may relieve dystonia. In a study of 10 patients with focal hand dystonia, Zeuner and colleagues (2002) showed that reading Braille for 30 to 60 minutes daily for 8 weeks improved spatial acuity and dystonia that was sustained for up to 1 year in some patients ( ). Sensory training to restore sensory representation of the hand along with mirror imagery and mental practice techniques also has been reported to be useful in the treatment of focal hand dystonia ( ; ). In one study of 54 pianists with musician’s dystonia the following multiple therapies have been tried: retraining (87%), hand therapy (42%), relaxation techniques (38%), physiotherapy (30%), psychotherapy (23%), acupuncture (21%), and body techniques (21%); 81.5% reported improvement, 5.6% reported complete recovery, but only 43% had objective evidence of improvement in task-specific motor performance ( ).
Siebner and colleagues (1999) showed that using repetitive transcranial magnetic stimulation (rTMS) delivered at low frequencies (1 Hz or less) for 20 minutes can temporarily (8/16 patients reported improvement that lasted longer than 3 hours) improve handwriting impaired by dystonic writer’s cramp, presumably by increasing inhibition (and thus reducing excitability) of the underlying cortex. Despite some encouraging results from open-label pilot studies, it remains to be seen whether rTMS or transcranial direct current stimulation (tDCS) will enter the mainstream of therapeutics of dystonia ( ). Recent controlled studies have had variable findings likely resulting from differences in methodology ( ).
Other modalities, including acupuncture as an adjuvant therapy combined with BTX, are currently being assessed in open-label studies. ( )
Oral pharmacologic therapy
No oral medications for the treatment of dystonia have been approved by the U.S. Food and Drug Administration (FDA). Before the availability of BTX and globus pallidus internus (GPi) deep brain stimulation (DBS), many oral agents were given to patients because no other effective approach was available. Currently, medications are used most frequently in combination with other interventions ( ). In a cross-sectional study of 2026 patients enrolled in the Dystonia Coalition Biorepository and Natural History project ( ) over a 4.5-year period (2011–2015), 17% were taking oral medications alone and 35% used both oral medications and BTX treatment. The benzodiazepines were the most frequently used and the dopaminergic antagonist the least. Patients with spasmodic dysphonia and limb dystonia were least likely to take oral medications. For generalized dystonia, anticholinergic agents were taken by 22% of patients; in contrast, 5% of patients with cervical dystonia and 3% of patients with blepharospasm were currently on this class of medication ( ). Controlled assessments of efficacy for any oral agent is lacking, although in retrospective studies, clonazepam was found to be more effective (40%) then anticholinergics (20%) or baclofen (20%), ( ). In fact, the response to any oral pharmacologic agent may depend on the subtype of dystonia. In one study, escitalopram tended to be of more benefit in those patients in whom binding was increased ( )
Dopaminergic therapies
Dopamine agonists
Although there is some evidence of reduced striatal dopamine release in dystonia, such as writer’s cramp ( ), pharmacologic treatment of dystonia, including the use of levodopa and other dopamine agonists, is based largely on an empirical rationale rather than a scientific one. Although case reports of efficacy are published ( ), no controlled trials in isolated dystonia are available. Unlike Parkinson disease (PD), in which therapy with levodopa replacement is based on the finding of depletion of dopamine in the brains of parkinsonian animals and humans, our knowledge of biochemical alterations in idiopathic dystonia is very limited. One exception is dopa-responsive dystonia (DRD), in which the biochemical and genetic mechanisms have been elucidated by molecular DNA and biochemical studies in patients ( ) and by studies of postmortem brains ( ). Decreased neuromelanin in the substantia nigra with otherwise normal nigral cell count and morphology and normal tyrosine hydroxylase immunoreactivity were found in one brain of a patient with classic DRD ( ). There was a marked reduction in dopamine in the substantia nigra and the striatum. These findings suggested that in DRD, the primary abnormality was a defect in dopamine synthesis. This proposal is supported by the finding of a mutation in the GTP cyclohydrolase I gene on chromosome 14q that indirectly regulates the production of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine ( ; ; ). Another form of DRD has been described in four cases belonging to two unrelated families of dopa-responsive cervical dystonia, presenting between 9 and 15 years of age and similar to classic DRD manifesting diurnal variation but no levodopa-induced dyskinesia ( ).
DRD usually manifests in childhood with dystonia, mild parkinsonian features, and pseudopyramidal signs (hypertonicity and hyperreflexia) predominantly involving the legs. Many patients have a family history of dystonia or PD. At least half of the patients have diurnal fluctuations, with marked progression of their symptoms toward the end of the day and a relief after sleep. Many patients with this form of dystonia are initially misdiagnosed as having cerebral palsy. Some patients with DRD are not diagnosed until adulthood, and family members of patients with typical DRD may present with adult-onset levodopa-responsive parkinsonism ( ). The take-home message from these reports is that a therapeutic trial of levodopa should be considered in all patients with childhood-onset dystonia, whether they have classic features of DRD or not. A trial of levodopa in adult-onset dystonia also has been recommended given the expanding phenotype of DRD, but the levodopa trial in dystonia remains controversial ( ; )
Most patients with DRD improve dramatically even with small doses of levodopa (100 mg of levodopa with 25 mg of decarboxylase inhibitor), but some might require doses of levodopa as high as 1000 mg per day. In contrast to patients with juvenile PD ( ), DRD patients usually do not develop levodopa-induced fluctuations or dyskinesias. If no clinically evident improvement is noted after 3 months of therapy, the diagnosis of DRD is probably in error, and levodopa can be discontinued. In addition to levodopa, patients with DRD also improve with dopamine agonists, anticholinergic drugs, and carbamazepine ( ). In contrast to patients with DRD, patients with idiopathic or other types of dystonia rarely improve with dopaminergic therapy ( ). Apomorphine, however, may ameliorate dystonia, perhaps by decreasing dopamine and serotonin release ( ).
Sepiapterin reductase deficiency (SRD) is a frequently underrecognized levodopa-responsive disorder, often misdiagnosed as cerebral palsy. In a study of 43 patients with SRD identified from 23 international medical centers, the average age at onset is 7 months, with delay to diagnosis of 9.1 years ( ). Clinical features included motor and language delays, oculogyric crises, diurnal fluctuation, axial hypotonia and limb hypertonia, dystonia, weakness, parkinsonism, hyperreflexia, mental retardation, psychiatric and/or behavioral abnormalities, autonomic dysfunction, sleep benefit, and sleep disturbances. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Typical cerebrospinal fluid findings: low 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and elevated total biopterin, dihydrobiopterin (BH2), and sepiapterin. Diagnosis can be confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. Whole-genome sequencing of a 14-year-old fraternal twin pair diagnosed with DRD (Mendelian Inheritance in Man #128230) identified compound heterozygous mutations in the sepiapterin reductase (SPR) gene ( ). Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of L-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins. Also, sapropterin (Kuvan), a pharmaceutical formulation of the natural cofactor for PAH (6R-tetrahydrobiopterin; BH4), approved for the treatment of phenylketonuria, may be tried ( ).
Dopamine antagonists
Although dopamine receptor–blocking drugs were used extensively in the past, most clinical trials have produced mixed results with these drugs. Because of the poor response and the possibility of undesirable side effects, particularly sedation, parkinsonism, and tardive dyskinesia, the use of these drugs in the treatment of dystonia should be discouraged ( ; ). Clozapine, an atypical neuroleptic, has been reported in a small open trial to be moderately effective in the treatment of segmental and generalized dystonia, but its usefulness was limited by potential side effects ( ). Although antidopaminergic drugs have been reported to be beneficial in the treatment of dystonia, the potential clinical benefit is usually limited by the development of side effects. Dopamine depleting drugs, such as tetrabenazine, however, have been found useful in some patients with dystonia, particularly those with tardive dystonia ( ; ). Tetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, has the advantage over other antidopaminergic drugs in that it does not cause tardive dyskinesia, although it may cause transient acute dystonic reaction ( ; ; ). Tetrabenazine is available in the United States, but it is dispensed by prescription under the trade name Nitoman or Xenazine 25 in other countries, including the United Kingdom. The more recently developed VAMT-2 inhibitors, such as velbenazine or deutetrabenazine have not been evaluated. It is possible that some of the new atypical neuroleptic drugs will be useful not only as antipsychotics, but also in the treatment of hyperkinetic movement disorders.
Risperidone, a D2 dopamine receptor–blocking drug with a high affinity for 5HT 2 receptors, has been reported to be useful in a 4-week trial of five patients with various forms of dystonia ( ). Clozapine, a D4 dopamine receptor blocker with relatively low affinity for the D2 receptors and high affinity for the 5-HT 2A receptors, has been reported to ameliorate the symptoms of tardive dystonia ( ). The treatment of tardive dystonia and other tardive syndromes is discussed in another chapter and in other reviews ( ; ).
Anticholinergic therapy
High-dosage anticholinergic medications, such as trihexyphenidyl, for dystonia were introduced by and confirmed by several groups ( ; ; ; ), including a small double-blind study ( ). Although helpful in all types of dystonias, the supremacy of BTX therapy for focal dystonias has relegated anticholinergic therapy to be most useful in the treatment of generalized and segmental dystonia. In the experience of Greene and colleagues (1988), patients with blepharospasm, generalized dystonia, tonic (in contrast to clonic) dystonia, and onset of dystonia at age younger than 19 years seemed to respond better to anticholinergic drugs than did other subgroups, but this difference did not reach statistical significance. Except for short duration of symptoms before onset of therapy, there was no other variable, such as gender or severity, that reliably predicted a favorable response. Treating patients within the first 5 years of disease onset was statistically significantly more successful than delaying treatment in both children and adults regardless of severity ( ). Thus, starting treatment early is important. Children usually tolerate the very high dosages of anticholinergic drugs, whereas adults do not. In one study of 20 cognitively intact patients with dystonia, 12 could tolerate 15 to 74 mg/day of trihexyphenidyl. Side effects included drug-induced impairments of recall and slowing of mentation, particularly in older patients ( ). Other anticholinergic side effects include dry mouth, sedation, cognitive slowing, confusion, mydriasis, urinary retention, and constipation. Anticholinergics are contraindicated if patients have a history of narrow-angle glaucoma ( ).
Diphenhydramine, a histamine-1 (H 1 ) antagonist with anticholinergic properties, has been reported to have an antidystonic effect in three of five patients ( ). However, the drug was not effective in 10 other patients with cervical dystonia, and it was associated with sedation and other anticholinergic side effects in most patients. Pyridostigmine, a peripherally acting anticholinesterase, and pilocarpine (a muscarinic agonist) eye drops often ameliorate many of the peripheral side effects, such as urinary retention and blurred vision. Pilocarpine (Salagen) 5 mg four times per day, cevimeline (Evoxac) 30 mg three times per day and synthetic saliva (Biotene, Glandosane, Salix) have been found effective in the treatment of dry mouth.
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