Treatment Guidelines

Botulinum Toxins (BTX)

BTX therapy has been the focus of several lengthy reviews and prior educational programs and workshops at the AAN, so this summary addresses only the key aspects^1-4. The bacterium Clostridium botulinum makes seven different forms of BTX designated A through G. They block neurotransmission at the neuromuscular junction by acting as proteases that cleave critical proteins required for the docking and exocytosis of synaptic vesicles containing acetylcholine. Weakness occurs until the release apparatus is restored by replacing the cleaved proteins or until axons sprout new terminals. Only two types have been developed for clinical application. BTX-A is available as Botox^TM, Dysport^TM or Xeomin^TM. BTX-B is available as Myobloc^TM or Neurobloc^TM.

For many dystonias, therapy with BTX is highly effective and the treatment of choice. Typical success rates are 80-90% for focal craniofacial and cervical dystonias, but lower for oromandibular and limb dystonias. Their use is supported by several double-blind and placebo-controlled trials, and extensive and long-term non-blinded experience. In most cases, benefits become evident 2-10 days after injections, they peak at 2-4 weeks, and they last for 10-14 weeks. Most patients return for re-injection at 3-4 months intervals. Intervals less than 3 months are discouraged because of a theoretical increased risk for developing immunological resistance, while intervals of 5-6 months or longer are discouraged because patients experience complete return of symptoms.

The most important factor determining success with BTX is proper selection of muscles for treatment and proper selection of doses for each muscle. The selection of muscles is based primarily on the clinical examination in concert with knowledge of the types of movements governed by each muscle. The use of ancillary EMG and/or stimulation to confirm targeting to appropriate muscles depends on the condition being treated and the preferences of the provider. EMG is valuable in some cases, such as focal hand dystonia where precise discrimination of multiple small muscles in close proximity in the forearm is challenging by clinical examination alone. On the other hand, EMG is rarely needed for blepharospasm and other facial dystonias, because these injections usually are made subcutaneously where the medication diffuses subcutaneously to the muscles. Many patients with cervical dystonia may not need EMG guidance, unless they have thick necks that make palpation of individual muscles difficult, complex patterns of movement where the involved muscles are unclear, or unreliable responses without EMG.

There are significant variations among providers in the number of injections per muscle, dilution factors, and doses applied. Targeting fewer injection sites minimizes pain from needle penetrations through the skin. At the same time, fewer sites requires delivery of larger volumes per site, thereby increasing local muscle discomfort and the risk of leakage from each site. Detailed guidelines are available for different forms of dystonia, anatomical charts for specific muscles involved, and doses for different formulations of BTX.

Doses and side effects vary according to the disorder treated. For cervical dystonia, the most common side effects include transient injection site pain, muscle weakness, dysphagia and dry mouth. For blepharospasm the most common side effects include transient pain, ecchymoses, ptosis, and dry or watery eyes. For spasmodic dysphonia, hoarseness or breathy voice is common shortly after injections but most often transient. For limb dystonia, the most common side effects are weakness and spread to nearby muscles.

Physical and Occupational Therapy

Many patients request various forms of physical (or occupational) therapy in lieu of other medical or surgical treatments. Although physical therapy rarely provides an adequate substitute for other therapies, it plays an important adjunctive role. Physical therapy can be very useful at the outset to mobilize joints and mitigate against contractures, and to provide safe exercise programs to maintain function. The physical therapist must have experience with dystonia and avoid interventions that cause pain or fatigue. An experienced therapist also may be able to design devices that take advantage of sensory tricks to suppress symptoms.

Voice Therapy for Laryngeal Dystonia

Voice therapy alone is not generally successful in patients with typical abductor or adductor spasmodic dysphonia, but it can be very effective in patients with muscular tension dysphonia. The exact relationship between muscular tension dysphonia and spasmodic dysphonia remains unclear, and the two conditions may co-exist. A trained speech pathologist or otolaryngologist usually can discriminate isolated muscle tension dysphonia from spasmodic dysphonia and determine whether voice therapy is likely to be successful.

Immobilization

Immobilization of a dystonic limb in solid casts or splinting devices, sometimes for periods of a month or more, has been advocated as treatment for dystonia. Unfortunately, the extent and duration of immobilization recommended for success are impractical for many patients. Additionally, therapeutic responses are inconsistent, and some patients may get worse. Immobilization therapy should not be recommended until further studies of its efficacy and safety are available.

References

1. Simpson DM, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008. 70: p. 1699-1706.
2. Dressler D, Adib Saberi F. Botulinum toxin: mechanisms of action. Eur Neurol. 2005. 53: p. 3-9.
3. Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry. 2004. 75: p. 951-7.
4. Hallett M, et al. Treatment of focal dystonias with botulinum neurotoxin. Toxicon. 2009. 54: p. 628-33.

Deep Brain Stimulation (DBS)

DBS of the internal segment of the globus pallidus is increasingly used in the treatment of medically refractory dystonias, including primary generalized dystonias, and focal or segmental dystonias that do not respond to less invasive methods^1-3. The use of DBS is supported by two placebo-controlled clinical trials^4-5, and multiple open, non-blinded series from different centers. Improvements vary widely from nil to nearly complete. Two independent and double-blinded trials encompassing a total of 62 patients with primary generalized or segmental dystonia showed average improvements on both the dystonia and disability subscales of the Fahn-Marsden rating scale to be approximately 50% at 3 months. The most significant complications include approximately 1% chance of stroke, immediate or delayed infection of hardware requiring its removal, mood or cognitive change, weakness, and dysphagia. These benefits can be life altering, but candidates must be advised regarding risks and potential for varying outcomes.

Based on early experience, some providers have concluded that primary generalized dystonias respond better than secondary dystonias to DBS. However, more recent studies have revealed this conclusion to be an overgeneralization. Excellent responses are regularly seen in some secondary dystonias, such as tardive dystonia, while consistently poor responses are seen in some others. Consultation with providers with broad experience is needed before recommending DBS for secondary dystonias.

Ablative Procedures

Pallidotomy and thalamotomy have been used for decades in the treatment of different forms of dystonia, including focal task-specific, segmental, and generalized dystonias³. Ablative procedures have been supplanted by DBS, since the latter is reversible and adjustable. Nevertheless, the ablative procedures may still be considered when implantation or maintenance of DBS hardware is not feasible or desired. The most significant complications of ablative procedures include stroke, infection, weakness, and dysphagia.

Selective Denervation

Various procedures have been used for denervating overactive muscles in cervical dystonia⁶. Patient selection is critical, since certain subpopulations have a better outcome than others. Experienced centers have reported good outcomes for 68-89% of patients. These procedures were used more commonly before the availability of BTX therapy, so they now are reserved primarily for patients who do not respond to chemodenervation. The most significant complications include permanent muscle weakness, cosmetic effects of muscle atrophy, dysesthesia, and dysphagia.

Myectomy

The surgical removal of muscle tissue once was commonly offered to patients with dystonia prior to the introduction of BTX therapy. Myectomy is rarely performed nowadays, although it is sometimes still used for blepharospasm and other medically refractory dystonias as a palliative measure.

Intrathecal Baclofen

Some patients experience significant improvements after chronic intrathecal delivery of baclofen^7-8. Patients with leg dystonia seem to have the best responses, particularly if there is concomitant spasticity. Implanted pumps must be refilled regularly and sometimes replaced. Complications may include equipment infection or malfunction, CSF leaks, overdose, and severe withdrawal reactions. This procedure has not gained widespread popularity because of inconsistent responses among different patients, maintenance requirements, risk of severe side effects from sudden medication discontinuation from pump failure, and increasing application of DBS.

References

1. Perlmutter JS, Mink JW. Deep brain stimulation. Annu Rev Neurosci. 2006. 29: p. 229-257.
2. Ostrem JL, Starr P. Treatment of dystonia with deep brain stimulation. NeuroRx. 2008. 5: p. 320-330.
3. Marks WJJ. Brain surgery for dystonia, in Handbook of dystonia. MA Stacey, Editor. 2007, Informa Healtcare USA, Inc: New York. p. 393-406.
4. Vidailhet M, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med. 2005. 352: p. 459-467.
5. Kupsch A, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med. 2006. 355: p. 1978-1990.
6. Arce CA. Selective denervation in cervical dystonia, in Handbook of dystonia. MA Stacey, Editor. 2007, Informa Healthcare USA, Inc.: New York. p. 381-392.
7. Albright AL, et al. Intrathecal baclofen for generalized dystonia. Dev Med Child Neurol. 2001. 43: p. 652-657.
8. Walker RH, et al. Intrathecal baclofen for dystonia: benefits and complications during six years of experience. Mov Disord. 2000. 15: p. 1242-1247.

Wilson’s Disease

Very effective treatments are available for a few rare disorders where dystonia may be a presenting or dominating feature on examination^1-3. Wilson’s disease is the prototype example. It is a disorder of copper metabolism. Approximately 85% of patients have some form of dystonia, often combined with Parkinsonism, tremor, or other neurological features. Copper chelation therapy can prevent progression and even reverse disability. Because Wilson’s disease has a fatally progressive course without treatment, it should be excluded with appropriate diagnostic testing in every child and young adult with dystonia. A low serum ceruloplasmin and a slit lamp exam by an ophthalmologist specifically looking for the presence of Kaiser-Fleischer rings provide useful screening tests. This may be followed by urinary tests of copper excretion and/or liver biopsy if diagnostic uncertainty remains.

Dopa-Responsive Dystonia

Dopa-responsive dystonia presents in children and young adults as a relatively isolated dystonia but it often is combined with Parkinsonism. Corticospinal features are reported for some cases, such as spasticity and brisk reflexes. Although dopa-responsive dystonia constitutes only a small fraction of all childhood dystonias, a trial of levodopa is warranted in all children and young adults with dystonia because of its dramatic and sustained efficacy⁴. A dramatic and sustained response can be considered diagnostic. Among those who respond to levodopa, the role for confirming the diagnosis via lumbar puncture to identify low CSF biopterin levels remains unclear. There are simple genetic tests for the most common forms of dopa-responsive dystonia associated with mutations of the GCH1 or TH genes, but sensitivity is not 100% for detecting all mutations.

Other Treatments

As ongoing research reveals additional causes for dystonia, the numbers of disorders with specific mechanism-based treatments has continued to grow. Guidelines for which disorders to consider and what tests to employ vary among different centers. The following disorders should be considered in the appropriate clinical setting. Biotin-responsive basal ganglia disease is a very rare condition that may present with prominent dystonia in children or young adults, often in combination with other neurological signs including Parkinsonism, ocular motility defects, and episodes of encephalopathy^5-7. An important clue is peculiar signal changes in the caudate and putamen on MRI. Symptoms can be reversed with biotin supplements; death ensues if the disorder untreated.

Vitamin E deficiency is dominated by ataxia with neuropathy, but dystonia may be a presenting feature and may predominate in later stages^8-10. Serum vitamin E levels are useful for diagnosis, and treatment involves dietary supplements. Deficiency of the glucose transporter, GLUT1, due to mutations in the SLC2A gene classically presents with psychomotor delay, seizures, and a mixed motor disorder. A more recently recognized phenotype of GLUT1 deficiency is paroxysmal exercise-induced dystonia. The diagnosis can be made via genetic testing and effective treatment requires a ketogenic diet.

Table 2: Treatable Disorders with Dystonia

References

1. Das SK, Ray K. Wilson's disease: an update. Nat Clin Pract Neurol., 2006. 2: p. 482-93.
2. Pfeiffer RF. Wilson's Disease. Semin Neurol. 2007. 27: p. 123-32.
3. Mak CM, Lam CW. Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci. 2008. 45: p. 263-90.
4. Segawa M, Nomura Y, Nishiyama N. Dopa-responsive dystonia, in Handbook of dystonia, MA Stacey, Editor. 2008, Informa Healthcare, Inc.: Yew York. p. 219-244.
5. Debs R, et al. Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations. Arch Neurol. 2010. 67: p. 126-30.
6. Ozand PT, et al. Biotin-responsive basal ganglia disease: a novel entity. Brain. 1998. 121: p. 1267-79.
7. El-Hajj TI, Karam PE, Mikati MA. Biotin-responsive basal ganglia disease: case report and review of the literature. Neuropediatrics. 2008. 39: p. 268-71.
8. Cavalier L, et al. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet. 1998. 62: p. 301-10.
9. Angelini L, et al. Myoclonic dystonia as unique presentation of isolated vitamin E deficiency in a young patient. Mov Disord. 2002. 17: p. 612-4.
10. Garcia Ruiz PJ, et al. Movement disorders in hereditary ataxias. J Neurol Sci 2002. 202: p. 59-64.

Focal and Segmental Dystonias

For most patients with focal and segmental dystonia, the treatment of choice is BTX. Although BTX is the treatment of choice, it typically is not provided at the first clinic visit. Instead, the first visit is used to complete diagnostic testing if needed, to provide counseling regarding expectations, to plan the doses and procedure required, and to obtain insurance approvals for the procedure. In the interval between the initial visit and the BTX procedure, a trial of at least one oral agent often can be initiated. Finding an oral agent with at least partial efficacy can be useful as adjunctive therapy or for times when symptoms flare up between BTX treatments. The selection of oral agents for empirical trials is guided by the type of dystonia, and anticipated side effects in relation to the patient’s age and other potential comorbidities.

• Cervical Dystonia
  For cervical dystonia, the initial choice for an adjunctive oral agent often is trihexyphenidyl. A benzodiazepine can be added if tremor is prominent, and some patients also benefit from a muscle relaxant. BTX alone, or combined with one adjunctive oral agent, suffices for the vast majority of patients. If combined treatment is inadequate or resistance to BTX develops, selective denervation or DBS can be considered. As for any surgical procedure, patient selection and counseling is critical for success.
• Blepharospasm and Other Lower Facial Dystonias
  For blepharospasm and other lower facial dystonias, a benzodiazepine provides a good initial choice for an adjunctive agent with BTX. Trihexyphenidyl is a second choice. However, BTX alone provides sufficient relief for the majority of these patients, so adjunctive oral medications often are not needed. Myectomy may be offered to those who do not respond to medical therapy.
• The Limb Dystonias
  The limb dystonias are among the most challenging of the focal dystonias to treat with BTX. BTX can be useful, but it is more difficult to obtain satisfactory results than in cervical and craniofacial dystonias. For limb dystonias of children and limb dystonias that are not task-specific in adults, a good initial choice is levodopa, followed by trihexyphenidyl. A benzodiazepine is useful if tremor is prominent. The adult-onset focal dystonias do not often respond to levodopa, so trihexyphenidyl and benzodiazepines are often used.

Generalized Dystonias

For patients with generalized dystonia, it is not feasible to target all involved body regions with BTX. Instead, the primary treatment modality involves oral medications. Generally, successive trials of oral agents are conducted with levodopa, trihexyphenidyl, baclofen, and sometimes other drugs. Although BTX may not be useful for comprehensive treatment of many generalized dystonias, it may be quite useful for treating the most discomforting aspects of a generalized dystonia. When medical therapy appears inadequate, more invasive approaches involving intrathecal baclofen or DBS are considered. As for any surgical procedure, patient selection is very important. Some generalized dystonias respond better to surgery than others, and some patients may not be good surgical candidates because of other comorbidities. Although these procedures are offered by many neurosurgeons, the best outcomes are likely to be achieved by those who are more experienced, and particularly those who work at centers with multidisciplinary teams.