Dystonia is a neurological syndrome in which the mechanism which allows muscles to relax can no longer function normally.¹ This causes involuntary spasm and contraction, along with uncontrollable repetitive or twisting movements of opposing muscles, resulting in the characteristic abnormal and awkward postures of what is described as one of the most disabling movement disorders. 

Despite some links to genetic mutations, the majority of dystonias occur without particular causation.²

Dystonia can be divided into many categories, based on the area of the body that is affected. The most common type, focal dystonia, affects one particular part of the body. Two or more adjacent body regions are affected in segmental dystonia, while the majority of the body, if not all, is affected in generalised dystonia.³

Scales for diagnosis

The severity of a patient’s dystonia can be measured objectively using different scales. Generalised forms of dystonia are measured using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), the Unified Dystonia Rating Scale (UDRS) and the Global Dystonia Scale (GDS).⁴

There are also other rating scales for more specific categories of dystonia; for example symptoms of cervical dystonia are commonly measured using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).^5,6

Treatment

The treatment of dystonia generally provides only symptomatic relief, mainly because there is still little knowledge regarding the pathogenesis of the disorder. The treatment option chosen is dependent on patient age and the anatomical distribution of the dystonia. Treatment must be adapted to suit the needs of the patient with the aim of improving quality of life by relieving muscle contractions, abnormal postures and associated pain. 

There are many options available for the treatment of dystonia. To begin with, oral medications are administered. Based upon the effect of these drugs in an individual patient, other treatments can be considered such as botulinum toxin and several surgical procedures.^2,5

Oral medications

Dopaminergic agents

Levodopa is a precursor to dopamine, which gets converted into its active form by the enzyme DOPA decarboxylase. Levodopa has proven to provide substantial improvement, and sometimes complete resolution of dystonia in a small subset of patients (5% of childhood dystonias),² this group being classed as having dopa-responsive dystonia (DRD). 

DRD is characterised by childhood onset, parkinsonian features, gait and postural abnormalities, diurnal fluctuation and autosomal dominant inheritance. Levodopa treatment should be considered in all childhood/young onset dystonias, as many DRDs may be misdiagnosed as cerebral palsy due to their multifaceted presentation. 

Small doses of levodopa (100mg of levodopa with 25mg decarboxylase inhibitor) have proven sufficient in providing substantial improvement in patients with DRD, however higher doses may be required.²

An inverse correlation is reported between the daily dose of levodopa and treatment duration in DRD. Levodopa-induced dyskinesias, which appear late in the course of DRD, are responsive to a decrease in daily dose of levodopa without a deterioration in motor function. This might also suggest that over time, a reduced dose of levodopa is required to treat symptoms of DRD.⁷

If no clinical improvement is evident after one month of treatment with adequate doses of levodopa, a diagnosis of DRD is unlikely. Other forms of dystonia have reported modest improvement with the treatment of levodopa.^5,8

Antidopaminergic drugs

Antidopaminergic drugs (dopamine receptor blocking drugs) are reported to be beneficial in the treatment of dystonia, however, their benefit is limited by the potential development of undesirable side effects, most notably sedation, parkinsonism and tardive dyskinesia. This is the case with clozapine, an atypical neuroleptic, which has proven to provide benefit in cases of segmental and generalised dystonia. Despite its benefits however, clozapine may lead to postural hypotension as well as the aforementioned adverse effects. Patients taking this drug must also be monitored to avoid agranlocytosis.^2,5

Dopamine depleting agents have proven successful in the treatment of dystonia. One such drug, tetrabenazine, acts in the central nervous system as an inhibitor of the vesicular monoamine transporter 2 (VMAT2). Unlike clozapine, it has not been reported to cause tardive dyskinesia, thus granting it an advantage. 

A study into the effect of tetrabenazine in hyperkinetic movement disorders resulted in 70% of dystonia patients studied reporting a marked or moderate abolishment of dystonia on their final visit. Drowsiness, parkinsonism, depression and akathisia were the most frequent side-effects reported, all of which were dose related, while less common side-effects included nausea and vomiting, anxiety and insomnia.^2,5

Anticholinergic drugs

Anticholinergic drugs such as trihexyphenidyl have proven beneficial in the treatment of generalised and segmental dystonia. 

Anticholinergic drugs can be well tolerated when the dose is started low and gradually increased. However, at higher doses, peripheral anti-muscarinic side-effects such as blurred vision, urinary retention, dry mouth, confusion, drowsiness, hallucinations and memory difficulty may develop. 

Peripherally acting anticholinesterases may be co-administered to improve these effects. However, the use of anticholinergic drugs in the treatment of segmental and generalised dystonia has markedly declined since the introduction of botulinum toxin therapy.

Other treatments

Muscle relaxants may be taken additionally to benefit those with little response to anticholinergic treatment or when the effects of botulinum toxin are wearing off. 

Benzodiazepines are the class of drug used and examples include diazepam, lorazepam and clonazepam. Clonazepam is proven to be particularly beneficial in the treatment of blepharospasm and myoclonus-dystonia. 

Oral baclofen may be effective in the treatment of levodopa-related wearing-off dystonia and oromandibular dystonia, and also in ‘spastic dystonias’ associated with stroke and cerebral palsy. However, intrathecal administration of baclofen has proven effective in the treatment of spastic dystonia, as studied in patients with severe segmental and generalised dystonia which was unresponsive to oral medication (first suggested by Narayan in 1991).^5,9,10

Botulinum toxin

Botulinum toxin (BT) is the most potent biological toxin and is used in the treatment of a variety of neurological, ophthalmic and other disorders characterised by abnormal, excessive or inappropriate contraction of muscles. 

BT produces its effects by blocking the release of acetylcholine from the presynaptic terminals into the neuromuscular junction; it is a selective inhibitor of cholinergic innervation of both striated and smooth muscle, and exocrine glands.¹¹

Acetylcholine is responsible for muscle contraction so by blocking its release, muscle contraction is weakened and muscles are somewhat paralysed. However, the use of BT is limited by its systemic anticholinesterase adverse effects such as dry mouth, blurred vision, memory difficulty and constipation (particularly in type A).¹²

There are seven antigenically distinct types of toxin, A to G, however only type A and type B have been licensed. Type A (Botox/Dysport) is approved as a therapeutic for patients with strabismus, blepharospasm and other facial nerve disorders, including haemifacial spasm. 

Type B (Myobloc/NeuroBloc) is approved for the treatment of cervical dystonia along with Botox. The treatment with BT has been researched predominantly in the treatment of cervical dystonia. Studies have proven BT is more beneficial in this area than trihexyphenidyl, providing relief from pain and improving head turning and functional capacity. Dysphagia and neck weakness were the most common reported side-effects.⁵

BT is also effective in the treatment of focal dystonias, for example oromandibular dystonia, and also provides relief in dystonic writer’s cramp and other task-specific dystonias. BT was studied in patients with cranial dystonia. The clinical improvement induced in these patients was found to be predominantly symptomatic, as there seemed to be no change in the abnormal intracortical activity.¹³

Another study of patients with cervical dystonia found that there was no difference in improvement between those treated with BT type A and B, as measured on the TWSTRS. However, side-effects such as dysphagia and dry mouth were more prevalent in those who received type B. Also, BT type A was found to have a significantly longer duration of efficacy (14 weeks versus 12.1 weeks, p = 0.0.33).

There is evidence to suggest that BT is both safe and effective with long lasting benefits leading to meaningful improvements in quality of life.^14,15 However, concern arises regarding the issue of antigenicity and development of immunoresistance. This was a problem with original formulations but improvements to the current formulation mean the occurrence of this is now quite rare. 

A study into the development of blocking antibodies in BT treatment was carried out in patients who were treated with BT type A and B in the past. One third (33%) of subjects developed de novo immunoresistance to type B. Therefore, although BT type B may be considered an alternative to type A, the previously mentioned side-effects as well as the increased risk of developing blocking antibodies with repeated use, limit its long-term efficacy. 

Surgery

Results from many different physiological and functional imaging studies of the basal ganglia suggest that there is excessive activity in both the direct (striatum-GPi) and indirect (striatum-GPe-GPi) pathways in dystonic patients. 

Pallidotomy and high-frequency stimulation of the GPi disrupt these abnormal discharge patterns and hence are considered rational treatment options for dystonic patients. By interfering with the abnormal activity of the GPi, overactivation of the cortex is reduced, a characteristic of dystonia. 

However, due to the lower risk of complications than in pallidotomy, deep-brain stimulation (DBS) is now favoured as surgical treatment for dystonia.⁵ An added benefit to DBS is that the stimulation parameters may be adjusted to suit the needs of each patient specifically. 

Evidence suggests that DBS in dystonic patients leads to an increase in body mass index (BMI). This increase is reported to be greater in patients who were treated with sub-thalamic nucleus DBS in comparison to those treated with GPi DBS (STN versus GPi, +7.99kg per year, p = 0.012).¹⁶ There is research to support the theory that DBS of the pallidum is effective in treating the motor symptoms of myoclonus dystonia and that it may have a stabilising effect on dopamine D2-receptor binding.¹⁷

The effectiveness of DBS of the internal globus pallidus (GPi) and the ventral intermediate nucleus of the thalamus for the treatment of myoclonus dystonia has been studied. Its efficacy was measured in terms of myoclonus and dystonia. 

While similar improvements in myoclonus scores (as measured by the Unified Myoclonus Rating Scale [UMRS]) were seen in both GPi and VIM stimulation, it appears that GPi stimulation causes greater improvement in dystonia scores (as measured by the BFMDRS) as compared to VIM stimulation. This suggests that GPi is a more effective target for treatment of myoclonus dystonia than VIM stimulation.¹⁸  Research is also supportive of GPi stimulation as treatment for generalised primary dystonia, particularly in patients who fail to respond to pharmacological therapy. GPi stimulation in these patients is proven to be effective, reversible and adaptable.¹⁹

Conclusion

Despite extensive research into various aspects of dystonia, there is as yet only limited knowledge regarding its aetiology and pathogenesis. As a result, there is no curative treatment available. 

Many different treatment options have been developed based on the current understanding of dystonia, but all simply treat the symptoms of this hugely disabling disorder. While the treatment of dystonia is individually planned for each patient, there is still huge variability in efficacy of treatment among patients, many of whom suffer various unpleasant side-effects. 

While this review deals primarily with treating the motor complications of dystonia, it is imperative that the non-motor elements, such as pain and depression, are not overlooked.²⁰ With regards to the future treatment of dystonia, while improved trials of existing treatment methods must be developed, a further understanding of the pathophysiology of the disease will lead to the emergence of new therapies targeted towards newfound evidence.²¹

References

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