Dystonia have found reduced D2 binding in the caudate and putamen.61,62 Similar
findings were seen in DYT1 non-manifesting carriers, indicating that the dopamine-related abnormalities do not directly cause dystonia.
Acetylcholine
A central role for cholinergic dysfunction in dystonia pathogenesis is suggested by the observation that anticholinergic medications are the most effective pharmacologic agents in improving dystonia symptoms in primary dystonia patients. In studies in torsinA transgenic mice, Pisani and colleagues have found evidence of abnormal cholinergic transmission, with a paradoxical excitation of cholinergic interneurons in response to activation of D2 receptors rather than the normal response of inhibition of firing activity that likely leads to enhanced acetylcholine release.63
More recently, they further
investigated the hypothesis that this abnormal cholinergic tone could disrupt synaptic plasticity in this DYT1 mouse model, and using cross-clamp electrophysiologic recordings found evidence of altered corticostriatal synaptic plasticity, and then further demonstrated that with pharmacologic normalization of striatal acetylcholine, normal plasticity could be fully restored in the transgenic mice. Conversely, when acetylcholine was pharmacologically increased, the plasticity abnormalities were seen in mice expressing normal torsinA and in non-transgenic controls. These findings support the notion that unbalanced cholinergic transmission plays a pivotal role in the abnormal synaptic plasticity of DYT1 dystonia, and also provide a clue to the ability of anticholinergic drugs to improve dystonia symptoms.64
Gamma-aminobutyric Acid
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter and is also important in shaping plastic responses of the CNS to somatosensory and other stimuli, including the maintenance and plasticity of cortical receptive fields. Drugs that potentiate GABA, such as benzodiazepines and baclofen, are modestly effective against dystonia symptoms. In animal studies, application of the GABA antagonist bicuculline to the motor cortex of monkeys produces abnormal movements similar to task-specific dystonia.65
Studies
measuring GABA levels in the cortex and striatum of patients with adult-onset primary dystonia found decreased GABA levels in cortical and subcortical regions contralateral to the dystonic limb.66
Treatment of Dystonia Pharmacologic Treatment
The medications that are most effective in the treatment of dystonia include anticholinergics (trihexyphenidyl), GABA agonists (baclofen and benzodiazepines), and dopaminergic agents. The effectiveness of these classes of drugs is consistent with the findings discussed above of alterations in dopminergic and cholinergic neurotransmission and reduced GABA-mediated inhibition in the dystonic CNS. Trihexyphenidyl is the first-line medication for treatment of childhood-onset primary generalized or segmental dystonia. Focal dystonia can be effectively treated with botulinum toxin injections. The toxin blocks the vesicular release of acetylcholine into the neuromuscular junction, causing temporary local chemodenervation and muscle weakness, reducing the excessive activity of the affected dystonic muscles. Botulinum toxin is the first-line treatment for cervical dystonia and blephorospasm, and is also frequently used to treat laryngeal dystonia (spasmodic
120
dysphonia), and focal limb dystonia. Aside from its direct peripheral effect of weakening affected muscles, botulinum toxin injections may also reduce afferent feedback from affected muscles, potentially normalizing the abnormal plastic changes in the CNS. Accordingly, DTI studies have shown normalization of white-matter abnormalities after botulinum toxin treatment in some dystonia patients,67
and in TMS
studies in cervical dystonia patients treated with botulinum toxin, abnormalities in hand motor cortex were reversed.68
Neurosurgical Treatment
Historically, dsytonia patients were treated surgically with pallidotomy or thalamotomy. These lesional surgeries provided significant benefit to dystonia symptoms in some cases, but also frequently caused permanent, disabling side effects, particularly dysarthria. Lesional surgeries have now been replaced by deep brain stimulation (DBS), which mimics a lesional effect but is reversible and adjustable. In the past two decades, DBS has come to the forefront as an important treatment option for patients with severe medically refractory primary dystonia. The current accepted target in DBS for dystonia is the globus pallidus (Gpi). DBS is thought to generate its clinical effect by inducing functional changes within the abnormal motor networks in dystonia and ultimately normalize pathologically overactive motor activation responses. In contrast to the rapid effect of DBS that occurs in Parkinson disease or essential tremor, the effect of DBS is typically delayed in dystonia, frequently taking weeks to months, consistent with the concept of dystonia as a disorder of sensorimotor connectivity that requires time to reorganize and accommodate changes along the entire motor circuit after DBS.
Two prospective, double-blinded, controlled trials of pallidal DBS in primary dystonia have been completed, with both demonstrating that it significantly reduces dystonia symptom severity and functional disability and improves quality of life.69,70
However, there is a distinct
variability in the response to DBS among dystonia patients, with some patients showing dramatic improvement whereas others benefit only modestly or not at all, and no single factor, including DYT1 gene status, has been found to be clearly predictive of response. A retrospective analysis found lack of fixed skeletal deformity, shorter duration of disease, and younger age at surgery to be the strongest predictors of response. The question of which patients with primary dystonia will have the best response to DBS therefore remains open and requires further investigation.
In secondary dystonia, data regarding the efficacy of DBS is scant and, with one recent exception, consists only of case reports or small cohorts with heterogeneous forms of secondary dystonia, with results ranging from no benefit to dramatic improvement. Most recently, Vidailhet et al. reported a multicenter prospective pilot study of bilateral pallidal DBS in 13 adults with dystonia-choreoathetosis cerebral palsy, and the response in these patients was again heterogeneous.71
The
question of whether DBS should be considered as a treatment option for secondary dystonia therefore also remains open.
In conclusion, dystonia is a neurofunctional disorder characterized by alterations at various levels and at multiple points along the sensorimotor circuit. Multiple causes can cause these disruptions
US NEUROLOGY
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