Partial cytochrome b deficiency and generalized dystonia

An 18-year-old female had clinical features of idiopathic torsion dystonia with bilateral hypodense putaminal lesions on computed tomography. Mitochondrial encephalomyopathy was suspected because of persistent lactic acidemia and myopathy. Studies of oxidative metabolism on isolated skeletal muscle mitochondria revealed partial cytochrome b deficiency indicating a defect in the cytochrome b - c1 complex. This finding represents a unique, multisystem syndrome of progressive dystonia, putaminal degeneration, myopathy, and mitochondrial cytochrome b deficiency. Mitochondrial metabolic disorders may be a cause of torsion dystonia when other known associated factors are absent.     

Dopaminergic deficiency causes delayed visual evoked potentials in rats

Flash and pattern visual evoked potentials (VEPs) to two temporal frequencies of stimulation were studied in nineteen rats. The effect of a tyrosine hydroxylase inhibitor and of a dopamine receptor blocker on the VEP was explored in ten animals. Significant latency change occurred following injection of either drug, while only the hydroxylase inhibitor reduced the VEP amplitude. These changes were not caused by the anesthesia used in these experiments, although the same anesthetics in higher doses did depress VEP amplitudes. When dopamine blockade was followed by administration of apomorphine, a dopamine agonist, VEP delays could be partially reversed. Besides conduction defects of myelinated axons, synaptic malfunction may also cause delays in sensory evoked potentials.     

Animal models of generalized dystonia

Dystonia is a prevalent neurological disorder characterized by abnormal co-contractions of antagonistic muscle groups that produce twisting movements and abnormal postures. The disorder may be inherited, arise sporadically, or result from brain insult. Dystonia is a heterogeneous disorder because patients may exhibit focal or generalized symptoms associated with abnormalities in many brain regions including basal ganglia and cerebellum. Elucidating the pathogenic mechanisms underlying dystonia has therefore been challenging. Animal models of dystonia exhibit similar heterogeneity and are useful for understanding pathogenesis. The neurochemical and neurophysiological abnormalities in rodents with idiopathic generalized dystonia suggest that dysfunctional output from basal ganglia, cerebellum, or from multiple systems is the cause of motor dysfunction. Findings from drug- or toxin-induced dystonia in rodents and nonhuman primates mirror the genetic models. The parallels between dystonia in humans and animals suggest that the models will continue to prove useful in determining pathogenesis. Furthermore, detailed characterization of the existing models of dystonia and the development of new models hold promise for the identification of novel therapeutics.     

Intrathecal baclofen for generalized dystonia

The aim of this study was to evaluate the effects of intrathecal bacolfen (ITB) on patients with severe generalized dystonia. Eighty-six participants ranging in age from 3 to 42 years (median age 13 years) with generalized dystonia refractory to oral medications were offered treatment with ITB. Dystonia was associated with cerebral palsy in 71% of participants. Response to ITB was tested by continuous infusions in 72%, and by bolus injections in 17% of participants who had both dystonia and spasticity. Ninety-one percent of participants responded to the screening infusion and 93% to the bolus injections. Pumps were implanted in 77 participants. Dystonia scores at 3, 6, 12, and 24 months were significantly decreased (p<0.005) compared with baseline scores. Dystonia scores were significantly lower in those with intrathecal catheters positioned at T4, or higher than in those with catheters at T6 or lower (p=0.005). Ninety-two percent of participants implanted with a pump retained their responses to ITB during a median follow-up of 29 months. Patient questionnaires indicated that quality of life and ease of care improved in 86% and speech improved in 33%. Side effects of ITB occurred in 26% of participants. Surgical complications occurred in 38% and included CSF leaks, infections, and catheter problems. ITB is probably the treatment of choice for generalized dystonia if oral medications are ineffective.     

Bilateral pallidotomy for generalized dystonia.

OBJECTIVE: To evaluate the efficacy and safety of bilateral pallidotomies in five patients with generalized dystonia. BACKGROUND: Generalized dystonias are frequently a therapeutic challenge, with poor responses to pharmacological treatment. GPi (globus pallidus internus) pallidotomies for Parkinson's disease ameliorate all kinds of dyskinesias/dystonia, and recent studies reported a marked improvement of refractory dystonias with this procedure. METHODS: Five patients with generalized dystonias refractory to medical treatment were selected; one posttraumatic and four idiopathic. The decision to perform bilateral procedures was based on the predominant axial involvement in these patients. Dystonia severity was assessed with the Burke-Fahn-Marsden Dystonia Scale (BFM). Simultaneous procedures were performed in all but one patient, who had a staged procedure. They were reevaluated with the same scale (BFM) by an unblinded rater at 1, 2, 3, 30, 60, 90, 120 and 180 days post-operatively. RESULTS: The four patients with idiopathic dystonia showed a progressive improvement up to three months; the patient with posttraumatic dystonia relapsed at three months. One patient had a marked improvement, being able to discontinue all the medications. A mean decrease in the BFM scores of 52,58% was noted. One patient had a trans-operative motor seizure followed by a transient hemiparesis secondary to rack hemorrhage; other was lethargic up to three days after the procedure. CONCLUSIONS: Our results show that bilateral GPi pallidotomies may be a safe and effective approach to medically refractory generalized dystonias; it can also be speculated that the posttraumatic subgroup may not benefit with this procedure.     

Depression in focal,segmental and generalized dystonia

Dystonia causes body disfigurement in the majority of those affected. Our aim was to test the hypothesis that low self-esteem resulting from the sense of disfigurement is an important component of self-reported depression in focal, segmental and generalized dystonia. Questionnaires to assess self-reported depression, self-esteem, body concept, disfigurement, disability and quality of life were completed by 329 community based dystonia patients. Moderate to severe depression was reported by 30 %. Self-reported depression had a strong somatic component, but patients also showed a specific concern with self-image. Extent of dystonia, body parts affected and marital status influenced self-reported depression in dystonia. Selfesteem, body concept, disfigurement and quality of life emerged as factors which accounted for the variance of self-reported depression in dystonia. These results suggest that in dystonia, disfigurement, negative body concept, low self-esteem, and the impact of the disease on quality of life make important contributions to depression. However, longitudinal followup is required to firmly establish the direction of causality between depression and these psychosocial variables in dystonia.     

Treatment of generalized tardive dystonia with clozapine

Tardive dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures, associated with prolonged exposure to antipsychotics. We report a case of a 35-year-old patient with schizophrenia who developed a generalized form of tardive dystonia after switching of clozapine to risperidone treatment that persisted after switch to olanzapine and during the period while treatment with an antipsychotic was discontinued. It was successfully managed with reintroduction of clozapine. The case may represent the first report of generalized tardive dystonia while taking risperidone. The possible pathophysiological bases of the disorder are discussed. The goal of our report is to emphasize that an adequate trial of clozapine is a worthwhile option in the cases of tardive dystonia, even where discontinuation of antipsychotics was unsuccesful.     

Early cinematographic studies of generalized dystonia.

Among movement disorders, dystonia is a particularly complex phenomenon and difficult to describe. For this reason, cinematographic documents were particularly important to the establishment of this disorder within the neurological nosology. The seminal 1944 article on dystonia by E. Herz anchored its arguments in moving film documentation, published with frame-by-frame demonstrations of dystonic patients. Although the original films that comprised the basis of this article have not been located, two related contemporaneous films, one by Herz in association with T.J. Putnam, and one by S.P. Goodhart and B.H. Balser, have been located. Incorporating standard and several innovative filming techniques, these films and their accompanying text material capture the particular movements of dystonia, revealing the anatomical patterns of the twisting spasms, and emphasize their action exacerbation. The films demonstrate the variety of dystonic movements appreciated during this period, consider psychogenic, postencephalitic, and hereditary forms, and refer to the treatment of dystonia by surgery and plaster casts.     

Globus pallidus internus pallidotomy for generalized dystonia

The authors present a young boy with severe generalized dystonia treated with bilateral simultaneous pallidotomy. Microelectrode recordings with the patient under propofol anesthesia showed that the mean discharge rate of globus pallidus internus (GPi) neurons was between 21 and 31 Hz. This contracts sharply with the mean GPi neuronal firing rates of approximately 80 Hz that are characteristic of Parkinson's disease. The patient had no immediate benefit from surgery, but a progressive improvement in both axial and limb dystonia began within 3 days. The Burke-Fahn-Marsden scores were 75 (maximum possible = 120) at baseline, 52 at 5 days, and 16 at 3 months after surgery. The mechanism of action of pallidotoy for dystonia and the reasons for the delayed and progressive improvement are unknown. Nevertheless, the magnitude of the improvement and the safety of the procedure in this one patient warrant a careful evaluation of pallidotomy for dystonia.     

双侧丘脑底核电刺激治疗原发性肌张力障碍

目的 研究双侧丘脑底核（STN）脑深部电刺激术（DBS）治疗原发性肌张力障碍的长期疗效：方法 比较15例行舣侧STN—DBS治疗的原发性肌张力障碍患者，手术前后的Burke—Fahn—Marsden肌张力障碍评分改善程度及长期改善效果。结果 15例原发性肌张力障碍患者中12例在开启刺激器后症状即刻得到部分缓解，以不自主运动、异常姿势及躯体的扭转改善为主，其中9例在刺激1—3d后、3例刺激1，周后改善75％以上，6个月后平均改善92％；1例在2个月后开始改善，6个月后改善90％以上；2例在1个月开始出现轻微改善，6个月后改善了76％：15例患者的长期随访结果显示其疗效稳定，经过1—3次程控后不需经常调整刺激参数：所有患者未出现手术相关并发症及永久性副作用。结论 双侧丘脑底核脑深部电刺激术对原发性肌张力障碍有显著的治疗效果，且疗效持久、稳定，无并发症及永久性副作用。比较GPi—DBS而言，STN—DBS起效快、最件刺激化点及参数易于确定、刺激参数水平低、长期疗效稳定，可能是原发性肌张力障碍DBS治疗的理想靶点。     

Levetiracetam for the treatment of generalized dystonia

We report the case of a woman with generalized dystonia whose symptoms improved with the use of levetiracetam. Improvements were noted in blepharospasm, cervical, and truncal dystonia. The patient has been on LEV for a total of 20 weeks, and has experienced sustained improvement of symptoms.     

Secondary generalized dystonia without basal ganglia damage

We report the case of a woman who developed generalized dystonia, severe cognitive deficits and dysphagia following an overdose of the hypoglycaemic drug, sulphonylurea. The MRI reveals frontal and temporal lobe atrophy, but no evidence of damage to the basal ganglia. This case adds to the small number of previously reported cases with secondary dystonia seemingly due to cortical rather than subcortical damage.     

Mexiletine in the treatment of torticollis and generalized dystonia

Mexiletine is an antiarrhythmic drug that has been reported to exert antidystonic properties. We performed an open-label study to collect further evidence of the antidystonic effect of mexiletine in spasmodic torticollis (ST) and to evaluate its possible use in generalized dystonia. We administered mexiletine to six patients with dystonia (three with generalized dystonia and three with ST) who had failed to respond to previous pharmacotherapy. The drug was started at a dose of 200 mg/d by mouth and increased up to a maximum dose of 800 mg/d. Patients were evaluated at regular intervals over a 6-week period with use of the Fahn & Marsden Dystonia Scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and videotaped. At the end of the trial, the videotapes were reviewed and scored by a blind observer. Patients were then followed for at least 1 year and evaluated every 3 months at the dose reached during the study period. No adverse effects were reported in five patients; in one patient, dizziness developed at the dosage of 800 mg/d, requiring a reduction of the dose. At the end of a 6-week period, a significant improvement in the rating scale for dystonia and in videotape ratings was observed after mexiletine treatment (p < 0.01). Our data indicate that mexiletine is a useful drug in dystonia treatment.     

Pyruvate dehydrogenase deficiency presenting as dystonia in childhood

Two individuals with pyruvate dehydrogenase (PDH) deficiency due to missense mutations in the gene for the E1alpha subunit (PDHA1) presented during childhood with dystonia. The first patient, a male, presented at age 4 years with dystonia affecting the lower limbs, which responded to treatment with combined carbidopa and levodopa. The second patient, a female, was first investigated at age 6 years because of a dystonic gait disorder. In both patients, the main clue to the biochemical diagnosis was a raised concentration of lactate in the cerebrospinal fluid. PDH activity was significantly reduced in cultured fibroblasts in both cases. Dystonia is a previously unrecognized major manifestation of PDH deficiency and is of particular interest as the mutations in the PDHA1 gene in these patients have both been identified previously in individuals with typical presentations of the condition.     

KMT2B rare missense variants in generalized dystonia

Background : Recently a novel syndrome of childhood‐onset generalized dystonia originating from mutations in lysine‐specific methyltransferase 2B (KMT2B) has been reported. Methods : We sequenced the exomes of 4 generalized dystonia‐affected probands recruited from a Prague movement disorders center (Czech Republic). Bioinformatics analyses were conducted to select candidate causal variants in described dystonia‐mutated genes. After cosegregation testing, checklists from the American College of Medical Genetics and Genomics were adopted to judge variant pathogenicity. Results : Three novel, predicted protein‐damaging missense variants in KMT2B were identified (p.Glu1234Lys, p.Ala1541Val, p.Arg1779Gln). Meeting pathogenicity criteria, p.Glu1234Lys was absent from population‐based controls, situated in a key protein domain, and had occurred de novo. The associated phenotype comprised adolescence‐onset generalized isolated dystonia with prominent speech impairment. Although linked to a similar clinical expression, p.Ala1541Val and p.Arg1779Gln remained of uncertain significance. Conclusions : Rare missense variation in KMT2B represents an additional cause of generalized dystonia. Application of sequence interpretation standards is required before assigning pathogenicity to a KMT2B missense variant. © 2017 International Parkinson and Movement Disorder Society     

Atlantoaxial dislocation in a child with generalized primary dystonia

We describe a 10-year-old boy with generalized dystonia who developed spastic quadriparesis within 1 month of dystonia onset. On neuroimaging, a craniovertebral junction anomaly with atlantoaxial dislocation and compressive myelopathy was present. We postulate that dystonia involving the neck led to atlantoaxial dislocation in this child with a craniovertebral junction anomaly.