Pallidal deep brain stimulation for DYT6 dystonia.

BACKGROUND: Mutations of the THAP1 gene were recently shown to underlie DYT6 torsion dystonia. Little is known about the response of this dystonia subtype to deep brain stimulation (DBS) at the internal globus pallidus (GPi). METHODS: Retrospective analysis of the medical records of three DYT6 patients who underwent pallidal DBS by one surgical team. The Burke-Fahn-Marsden Dystonia Rating scale served as the primary outcome measure. Comparison is made to 23 patients with DYT1 dystonia also treated with GPi-DBS by the same team. RESULTS: In contrast with the DYT1 patients who exhibited a robust and sustained clinical response to DBS, the DYT6 patients exhibited more modest gains during the first 2 years of therapy, and some symptom regression between years 2 and 3 despite adjustments to the stimulation parameters and repositioning of one stimulating lead. Microelectrode recordings made during the DBS procedures demonstrated no differences in the firing patterns of GPi neurons from DYT1 and DYT6 patients. DISCUSSION: Discovery of the genetic mutations responsible for the DYT6 phenotype allows for screening and analysis of a new homogeneous group of dystonia patients. DYT6 patients appear to respond less robustly to GPi-DBS than their DYT1 counterparts, most likely reflecting differences in the underlying pathophysiology of these distinct genetic disorders. CONCLUSIONS: While early results of pallidal DBS for DYT6 dystonia are encouraging, further research and additional subjects are needed both to optimise stimulation parameters for this population and to elucidate more accurately their response to surgical treatment.

[Case of DYT1 dystonia (early-onset torsion dystonia) showing long-term focal dystonia in the arm].

DYTI dystonia (DYT1-D, early-onset torsion dystonia) is caused by a GAG deletion in the DYTI gene. Here we report a girl with child-onset familial DYT1-D showing localized arm involvement. The patient developed postural and action dystonia in the right and left arms at 7 and 9 years, respectively. She was misdiagnosed as hysteria due to lack of abnormalities on laboratory tests. At 11 years of age she was introduced to our clinic. Increased muscle tonus and dystonic discharges seen on surface electromyogram in the right arm and the sternocleidomastoid muscle led to the diagnosis of dystonia. A GAG deletion in the DYTI gene was confirmed in the patient, her healthy father and paternal grandfather with torsion dystonia. Titration of levodopa resulted in the fluctuation of her arm dystonia. Combined therapy by levodopa and trihexyphenidyl relieved postural dystonia in the right arm but not action dystonia in the left. Both types of dystonia in the right and left arms were well ameliorated by the additional increase of levodopa. Somatosensory evoked potentials demonstrated abnormal premovement gating. The latency and accuracy of the amplitude were disturbed in visually guided saccadic eye movement. Now at more than 11 years after onset, the patient has not shown torsion or involvement of the lower extremities. Most DYT1-D patients are refractory to medication and early surgical intervention is recommended. However, the presence of DYT1-D patients showing a milder disease course should also be considered.

[Continuous infusion of baclofen and an antibiotic for treating meningitis related to refilling of an intrathecal infusion pump reservoir]. / Infusión continua de baclofeno con antibiótico para el tratamiento de meningitis asociada a relleno del reservorio de la bomba de perfusión intratecal.

Baclofen via intrathecal infusion pump is a widely used treatment severe spasticity. Complications are rare and usually mild, though they can also be serious. The sudden discontinuation of intrathecal baclofen may have significant adverse effects. We report the case of a 59-year-old man with chronic spasticity and torsion dystonia who developed meningitis due to Staphylococcus epidermidis due to contamination of the intrathecal, infusion pump reservoir during refilling. It was decided to treat the patient by administering vancomycin through the pump, together with the baclofen. We believe that changing the intrathecal perfusion pump is not necessary as the first measure to take in these cases. Combined infusion of baclofen and an antibiotic through the pump makes it possible to maintain antispastic treatment, sterilize the pump reservoir and tubes, and effectively treat infections that develop during use of these systems.

Dystonia: genetics and treatment update.

BACKGROUND: Dystonia refers to a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Although age at onset, anatomic distribution, and family history are essential elements in the evaluation of dystonia, new classification increasingly relies on etiologic and genetic data. In recent years, much progress has been made on the genetics of various forms of dystonia and its pathophysiology underlying the clinical signs. The treatment of dystonia has continued to evolve to include newer medications, different forms of botulinum toxin, and various surgical procedures. REVIEW SUMMARY: In this article, the author reviewed and summarized the history of dystonia, its evolving classification, and recent genetic data, as well as its clinical investigation and treatment. CONCLUSIONS: Recent advances in molecular biology have led to the discovery of novel dystonia genes and loci, updating classification schemes, and better understanding of underlying pathophysiology. Treatment strategies for dystonia have significantly been updated with the introduction of different forms of botulinum toxin therapy, new pharmacologic agents, and most recently pallidal deep brain stimulation. A systematic approach to the diagnosis and treatment evaluation of dystonic patients provides optimal care for long-term management.

Dystonia musculorum deformans: implications of therapeutic response to levodopa and carbamazepine.

Sporadic, autosomal recessive and dominant forms of dystonia musculorum deformans have been recognized. This communication reports the results of treatment of six patients with this condition. Two patients with the recessive form responded to levodopa therapy. Three patients who responded to carbamazepine therapy probably have the dominant form. In one patient, response to carbamazepine therapy was equivocal. It is suggested that such therapeutic responsiveness may reflect underlying biochemical differences in the recessive and dominant forms of the disease.

Serum trihexyphenidyl levels in the treatment of torsion dystonia.

Using a radioreceptor technique, we assayed serum trihexyphenidyl levels in patients with dystonia being treated chronically with high dosage. We found a significant correlation between total daily dose and the daily lowest (trough) serum levels. There was no relationship between serum levels and therapeutic response or toxicity. Toxicity was more closely related to patient age than to serum level. Although levels may be useful to monitor patient compliance, they cannot be used to judge adequacy of therapy.

Quantitative evaluation of the effects of L-dopa in torsion dystonia: a case report.

We used electrophysiologic methods in the diagnosis of torsion dystonia and the evaluation of therapy in a 7-year-old child. Electromyographic (EMG) activity patterns in five leg muscles were recorded during specific voluntary and passive movements as well as during gait. We found patterns of coactivation in leg muscles in walking or isolated movements, and a shortening reaction was seen in the tibialis anterior. These findings in combination with clinical observations led to the diagnosis of torsion dystonia and the choice of L-dopa therapy. Beneficial effects of therapy were assessed by the same methods.

Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl.

We studied trihexyphenidyl in the treatment of torsion dystonia in a prospective, double-blind crossover protocol. Thirty-one patients completed the protocol. Twenty-two (71%) had a clinically significant response. After a mean follow-up of 2.4 years, 68% of patients continued to take trihexyphenidyl, and 42% continued to show a considerable or dramatic benefit. The 30-mg dose used was generally well tolerated. High-dosage trihexyphenidyl therapy is effective in the management of torsion dystonia.

Lisuride in dystonia.

Lisuride hydrogen maleate, 0.4 to 5 (mean, 3) mg/d, was given orally to 42 subjects with various types of dystonia. In seven of the eight patients who improved (one with segmental dystonia, one with myoclonic dystonia, two with spasmodic torticollis, two with cranial dystonia, and two with tardive dystonia), the response was confirmed by double-blind placebo substitution. No patients with a suspected structural brain lesion improved. There was no consistent pattern of response among those patients with different forms of idiopathic (primary) dystonia. Lisuride improved some patients, but had no effect on other, apparently identical, patients.

[Long-term treatment with L-DOPA in a case of torsion dystonia (authors transl)]. / L-DOPA-Langzeitbehandlung einer Torsionsdystonie

A 36-year old woman had been able to move from place to place only by crawling until 1971 after she had been treated with L-DOPA, the dose of which was increased to a maximum of 2.5 g daily. Within 4 weeks there was a diminution of her increased muscle tone and she experienced a dramatic improvement in her daily living activities, being able to walk without assistance for the first time in 20 years. This improvement has continued with a daily maintenance dose of 1.25 g. For patients with torsion dystonia, where the so-called myostatic component preponderates, cautious application of L-DOPA seems to be justified and further clinical studies are suggested.

Dystonia update.

Dystonia is a syndrome of sustained muscle spasms of presumed central nervous system origin. Recent advances in molecular biology have permitted clearer understanding of the genetics of various forms of dystonia and suggest pathophysiological deficits at the origin of the clinical signs. Treatment has involved centrally-acting drugs, specifically the anticholinergic medications, as well as peripherally acting agents that block neuromuscular transmission (botulinum toxin). Some forms of dystonia are particularly responsive to levodopa. A systematic approach to the diagnostic and treatment evaluation of dystonic patients permits optimal care for long-term management.

Effect of supplemental ascorbic acid in a case of torsion dystonia.

Determinations of various catecholamines and their metabolites have been performed on 24-hr urine collecions obtained from a patient with torsion dystonia and compared to values obtained in a control population. This study was initiated following significant symptomatic worsening by the patient with supplemental ascorbic acid at a dosage of 2 g/day. Compared to base-line values, there resulted no significant alteration in urinary excretion of DOPA, dopamine, norepinephrine, epinephrine, or VMA for either the patient or a group of controls, receiving 1 g/day vitamin C. MHPG is the glycol metabolite of norepinephrine, and is produced both in central and systemic tissues, whereas VMA is not synthesized in brain. The MHPG excretion for the patient increased 150% with supplemental ascorbate, whereas the control individuals demonstrated a mean increase of 19.6%. It is possible that the symptomatic worsening by the patient and the increased excretion of MHPG in response to supplemental ascorbic acid are causally related. Ascorbic acid affects catecholamine biosynthesis at two metabolic loci; it is the necessary cofactor for dopamine-beta-hydroxylase and, by maintaining biopterin in reduced form, facilitates tyrosine hydroxylase holoenzyme activity. Thus, the vitamin may have effected increased central synthesis or turnover of norepinephrine, or both, with resultant clinical worsening.

Involuntary movement disorders.

Excluding surgical procedures, this article focuses on clinical pharmacotherapeutic approaches to treatment of parkinsonism and tremor, chorea, dystonia, tic, and tardive dyskinesia.

Post-traumatic cervical dystonia: a distinct entity?

BACKGROUND/OBJECTIVE: The incidence of head/neck trauma preceding cervical dystonia (CD) has been reported to be 5-21%. There are few reports comparing the clinical characteristics of patients with and without a history of injury. Our aim was to compare the clinical characteristics of idiopathic CD (CD-I) to those with onset precipitated by trauma (CD-T). METHODS: We evaluated 114 consecutive patients with CD over a 9-month period. All patients were interviewed using a detailed questionnaire and had a neurological examination. Their clinical charts were also reviewed. RESULTS: Fourteen patients (12%) had mild head/neck injury within a year preceding the onset of CD. Between the two groups (CD-I and CD-T), the gender distribution (F:M of 3:2), family history of movement disorders (32% vs. 29%), the prevalence of gestes antagonistes (65% vs. 64%), and response to botulinum toxin were similar. There were non-specific trends, including an earlier age of onset (mean ages 43.3 vs. 37.6), higher prevalence of neck pain (86% vs. 100%), head tremor (67% vs. 79%), and dystonia in other body parts (23% vs. 36%) in CD-T. CONCLUSIONS: CD-I and CD-T are clinically similar. Trauma may be a triggering factor in CD but this was only supported by non-significant trends in its earlier age of onset.

[Dystonia musculorum deformans. Favorable effect of bromocriptine]. / Dystonia musculorum deformans. Effet favorable de la bromocriptine.

A 25 year-old woman suffered from a severe dystonia musculorum deformans since the age of 14. No similar cases were recorded in the family. Examination showed torsion spasm and a cogwheel phenomenon in both superior limbs. Signs disappeared on bromocriptine 22,5 mg/day then reappeared when dosages where progressively reduced. With 12.5 mg/day after 1 year of treatment, the patient leads a normal life including university studies.

[Movement disorders: dystonias which are apparently psychosomatic. Torsion dystonias]. / Movimientos anormales: distonías aparentemente psicosomáticas. Distonías de torsión.

In neuropediatric clinical practice, disorders of movement include a wide diversity of conditions, amongst which the dystonias are uncommon in our practice, although they have to be considered amongst the possible diagnoses in some cases. The great variety of clinical symptoms and age of onset together with the nonspecific, erratic clinical course make diagnosis difficult. Some clinical pictures of genuine torsion disorders may be confused with hysterical conversion disorders, somatizations or Munchausen's syndrome. Diagnosis requires clinical knowledge of both conditions--torsion dystonia as opposed to hysteria or a conversion reaction--and considerable ability and experience. Genetics and molecular studies have helped to clarify some difficult diagnostic problems and facilitated both diagnosis and treatment. In a diagnostic video session we show the case of a seven year old boy who initially presented with a dystonic disorder. There was some doubt as to the aetiology and different types of treatment were given by different specialists. The true diagnosis was reached after molecular genetic studies.

[Recessive dopa-responsive form of dystonia due to a mutation of the tyrosine hydroxylase gene]. / Dystonie dopa-sensible forme récessive mutation du gène de la tyrosine-hydroxylase.

The cause of Dystonia Musculorum Deformans (DMD) is most frequently unknown, therefore the treatment can only be symptomatic and often disappointing. In 1971 we reported the first two cases of recessive dopa-responsive dystonia, simulating a severe form of idiopathic DMD, however remarkably well reacting to levodopa treatment. We found that the first above mentioned two cases are related to mutations in the tyrosine hydroxylase gene itself in the chromosome 11p. An other variety which is dominant, with marked diurnal fluctuation, is due to mutations of a cofactor of the tyrosine hydroxylase, located in chromosome 14q. Consequently a trial of dopa treatment should be given in all diseases evoking a DMD diagnosis. Further more it is possible to confirm the diagnosis by a genetic inquiry.

[Familial dystonia: a case of idiopathic torsion dystonia]. / Dystonia rodzinna--opis przypadku samoistnej dystonii torsyjnej (SDT).

A 43 year old man suffered from the involuntary movements since 10-th year of age. Those movements, initially mild, have progressed in the course of the disease. In the neurological examination the dystonic involuntary movements of the neck, trunk and limbs, more expressed on the right side, were observed. The laboratory findings were normal, except the level of dopamine beta-hydroxylase, which was increased. Similar results were observed also in the closest relatives of our patient. After the treatment with high doses of L-Dopa we achieved a considerable decrease of the symptoms.

[Involuntary movements as a complication of treatment of extrapyramidal disorders with L-dopa]. / Ruchy mimowolne jako powiklanie l-dopa terapii chorób ukladu pozapiramidowego.

The frequency of dyskinesias connected with L-DOPA treatment of certain extrapyramidal system diseases was studied. Among 111 studied patients with Parkinson's disease drug-induced dyskinesias were observed in 56 cases (that is 50% of the treated patients) while in the group of other extrapyramidal system diseases (torsion dystonia, Hallervorden-Spatz disease, Huntington's chorea with increased muscular tonus) they were observed in only 8 cases (of 73 treated ones - about 11%). Two groups of patients with Parkinson's disease were isolated - differing in the susceptibility to dyskinesia development: those susceptible to dyskinesia which developed nearly immediately after starting treatment, and those non-susceptible, in whom dyskinesia appeared only after years of treatment. The pathomechanism of drug-induced dyskinesia development in these groups is discussed.

[Functional state of non-specific brain systems in dystonia musculorum deformans]. / O funktsional'nom sostoianii nespetsificheskikh sistem mozga pri deformiruiushchei myshechnoi distonii.

The paper deals with the results of an electropolygraphical study of night-sleep structure, as well as a clinical and experimental-psychological study of 27 patients with deforming muscular dystony. The quantitative and qualitative characteristics of functional shifts in different links of the nonspecific system in the known clinical forms and at different stages of the disease are given. The data were obtained with the aid of correlational statistical methods and were used for a clinico-physiological analysis of the syndrome of deforming muscular dystony. It is demonstrated that changes of a functional state of the nonspecific brain systems correlate with motor, emotional-personal vegetative and electroencephalographical manifestations of deforming muscular dystony.