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Thirty-nine patients with the idiopathic blepharospasm-oromandibular dystonia syndrome are described. All presented in adult life, usually in the sixth decade; women were more commonly affected than men. Thirteen had blepharospasm alone, nine had oromandibular dystonia alone, and 17 had both. Torticollis or dystonic writer's camp preceded the syndrome in two patients. Eight other patients developed toritocollis, dystonic posturing of the arms, or involvement of respiratory muscles. No cause or hereditary basis for the illness were discovered. The evidence to indicate that this syndrome is due to an abnormality of extrapyramidal function, and that it is another example of adult-onset focal dystonia akin to spasmodic torticollis and dystonic writer's cramp, is discussed.
The clinical, biochemical, and pharmacologic responses to L-dopa were studied in 87 patients with Parkinson's disease. Eleven of the 87 patients had a long-duration response, 39 had a short-duration response, and 37 had a combination of both. Thirty-four of the 39 patients with short-duration response to L-dopa experienced a consistent and reproducible sequence of clinical and biochemical events after each dose, characterized by improvement of parkinsonism and a single phase of dystonia occurring during or shortly after the peak of dopa concentration in plasma and during maximal clinical improvement. We have called this the I-D-I- response, for Parkinsonism-Improvement-Dystonia-Improvement-Parkinsonism. The remaining five patients all had the onset of the disease at an unusually young age and showed a distinctly different response pattern consisting of a first phase of dystonia, before there was any improvement, followed by a phase of improvement without dystonia and then by a second phase of dystonia before the abrupt return of parkinsonism. We have called this the D-I-D response, for Parkinsonism-Dystonia-Improvement-Dystonia-Parkinsonsim. Dystonia occurs in the D-I-D- response when the concentration of dopa in plasma passes through a critical but relatively low level, whereas it remains absent as long as the concentration of dopa remains above that level. In the I-D-I- response, dystonia is avoided by keeping the plasma concentration of dopa low, in the D-I-D- response by keeping it high. It is postulated that in the D-I-D response postsynaptic depolarization blockade due to supramaximal stimulation of the neuronal system mediating dystonia occurs, whereas in the I-D-I response the postsynaptic members of the same neuronal population respond with excitation but not with depolarization blockade.
Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), the respective metabolites of dopamine and serotonin, were measured in ventricular fluid obtained from 20 patients with torsion dystonia at the time of ventriculography prior to thalamic surgery. The patients could be divided into two distinct types of dystonia--childhood-onset and adult-onset--which were identifiable on clinical and biochemical grounds. In the 14 patients with childhood-onset dystonia, the first symptom appeared in one limb in early childhood and the disease usually progressed rapidly. In the six patients with adult-onset dystonia, the first symptom usually appeared in axial muscles after adolescence and the disease progressed slowly. Ventricular fluid HVA levels were significantly lower in the patients with adult-onset dystonia than in those with childhood-onset dystonia. The differences suggest diminished dopaminergic activity, possibly secondary to nigrostriatal dysfunction, in adult-onset dystonia.
A family study of 32 patients with torsion dystonia has shown at least two forms of generalized dystonia with onset in childhood. These two forms, an autosomal dominant and an autosomal recessive, are clinically indistinguishable. There were at least three families and probably about six to eight patients with the autosomal recessive variety. The remaining nine to 11 patients with generalized childhood dystonia are thought, because of a probable paternal age effect, to be examples of new dominant mutations. Since fitness with childhood onset is 1/20 of normal, most childhood dominant cases appear sporadically. Most of the other 15 patients (12 with onset in adult life) appear to have a non-genetic torsion dystonia, although an example of a benign adult-onset dominant form associated with a tremor has been observed. It is concluded that there are at least two forms of genetic torsion dystonia, an autosomal recessive form with onset in childhood, which, on evidence from America, is particularly common in Ashkenazi Jews, and one or more dominant forms, with onset in childhood or adult life. The majority of adult-onset isolated cases of idiopathic torsion dystonia seem to be due to exogenous but unidentified causes.
Dystonia occurs frequently following administration of neuroleptic or antiemetic drugs. This acute manifestation is not likely to be a simple consequence of reduced dopaminergic activity, because it was never reported to occur following the use of drugs which deplete dopamine stores, like reserpine and tetrabenazine. Based on the fact that dopamine-beta-hydroxylase levels are frequently elevated in patients with the dominant form of torsion dystonia it is suggested that dystonia results from impairment of a normal dopaminergic-noradrenergic balance, in which noradrenergic tone preponderates. A relative norepinephrine hyperactivity may be caused by dopaminergic blockade (as occurs in drug-induced dystonia) or from enhanced release of norepinephrine (in idiopathic torsion dystonia).
The origins of dystonia musculorum deformans are now considered to be organic. However, misdiagnosis of dystonia as a functional psychiatric disorder--usually conversion reaction--has persisted. The present study describes personality traits as measured by the Minnesota Multiphasic Personality Inventory in 30 persons with dystonia and in a control group of 37 persons with cerebral palsy. The data, examined by diagnosis, level of disability, and sex, showed no differences for diagnostic groups or levels of disability. Males scored in the direction of greater psychopathology than did females. The male dystonics showed the highest elevations of MMPI scales of all the groups. Although only one person with dystonia musculorum deformans and none with cerebral palsy produced the profile usually associated with conversion reaction, 36% of all profiles showed two scales above a T score of 70. This finding suggested that young adults with a physically disabling disease may be at higher risk for developing maladaptive personality traits.
In this chapter, we have attempted to demonstrate that chronic manganese intoxication, in both animals and man, is a better model of dystonia than of Parkinson's disease. It is proposed that many of the monoamine and endocrine changes in dystonia may be the result of disturbances in manganese metabolism. A search for such modifications in human dystonia victims is presently underway. Preliminary studies indicate that head and pubic hair manganese concentrations are elevated in dystonia patients.
Among 1,152 psychiatric inpatients who received a phenothiazine, a butyrophenone, or a thioxanthene, 116 developed dystonia attributed to one or more of these drugs. The highest frequencies of dystonia occurred among recipients of haloperidol and the long-acting injectable fluphenazines. For all patients at risk, dystonia was more common in men and in younger patients. For chlorpromazine, high doses, male sex, and low age were each positively associated with dystonia.
INTRODUCTION: Pathogenic variants in KMT2B cause early-onset dystonia, but a mouse model that has undergone comprehensive, dystonia-oriented phenotyping is lacking. METHODS: We conducted detailed phenotyping on heterozygous Kmt2b constitutive knockout mice and wild-type littermates, assessing growth, neurobehavioural traits, motor coordination, sensorimotor gating, social behaviour and metabolic parameters, combined with striatal RNA sequencing. RESULTS: Kmt2b knockout mice of both sexes were viable but significantly smaller and lighter than littermate controls. Knockouts were hyperlocomotive in the open field and showed approximately two-fold larger acoustic startle responses; unexpectedly, prepulse inhibition was enhanced rather than reduced at all prepulse intensities. On the balance beam, knockouts crossed more slowly and paused more frequently; female knockouts also paused more on the ladder rung task. Frame-by-frame video analysis revealed a claw-like hindpaw posture characterized by abnormal inward flexion of the digits. Knockout mice spent less time investigating a novel conspecific, while social recognition memory remained intact. Striatal RNA sequencing confirmed reduction of Kmt2b transcript to approximately half of control levels and identified 177 differentially expressed genes, including Maob, encoding monoamine oxidase B; gene set enrichment analysis implicated neurodevelopmental, glial and mitochondrial processes. Nociception, vision, body-weight-adjusted grip strength, and clinical chemistry and haematological measures were largely unaffected. CONCLUSION: Heterozygous Kmt2b knockout mice show hyperlocomotion, altered sensorimotor gating, impaired motor coordination with dystonic-like paw posturing and reduced sociability, alongside a striatal transcriptomic signature implicating neurodevelopmental processes. The model mirrors aspects of human KMT2B-related dystonia and provides a platform for mechanistic study; environmental or pharmacological challenge may be needed to unmask overt dystonic features.
BACKGROUND: A growing number of identified genes increasingly reveal genetic overlaps between neurodevelopmental disorders and combined dystonia syndromes. CASE REPORT: We report a 61-year-old man with a neurodevelopmental disorder, mild ataxic signs and generalized dystonia who had been misdiagnosed with cerebral palsy for 40 years. Whole-exome sequencing identified a novel heterozygous pathogenic frameshift variant in TBL1XR1. DISCUSSION: TBL1XR1 variants are classically associated with Pierpont syndrome and autism spectrum disorder. Although movement disorders have been reported, this case suggests generalized dystonia as a possible additional manifestation. It highlights the value of retrospective genetic phenotyping and next-generation sequencing in adults with long-standing neurodevelopmental diagnoses.
In summary, then, without consideration of specific circuits or transmitter agents, one can conceive of a hypothetical model that involves both learning and the functional nature of the defect in torticollis and focal dystonia to describe the results obtained. The model must be further elaborated upon and tested, preferably in a quantitative manner. Naturally, the specific finding of a defective transmitter agent (e.g., GABA) such as described in parkinsonian syndrome (dopamine) or the interruption of a specific pathway that causes and improves a dyskinesia is desirable. In this chapter we have described the use of integrated EMG feedback for the treatment of focal dystonia or spasmodic torticollis. Although we have achieved significant results, it remains clear that further research in the treatment of these disorders is required. However, since this treatment does not require medication or surgery and the possibility for significant improvement is greater than 40%, it should be attempted in patients with focal dystonia or torticollis prior to other forms of therapy. SFT should be considered as a standard mode in the medical armamentarium used for the treatment of these disorders, either primarily or in conjunction with other forms of medical, surgical, and physical therapy.
Carbamazepine is an anticonvulsant most effective in treating complex partial and generalized tonic-clonic seizures. We have cared for three children in whom four episodes of dystonia proceeding to opisthotonus occurred in association with carbamazepine use. The patients, a 4-year-old with microcephaly and severe retardation, a 1-year-old with cerebral dysgenesis, and a 5-year-old with spastic quadriplegia and mild retardation, all had seizures unresponsive to multiple anticonvulsant combinations. In all three patients carbamazepine was introduced and gradually increased to a maximum dosage of 25 mg/kg of body weight per day. Dystonic symptoms began two to three weeks after introduction of therapy and subsided within three weeks after discontinuation. In one child, a second course of carbamazepine resulted in a return of the dystonia. The currently available clinical and neuropharmacologic data suggest that carbamazepine may be an antagonist of dopamine and that this property is responsible for the production of dystonia.
A study of the catecholamine excretion, their precursor DOPA and final metabolites--Homovaniline and vanilylphenylglycolic acid in torsion dystonia, detected certain changes which were different in patients with various clinical forms of the disease. On the basis of clinical and biochemical data 3 forms of torsion dystonia were distinguished: 1) with a prevalence in the clinical picture of muscle rigidity, leading to the development of pathological postures; 2) hyperkinetic forms and 3) mixed forms. In patients of the first group there was a decreased excretion of all catecholamines. On the basis of obtained data the conclusion is made that there is a drop in the intensity of the process of dophamine synthesis and an increase of its catabolism. In the hyperkinetic form, on the contrary, there is a tendency to an increase of dophamine synthesis. It is assumed that there is a drop in the intensity of the process of adrenaline synthesis and an increase of its catabolism. On the basis of biochemical heterogeneity of torsion dystonia the authors recommended different approaches in treating different forms of this disease. In a prevalent muscular rigidity the functions of the dophaminergic systems should be intensified: on the one hand, by administering precursors of dophamine L-DOPA, on the other--by inhibiting antagonistic activity with the aid of different cholinolytic preparations. In a hyperkinetic form a favorable effect is attained by preparations, inhibiting the dophaminergic activity (mainly preparations of the phenothiazine and butyrophenon series).
Taking as starging point three patients who unsuccessfully underwent both medical treatment and different neurosurgical interventions, the Authors discuss the problem of the dystonia musculorum deformans nosographic arrangement and its present therapeutical possibilities. They believe that the dystonia musculorum deformans must be considered, rather than as a syndrome, as a real disease, to be distinguished in particular from the various infantile dystonic syndromes and from spasmodic torticollis. In fact in these last morbid forms, at least from a neurosurgical standpoint, the therapeutical possiblities are not so uncertain as those of the dystonia musculorum deformans.
A girl from a Spanish Gypsy family developed idiopathic torsion dystonia when 12 years old. Parents were first cousins and both the pattern of clinical involvement and the rate of progression corresponded to that usually found in the autosomal recessive form of the disorder. Serum dopamin-beta-hydroxylase activity in the patient and close family members were also in keeping with this hereditary form. A nationwide inquiry failed to detect further cases of torsion dystonia among Gypsies, but revealed a relatively large number of recessively inherited disorders of the nervous system in this inbred, genetically isolated population. Thirty-six additional cases of torsion dystonia were collected from the general Spanish population, including four with a family history for this condition. The gene responsible for the recessive illness appears to be rare in many countries, explaining the sporadic nature of the disorder and its eventual appearance only in genetic isolates or after consanguineous matings.
The occurence of extranuchal dystonia, facial spasm, parkinsonian symptoms (facial masking, bradykinesia, rigidity), tremor and family history of tremor was tabulated in a group of 30 patients with IST. The incidence of extranuchal dystonia increased as severity of IST increased. There was a strong trend for severity of extranuchal dystonia to increase as severity of torticollis increased, which was significant (p less than 0.001). There was a similar trend for severity of facial spasm to increase with increasing severity of torticollis (p less than 0.025). Parkinsonian features were seen in 10 of 30 patients, and in three the diagnosis of Parkinson's disease could be entertained. Tremor was seen in 26 of 30 patients being mild in 12, moderate in 11, and severe in three. A family history of tremor was present in 16 of 28 cases for whom history was available (12 primary, four secondary relations). The results are most consistent with the hypothesis that IST is a variant of DMD with tremor as an integral part of the disease and tremor represents a forme of the disease in family members.
The study is related to a clinical and REG study of 387 patients with cerebral forms of neurocirculatory dystonia, proceeding against the background of normal, increased and decreased arterial pressure. These studies were performed in order to clarify the question of the state of cerebral hemodynamics in this form of vascular pathology. The study detected some general regularities of the changes of cerebral hemodynamics (an increase of the cerebral vascular tone, difficulties of the venous outflow, signs of vascular dystonia in the form of unstable curves and intrahemispheric asymmetry) and some traits in different types of neurocirculatory dystonia as well as some traits of semiotics.