Pain processing in functional and idiopathic dystonia: An exploratory study

Background : Pain is often experienced by patients with functional dystonia and idiopathic cervical dystonia and is likely to be determined by different neural mechanisms. Objective : In this exploratory study, we tested the sensory‐discriminative and cognitive‐emotional component of pain in patients with functional and idiopathic dystonia. Methods : Ten patients with idiopathic cervical dystonia, 12 patients with functional dystonia, and 16 age‐ and sex‐matched healthy controls underwent psychophysical testing of tactile and pain thresholds and pain tolerance. We delivered electrical pulses of increasing intensity to the index finger of each hand and the halluces of each foot. Pain threshold and pain tolerance were respectively defined as the (1) intensity at which sensation changed from unpainful to faintly painful and (2) intensity at which painful sensation was intolerable. Results : No differences were found between the three groups for tactile and pain thresholds assessed in hands and feet. Pain tolerance was significantly increased in all body regions only in functional dystonia. Patients with continuous functional dystonia had higher pain tolerance compared to subjects with paroxysmal functional dystonia and idiopathic cervical dystonia. There was no correlation between pain tolerance and pain scores, depression, anxiety, disease duration, and motor disability in both groups. Conclusions : Patients with functional dystonia have a dissociation between the sensory‐discriminative and cognitive‐emotional components of pain, as revealed by normal pain thresholds and increased pain tolerance. Abnormal connectivity between the motor and limbic systems might account for abnormal pain processing in functional dystonia. © 2018 International Parkinson and Movement Disorder Society     

A 9-year review of dystonia from a movement disorders clinic in Singapore

The clinical features of dystonia have not been evaluated in Southeast Asia. We therefore investigated the clinical spectrum and characteristics of dystonia in Singapore, a multi-ethnic Southeast Asian country comprising 77% Chinese, 14% Malays, and 8% Indians. We identified all dystonia patients from the Movement Disorders database and Botulinum Toxin clinic between 1995 and November 2004. Their medical records were reviewed to verify the diagnosis of dystonia and obtain demographic and clinical data using a standardized data collection form. A total of 119 (73%) patients had primary dystonia whilst 45 (27%) had secondary dystonia. There were 77% Chinese, 9% Malays, and 8% Indians. The most common focal dystonia were cervical dystonia (47%), writer's cramp (32%), and blepharospasm (11%). There was no significant difference in the distribution of dystonia between the different races. Males were noted to have earlier onset of dystonia overall. There was a significant male predominance in primary dystonia overall (M:F 1.6:1, P=0.008) and in the subgroup of focal dystonia (M:F 1.6:1, P=0.037). This contrasts with previous studies that found a female predominance. The role of genetic, hormonal, and environmental factors and their interactions need to be investigated to better understand the gender differences in the occurrence of dystonia.     

High risk neurological gait syndrome and vascular dementia

Summary We defined a ‘high-risk neurological gait’ (HRNG) syndrome based on presence of any one of hemiparetic, frontal, and unsteady gaits, and examined its validity to predict vascular dementia (VD) over 3 and 5 years in 399 nondemented older adults, age 75 and over. Cox analysis was used to estimate hazard ratios (HR) for VD adjusted for potential confounders. At baseline, 54 subjects had HRNG. 14 subjects developed VD over 3 years and 25 by 5 years. HRNG predicted risk of VD within the first three (HR 3.3, 95% CI 1.8–5.9) and five years (HR 2.7, 95% CI 1.7–4.2). Including executive dysfunction (Digit symbol scores <16) improved validity; subjects with HRNG and executive dysfunction (HR 12.5, 95% CI 5.5–28.4) or either (HR 5.9, 95% CI 3.6–9.7) had higher risk of VD over five years. Diagnosing HRNG is a clinically relevant approach to identifying older adults at high risk of VD over short intervals.     

Lower limb involvement in adult‐onset primary dystonia: frequency and clinical features

Background and purpose: Despite the growing number of reports describing adult‐onset primary lower limb dystonia (LLD) this entity has never been systematically evaluated in the general population of patients with primary adult‐onset dystonia. Methods: From outpatients with adult‐onset primary dystonia attending nine Italian University centres for movement disorders we consecutively recruited 579 patients to undergo a standardized clinical evaluation. Results: Of the 579 patients assessed, 11 (1.9%) (8 women, 3 men) had LLD, either alone (n = 4, 0.7%) or as part of a segmental/multifocal dystonia (n = 7, 1.2%). The age at onset of LLD (47.9 ± 17 years) was significantly lower than the age at onset of cranial dystonias (57.9 ± 10.7 years for blepharospasm, and 58.9 ± 11.8 years for oromandibular dystonia) but similar to that of all the other adult‐onset primary dystonias. The lower limb was either the site of dystonia onset (36.4%) or the site of dystonia spread (63.6%). In patients in whom LLD was a site of spread, dystonia seemed to spread following a somatotopic distribution. Only one patient reported a recent trauma involving the lower limb whereas 36.4% of the patients reported pain at the site of LLD. Only 64% of our patients needed treatment for LLD, and similarly to previously reported cases, the most frequently tried treatments was botulinum toxin and trihexyphenidyl. Conclusion: The lower limb is an uncommon but possible topographical site of dystonia in adulthood that should be kept in consideration during clinical evaluation.     

An unusual case of rhythmic movement disorder

Rhythmic movement disorder is one of the sleep-wake transition disorders listed in the International Classification of Sleep Disorders. According to this classification, the condition commonly occurs in infants and toddlers, and persistence beyond 4 years of age is unusual. Recently, we encountered a case in which rhythmic movement disorder persisted up until the age of 12 years with spikes registering on the sleep electroencephalogram. Epileptic seizure was ruled out because of the characteristic rolling movement, absence of any other epileptic symptoms (e.g. vocalization and tonic-clonic seizure) and cessation as a result of removal of the blanket.     

Genetic classification and molecular mechanisms of primary dystonia*★

BACKGROUND： Primary dystonia is a heterogeneous disease, with a complex genetic basis. In previous studies, primary dystonia was classified according to age of onset, involved regions, and other clinical characteristics. With the development of molecular genetics, new virulence genes and sites have been discovered. Therefore, there is a gradual understanding of the various forms of dystonia, based on new viewpoints. There are 15 subtypes of dystonia, based on the molecular level, i.e., DYT1 to DYT15. OBJECTIVE： To analyze the genetic development of dystonia in detail, and to further investigate molecular mechanisms of dystonia. RETRIEVAL STRATEGY： A computer-based online search was conducted in PubMed for English language publications containing the keywords ＂dystonia and genetic＂ from January 1980 to March 2007. There were 105 articles in total. Inclusion criteria： ① the contents of the articles should closely address genetic classification and molecular mechanisms of primary dystonia; ② the articles published in recent years or in high-impact journals took preference. Exclusion criteria： duplicated articles. LITERATURE EVALUATION： The selected articles were on genetic classification and molecular genetics mechanism of primary dystonia. Of those, 27 were basic or clinical studies. DATA SYNTHESlS： ① Dystonia is a heterogeneous disease, with a complex genetic basis. According to the classification of the Human Genome Organization, there are 15 dystonia subtypes, based on genetics, i.e., DYT1-DYT15, including primary dystonia, dystonia plus syndrome, degeneration plus dystonia, and paroxysmal dyskinesia plus dystonia.② To date, the chromosomes of 13 subtypes have been localized; however, DYT2 and DYT4 remain unclear. Six subtypes have been located within virulence genes. Specifically, torsinA gene expression results in the DYTI genotype; autosomal dominant GTP cyclohydrolase 1 gene expression and recessive tyrosine hydroxylase expression result in the DYT5 genotype, respectively; the epsil     

The use of Fogs' test to assess associated movements in Parkinsonism,dystonia, and controls

The Fogs' test elicits non‐homologous associated movements which reflect underlying pathology or immaturity of the CNS, but has not been thoroughly studied. We filmed participants performing a modified Fogs' test and developed a reliable scoring system for the associated movements. We assessed scores in healthy controls of all ages and compared scores in dystonia and parkinsonism to age similar controls. Associated movements were marked in children, lessened as they matured into adults, and then increased in old age. Associated movements were marked in dystonia but not in parkinsonism. Our scoring system showed robust inter‐ and intra‐rater reliability. The Fogs' test is a reliable addition to the clinical examination that can be used to screen for both normal and abnormal neurological status. We suggest a potential neural pathway via cervical‐lumbosacral connections within the spinal cord which are modulated by propriospinal and cerebral input. © 2010 Movement Disorder Society     

The syndrome of deafness‐dystonia: Clinical and genetic heterogeneity

The syndrome of deafness‐dystonia is rare and refers to the association of hearing impairment and dystonia when these are dominant features of a disease. Known genetic causes include Mohr‐Tranebjaerg syndrome, Woodhouse‐Sakati syndrome, and mitochondrial disorders, but the cause frequently remains unidentified. The aim of the current study was to better characterize etiological and clinical aspects of deafness‐dystonia syndrome. We evaluated 20 patients with deafness‐dystonia syndrome who were seen during the period between 1994 and 2011. The cause was identified in only 7 patients and included methylmalonic aciduria, meningoencephalitis, perinatal hypoxic‐ischemic injury, large genomic deletion on chromosome 7q21, translocase of inner mitochondrial membrane 8 homolog A (TIMM8A) mutation (Mohr‐Tranebjaerg syndrome), and chromosome 2 open reading frame 37 (C2orf37) mutation (Woodhouse‐Sakati syndrome). The age of onset and clinical characteristics in these patients varied, depending on the etiology. In 13 patients, the cause remained unexplained despite extensive work‐up. In the group of patients who had unknown etiology, a family history for deafness and/or dystonia was present the majority of patients, suggesting a strong genetic component. Sensory‐neural deafness always preceded dystonia. Two clinical patterns of deafness‐dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia. Deafness‐dystonia syndrome is etiologically and clinically heterogeneous, and most patients have an unknown cause. The different age at onset and variable family history suggest a heterogeneous genetic background, possibly including currently unidentified genetic conditions. © 2013 Movement Disorder Society     

Distinct roles of brain activity and somatotopic representation in pathophysiology of focal dystonia

Two main neural mechanisms including loss of cortical inhibition and maladaptive plasticity have been thought to be involved in the pathophysiology of focal task‐specific dystonia. Such loss of inhibition and maladaptive plasticity likely correspond to cortical overactivity and disorganized somatotopy, respectively. However, the most plausible mechanism of focal task‐specific dystonia remains unclear. To address this question, we assessed brain activity and somatotopic representations of motor‐related brain areas using functional MRI and behavioral measurement in healthy instrumentalists and patients with embouchure dystonia as an example of focal task‐specific dystonia. Dystonic symptoms were measured as variability of fundamental frequency during long tone playing. We found no significant differences in brain activity between the embouchure dystonia and healthy wind instrumentalists in the motor‐related areas. Assessment of somatotopy, however, revealed significant differences in the somatotopic representations of the mouth area for the right somatosensory cortex between the two groups. Multiple‐regression analysis revealed brain activity in the primary motor and somatosensory cortices, cerebellum, and putamen was significantly associated with variability of fundamental frequency signals representing dystonic symptoms. Conversely, somatotopic representations in motor‐related brain areas were not associated with variability of fundamental frequency signals in embouchure dystonia. The present findings suggest that abnormal motor‐related network activity and aberrant somatotopy correlate with different aspects of mechanisms underlying focal task‐specific dystonia.     

Genotype‐phenotype correlations,dystonia and disease progression in spinocerebellar ataxia type 14

Background: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia. Methods: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In‐depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations. Results: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task‐induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11. Conclusion: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Onset and progression of primary torsion dystonia in sporadic and familial cases

Four hundred and sixty records of patients with primary torsion dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 ± 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 ± 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 ± 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.     

A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force

To review the literature on primary dystonia and dystonia plus and to provide evidence-based recommendations. Primary dystonia and dystonia plus are chronic and often disabling conditions with a widespread spectrum mainly in young people. Computerized MEDLINE and EMBASE literature reviews (1966-1967 February 2005) were conducted. The Cochrane Library was searched for relevant citations. Diagnosis and classification of dystonia are highly relevant for providing appropriate management and prognostic information, and genetic counselling. Expert observation is suggested. DYT-1 gene testing in conjunction with genetic counselling is recommended for patients with primary dystonia with onset before age 30 years and in those with an affected relative with early onset. Positive genetic testing for dystonia (e.g. DYT-1) is not sufficient to make diagnosis of dystonia. Individuals with myoclonus should be tested for the epsilon-sarcoglycan gene (DYT-11). A levodopa trial is warranted in every patient with early onset dystonia without an alternative diagnosis. Brain imaging is not routinely required when there is a confident diagnosis of primary dystonia in adult patients, whereas it is necessary in the paediatric population. Botulinum toxin (BoNT) type A (or type B if there is resistance to type A) can be regarded as first line treatment for primary cranial (excluding oromandibular) or cervical dystonia and can be effective in writing dystonia. Actual evidence is lacking on direct comparison of the clinical efficacy and safety of BoNT-A vs. BoNT-B. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for generalized or cervical dystonia, after medication or BoNT have failed to provide adequate improvement. Selective peripheral denervation is a safe procedure that is indicated exclusively in cervical dystonia. Intrathecal baclofen can be indicated in patients where secondary dystonia is combined with spasticity. The absolute and comparative efficacy and tolerability of drugs in dystonia, including anticholinergic and antidopaminergic drugs, is poorly documented and no evidence-based recommendations can be made to guide prescribing.     

An overview of neurological and neuromuscular signs in mitochondrial diseases

Mitochondrial disorders have a broad clinical spectrum and are genetically heterogeneous, involving two genomes. These disorders may be develop at any age, with isolated or multiple system involvement, and any pattern of inheritance. Neurological involvement is the most frequent, and concerns muscular, peripheral and central nervous system. Among these diverse signs, some are suggestive of mitochondrial disease, such as progressive external ophthalmoplegia, exercise intolerance, psychomotor regression, stroke-like episodes, refractory epilepsy and Epilepsia Partialis Continua. Others are less specific and mitochondrial hypothesis may be evocated because of either association of different neuromuscular signs or a multisystemic involvement. This review describes the wealth of this neurological and neuromuscular symptomatology through different syndromes reported in the literature, according to preponderant signs and to modes of inheritance, as key elements to guide genetics testing.     

Rett syndrome: An overlooked diagnosis in women with stereotypic hand movements,psychomotor retardation,Parkinsonism, and dystonia?

Rett syndrome is an X-linked neurodevelopmental disorder resulting in profound psychomotor retardation. It is usually diagnosed by a pediatrician or pediatric neurologist. Adult neurologists may, therefore, overlook the possibility of Rett syndrome in women with psychomotor retardation of unknown etiology. We report the case of a woman diagnosed with Rett syndrome at age 49 years. This report emphasizes the diagnostic value of movement disorders, including hand stereotypies, Parkinsonism, and dystonia, in adults with Rett syndrome.