Objective, computerized video-based rating of blepharospasm severity

OBJECTIVE: To compare clinical rating scales of blepharospasm severity with involuntary eye closures measured automatically from patient videos with contemporary facial expression software. METHODS: We evaluated video recordings of a standardized clinical examination from 50 patients with blepharospasm in the Dystonia Coalition's Natural History and Biorepository study. Eye closures were measured on a frame-by-frame basis with software known as the Computer Expression Recognition Toolbox (CERT). The proportion of eye closure time was compared with 3 commonly used clinical rating scales: the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale. RESULTS: CERT was reliably able to find the face, and its eye closure measure was correlated with all of the clinical severity ratings (Spearman ρ = 0.56, 0.52, and 0.56 for the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale, respectively, all p < 0.0001). CONCLUSIONS: The results demonstrate that CERT has convergent validity with conventional clinical rating scales and can be used with video recordings to measure blepharospasm symptom severity automatically and objectively. Unlike EMG and kinematics, CERT requires only conventional video recordings and can therefore be more easily adopted for use in the clinic

Neuropathological features of genetically confirmed DYT1 dystonia: investigating disease-specific inclusions.

IntroductionEarly onset isolated dystonia (DYT1) is linked to a three base pair deletion (¿GAG) mutation in the TOR1A gene. Clinical manifestation includes intermittent muscle contraction leading to twisting movements or abnormal postures. Neuropathological studies on DYT1 cases are limited, most showing no significant abnormalities. In one study, brainstem intraneuronal inclusions immunoreactive for ubiquitin, torsinA and lamin A/C were described. Using the largest series reported to date comprising 7 DYT1 cases, we aimed to identify consistent neuropathological features in the disease and determine whether we would find the same intraneuronal inclusions as previously reported.ResultThe pathological changes of brainstem inclusions reported in DYT1 dystonia were not replicated in our case series. Other anatomical regions implicated in dystonia showed no disease-specific pathological intracellular inclusions or evidence of more than mild neuronal loss.ConclusionOur findings suggest that the intracellular inclusions described previously in DYT1 dystonia may not be a hallmark feature of the disorder. In isolated dystonia, DYT1 in particular, biochemical changes may be more relevant than the morphological changes

Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease

Lesch-Nyhan disease (LND) is a severe neurological disorder caused by loss-of-function mutations in the gene encoding hypoxanthine phosphoribosyltransferase (HPRT), an enzyme required for efficient recycling of purine nucleotides. Although this biochemical defect reconfigures purine metabolism and leads to elevated levels of the breakdown product urea, it remains unclear exactly how loss of HPRT activity disrupts brain function. As the rat is the preferred rodent experimental model for studying neurobiology and diseases of the brain, we used genetically-modified embryonic stem cells to generate an HPRT knock-out rat. Male HPRT-deficient rats were viable, fertile and displayed normal caged behaviour. However, metabolomic analysis revealed changes in brain biochemistry consistent with disruption of purine recycling and nucleotide metabolism. Broader changes in brain biochemistry were also indicated by increased levels of the core metabolite citrate and reduced levels of lipids and fatty acids. Targeted MS/MS analysis identified reduced levels of dopamine in the brains of HPRT-deficient animals, consistent with deficits noted previously in human LND patients and HPRT knock-out mice. The HPRT-deficient rat therefore provides a new experimental platform for future investigation of how HPRT activity and disruption of purine metabolism affects neural function and behaviour

Worldwide barriers to genetic testing for movement disorders.

BACKGROUND AND PURPOSE: Despite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization. METHODS: The Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members. RESULTS: Survey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe. CONCLUSIONS: This survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15–18 weeks' gestation, or chorionic villus cells obtained at about 10–12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments

Interrater reliability of motor severity scales for hemifacial spasm

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants\u27 motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee\u27s scale), clinical grading of spasm intensity (Chen\u27s scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc\u27s scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from poor to moderate ; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee\u27s, Chen\u27s, and Tunc\u27s scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc\u27s scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc\u27s scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training

Plasticity and dystonia: a hypothesis shrouded in variability.

Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia

HPRT Deficiency Coordinately Dysregulates Canonical Wnt and Presenilin-1 Signaling: A Neuro-Developmental Regulatory Role for a Housekeeping Gene?

We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/β-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of β-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro-regulatory defects played by HPRT expression and suggest new directions for investigating mechanisms of aberrant neurogenesis and neuropathology in LND and potential new targets for restoration of effective signaling in this neuro-developmental defect

The Pain in Dystonia Scale (PIDS)-Development and Validation in Cervical Dystonia.

BACKGROUND: A better understanding of pain in adult-onset idiopathic dystonia (AOID) is needed to implement effective therapeutic strategies. OBJECTIVE: To develop a new rating instrument for pain in AOID and validate it in cervical dystonia (CD). METHODS: Development and validation of the Pain in Dystonia Scale (PIDS) comprised three phases. In phase 1, international experts and participants with AOID generated and evaluated the preliminary items for content validity. In phase 2, the PIDS was drafted and revised by the experts, followed by cognitive interviews to ensure self-administration suitability. In phase 3, the PIDS psychometric properties were assessed in 85 participants with CD and retested in 40 participants. RESULTS: The final version of PIDS evaluates pain severity (by body-part), functional impact, and external modulating factors. Test-retest reliability showed a high-correlation coefficient for the total score (0.9, P < 0.001), and intraclass correlation coefficients were 0.7 or higher for all items in all body-parts subscores. The overall PIDS severity score showed high internal consistency (Cronbach's α, 0.9). Convergent validity analysis revealed a strong correlation between the PIDS severity score and the Toronto Western Spasmodic Torticollis Rating Scale pain subscale (0.8, P < 0.001) and the Brief Pain Inventory-short form items related to pain at time of the assessment (0.7, P < 0.001) and impact of pain on daily functioning (0.7, P < 0.001). CONCLUSION: The PIDS is the first specific questionnaire developed to evaluate pain in all patients with AOID, here, demonstrating high-level psychometric properties in people with CD. Future work will validate PIDS in other forms of AOID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society