Ultrastructural analysis of nigrostriatal dopaminergic terminals in a knockin mouse model of DYT1 dystonia.

DYT1 dystonia is associated with decreased striatal dopamine release. In this study, we examined the possibility that ultrastructural changes of nigrostriatal dopamine terminals could contribute to this neurochemical imbalance using a serial block face/scanning electron microscope (SBF/SEM) and three-dimensional reconstruction to analyse striatal tyrosine hydroxylase-immunoreactive (TH-IR) terminals and their synapses in a DYT1(ΔE) knockin (DYT1-KI) mouse model of DYT1 dystonia. Furthermore, to study possible changes in vesicle packaging capacity of dopamine, we used transmission electron microscopy to assess the synaptic vesicle size in striatal dopamine terminals. Quantitative comparative analysis of 80 fully reconstructed TH-IR terminals in the WT and DYT1-KI mice indicate (1) no significant difference in the volume of TH-IR terminals; (2) no major change in the proportion of axo-spinous versus axo-dendritic synapses; (3) no significant change in the post-synaptic density (PSD) area of axo-dendritic synapses, while the PSDs of axo-spinous synapses were significantly smaller in DYT1-KI mice; (4) no significant change in the contact area between TH-IR terminals and dendritic shafts or spines, while the ratio of PSD area/contact area decreased significantly for both axo-dendritic and axo-spinous synapses in DYT1-KI mice; (5) no significant difference in the mitochondria volume; and (6) no significant difference in the synaptic vesicle area between the two groups. Altogether, these findings suggest that abnormal morphometric changes of nigrostriatal dopamine terminals and their post-synaptic targets are unlikely to be a major source of reduced striatal dopamine release in DYT1 dystonia.

Proprioceptive Modulation of Pallidal Physiology in Cervical Dystonia.

BACKGROUND: There is a growing body of evidence suggesting that botulinum toxin can alter proprioceptive feedback and modulate the muscle-spindle output for the treatment of dystonia. However, the mechanism for this modulation remains unclear. METHODS: We conducted a study involving 17 patients with cervical dystonia (CD), seven of whom had prominent CD and 10 with generalized dystonia (GD) along with CD. We investigated the effects of neck vibration, a form of proprioceptive modulation, on spontaneous single-neuron responses and local field potentials (LFPs) recorded from the globus pallidum externus (GPe) and internus (GPi). RESULTS: Our findings demonstrated that neck vibration notably increased the regularity of neck-sensitive GPi neurons in focal CD patients. Additionally, in patients with GD and CD, the vibration enhanced the firing regularity of non-neck-sensitive neurons. These effects on single-unit activity were also mirrored in ensemble responses measured through LFPs. Notably, the LFP modulation was particularly pronounced in areas populated with burst neurons compared to pause or tonic cells. CONCLUSION: The results from our study emphasize the significance of burst neurons in the pathogenesis of dystonia and in the efficacy of proprioceptive modulation for its treatment. Moreover, we observed that the effects of vibration on focal CD were prominent in the α band LFP, indicating modulation of pallido-cerebellar connectivity. Moreover, the pallidal effects of vibration in GD with CD involved modulation of cerebro-pallidal θ band connectivity. Our analysis provides insight into how vibration-induced changes in pallidal activity are integrated into the downstream motor circuit. © 2023 International Parkinson and Movement Disorder Society.

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 International Parkinson and Movement Disorder Society.

Isolated Cervical Dystonia: Diagnosis and Classification.

This document presents a consensus on the diagnosis and classification of isolated cervical dystonia (iCD) with a review of proposed terminology. The International Parkinson and Movement Disorder Society Dystonia Study Group convened a panel of experts to review the main clinical and diagnostic issues related to iCD and to arrive at a consensus on diagnostic criteria and classification. These criteria are intended for use in clinical research, but also may be used to guide clinical practice. The benchmark is expert clinical observation and evaluation. The criteria aim to systematize the use of terminology as well as the diagnostic process, to make it reproducible across centers and applicable by expert and non-expert clinicians. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations, which are incorporated into the current criteria. Three iCD presentations are described in some detail: idiopathic (focal or segmental) iCD, genetic iCD, and acquired iCD. The relationship between iCD and isolated head tremor is also reviewed. Recognition of idiopathic iCD has two levels of certainty, definite or probable, supported by specific diagnostic criteria. Although a probable diagnosis is appropriate for clinical practice, a higher diagnostic level may be required for specific research studies. The consensus retains elements proven valuable in previous criteria and omits aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of iCD expands, these criteria will need continuous revision to accommodate new advances. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes.

PURPOSE OF REVIEW: We describe here how such mechanisms shared by different genetic forms can give rise to motor performance dysfunctions with a clinical aspect of dystonia. RECENT FINDINGS: The continuing discoveries of genetic causes for dystonia syndromes are transforming our view of these disorders. They share unexpectedly common underlying mechanisms, including dysregulation in neurotransmitter signaling, gene transcription, and quality control machinery. The field has further expanded to include forms recently associated with endolysosomal dysfunction. SUMMARY: The discovery of biological pathways shared between different monogenic dystonias is an important conceptual advance in the understanding of the underlying mechanisms, with a significant impact on the pathophysiological understanding of clinical phenomenology. The functional relationship between dystonia genes could revolutionize current dystonia classification systems, classifying patients with different monogenic forms based on common pathways. The most promising effect of these advances is on future mechanism-based therapeutic approaches.

Feedback-dependent neuronal properties make focal dystonias so focal.

Focal dystonia, by definition, affects a specific body part; however, it may have a widespread neural substrate. We tested this hypothesis by examining the intrinsic behaviour and the neuronal properties that are modulated by changes in the physiological behaviour of their connections, that is feedback dependence, of the isolated pallidal neurons. During deep brain stimulation surgery in 12 patients with isolated cervical dystonia (without hand involvement), we measured spontaneous as well as evoked single-unit properties in response to fist making (hand movement) or shoulder shrug (neck movements). We measured the activity of isolated neurons that were only sensitive to the neck movements, hand movement, or not responsive to hand or neck movements. The spontaneous firing behaviour, such as the instantaneous firing rate and its regularity, was comparable in all three types of neurons. The neck movement-sensitive neurons had prominent bursting behaviour in comparison with the hand neurons. The feedback dependence of the neck movement-sensitive neurons was also significantly impaired when compared to hand movement-sensitive neurons. Motor-evoked change in firing rate of neck movement-sensitive neurons rapidly declined; the decay time constant was much shorter compared to hand movement-sensitive neurons. These results suggest that in isolated cervical dystonia, at the resolution of single neurons, the deficits are much widespread, affecting the neurons that drive the neck movement as well as the hand movements. We speculate that clinically discernable dystonia occurs when additional abnormality is added to baseline dysfunctional network, and one source of such abnormality may involve feedback.

Rational Design of Novel Therapies for Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses. OBJECTIVES: A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms. METHODS: Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated. CONCLUSIONS: Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society.

A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments. OBJECTIVES: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. RESULTS: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. CONCLUSIONS: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

BACKGROUND AND PURPOSE: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread. METHODS: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping. RESULTS: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread. CONCLUSIONS: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

AIM: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families. METHOD: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases. RESULTS: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure. INTERPRETATION: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.

Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study.

OBJECTIVE: Isolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients. METHODS: Patients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread. RESULTS: 487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009). CONCLUSIONS: Initial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.

Clinical and Demographic Characteristics of Upper Limb Dystonia.

BACKGROUND: Knowledge of characteristics in upper limb dystonia remains limited, derived primarily from small, single-site studies. OBJECTIVE: The objective of this study was to characterize demographic and clinical characteristics of upper limb dystonia from the Dystonia Coalition data set, a large, international, multicenter resource. METHODS: We evaluated clinical and demographic characteristics of 367 participants with upper limb dystonia from onset, comparing across subcategories of focal (with and without dystonia spread) versus nonfocal onset. RESULTS: Focal onset occurred in 80%; 67% remained focal without spread. Task specificity was most frequent in this subgroup, most often writer's cramp and affecting the dominant limb (83%). Focal onset with spread was more frequent in young onset (<21 years). Focal onset occurred equally in women and men; nonfocal onset affected women disproportionately. CONCLUSIONS: Upper limb dystonia distribution, focality, and task specificity relate to onset age and likelihood of regional spread. Observations may inform clinical counseling and design, execution, and interpretation of future studies. © 2020 International Parkinson and Movement Disorder Society.

Network localization of cervical dystonia based on causal brain lesions.

Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed 'lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment.

Blepharospasm 40 years later.

Forty years ago, C.D. Marsden proposed that blepharospasm should be considered a form of adult-onset focal dystonia. In the present paper, we provide a comprehensive overview of the findings regarding blepharospasm reported in the past 40 years. Although prolonged spasms of the orbicularis oculi muscles remain the clinical hallmark of blepharospasm, patients with blepharospasm may be characterized by various types of involuntary activation of periocular muscles. In addition to motor features, blepharospasm patients may also have nonmotor manifestations, including psychiatric, mild cognitive, and sensory disturbances. The various motor and nonmotor symptoms are not present in all patients, suggesting that blepharospasm is phenomenologically a heterogeneous condition. This emphasizes the need for tools for severity assessment that take into account both motor and nonmotor manifestations. The cause of blepharospasm remains elusive, but several lines of evidence indicate that blepharospasm is a multifactorial condition in which one, or several, as yet unknown genes together with epigenetic and environmental factors combine to reach the threshold of the disease. Although blepharospasm was originally believed to be solely a basal ganglia disorder, neurophysiological and neuroimaging evidence point to anatomical and functional involvement of several brain regions. The contribution of multiple areas has led to the hypothesis that blepharospasm should be considered as a network disorder, and this might reflect the varying occurrence of motor and nonmotor manifestations in blepharospasm patients. Despite advances in the aetiology and pathophysiology, treatment remains symptomatic. © 2017 International Parkinson and Movement Disorder Society.

Cervical dystonia: a neural integrator disorder.

Ocular motor neural integrators ensure that eyes are held steady in straight-ahead and eccentric positions of gaze. Abnormal function of the ocular motor neural integrator leads to centripetal drifts of the eyes with consequent gaze-evoked nystagmus. In 2002 a neural integrator, analogous to that in the ocular motor system, was proposed for the control of head movements. Recently, a counterpart of gaze-evoked eye nystagmus was identified for head movements; in which the head could not be held steady in eccentric positions on the trunk. These findings lead to a novel pathophysiological explanation in cervical dystonia, which proposed that the abnormalities of head movements stem from a malfunctioning head neural integrator, either intrinsically or as a result of impaired cerebellar, basal ganglia, or peripheral feedback. Here we briefly recapitulate the history of the neural integrator for eye movements, then further develop the idea of a neural integrator for head movements, and finally discuss its putative role in cervical dystonia. We hypothesize that changing the activity in an impaired head neural integrator, by modulating feedback, could treat dystonia.

Clinimetric testing of the comprehensive cervical dystonia rating scale.

INTRODUCTION: The aim of this study was to test the clinimetric properties of the Comprehensive Cervical Dystonia Rating Scale. This is a modular scale with modifications of the Toronto Western Spasmodic Torticollis Rating Scale (composed of three subscales assessing motor severity, disability, and pain) now referred to as the revised Toronto Western Spasmodic Torticollis Scale-2; a newly developed psychiatric screening instrument; and the Cervical Dystonia Impact Profile-58 as a quality of life measure. METHODS: Ten dystonia experts rated subjects with cervical dystonia using the comprehensive scale. Clinimetric techniques assessed each module of the scale for reliability, item correlation, and factor structure. RESULTS: There were 208 cervical dystonia patients (73% women; age, 59 ± 10 years; duration, 15 ± 12 years). Internal consistency of the motor severity subscale was acceptable (Cronbach's alpha = 0.57). Item to total correlations showed that elimination of items with low correlations (<0.20) increased alpha to 0.71. Internal consistency estimates for the subscales for disability and pain were 0.88 and 0.95, respectively. The psychiatric screening scale had a Cronbach's alpha of 0.84 and satisfactory item to total correlations. When the subscales of the Toronto Western Spasmodic Torticollis Scale-2 were combined with the psychiatric screening scale, Cronbach's alpha was 0.88, and construct validity assessment demonstrated four rational factors: motor; disability; pain; and psychiatric disorders. The Cervical Dystonia Impact Profile-58 had an alpha of 0.98 and its construction was validated through a confirmatory factor analysis. CONCLUSIONS: The modules of the Comprehensive Cervical Dystonia Rating Scale are internally consistent with a logical factor structure.

A new knock-in mouse model of l-DOPA-responsive dystonia.

Abnormal dopamine neurotransmission is associated with many different genetic and acquired dystonic disorders. For instance, mutations in genes critical for the synthesis of dopamine, including GCH1 and TH cause l-DOPA-responsive dystonia. Despite evidence that implicates abnormal dopamine neurotransmission in dystonia, the precise nature of the pre- and postsynaptic defects that result in dystonia are not known. To better understand these defects, we generated a knock-in mouse model of l-DOPA-responsive dystonia (DRD) mice that recapitulates the human p.381Q>K TH mutation (c.1141C>A). Mice homozygous for this mutation displayed the core features of the human disorder, including reduced TH activity, dystonia that worsened throughout the course of the active phase, and improvement in the dystonia in response to both l-DOPA and trihexyphenidyl. Although the gross anatomy of the nigrostriatal dopaminergic neurons was normal in DRD mice, the microstructure of striatal synapses was affected whereby the ratio of axo-spinous to axo-dendritic corticostriatal synaptic contacts was reduced. Microinjection of l-DOPA directly into the striatum ameliorated the dystonic movements but cerebellar microinjections of l-DOPA had no effect. Surprisingly, the striatal dopamine concentration was reduced to ∼1% of normal, a concentration more typically associated with akinesia, suggesting that (mal)adaptive postsynaptic responses may also play a role in the development of dystonia. Administration of D1- or D2-like dopamine receptor agonists to enhance dopamine signalling reduced the dystonic movements, whereas administration of D1- or D2-like dopamine receptor antagonists to further reduce dopamine signalling worsened the dystonia, suggesting that both receptors mediate the abnormal movements. Further, D1-dopamine receptors were supersensitive; adenylate cyclase activity, locomotor activity and stereotypy were exaggerated in DRD mice in response to the D1-dopamine receptor agonist SKF 81297. D2-dopamine receptors exhibited a change in the valence in DRD mice with an increase in adenylate cyclase activity and blunted behavioural responses after challenge with the D2-dopamine receptor agonist quinpirole. Together, our findings suggest that the development of dystonia may depend on a reduction in dopamine in combination with specific abnormal receptor responses.