Dystonia Associated with Idiopathic Slow Orthostatic Tremor

Background: We aimed to characterize the clinical and electrophysiological features of patients with slow orthostatic tremor. Case Report: The clinical and neurophysiological data of patients referred for lower limb tremor on standing were reviewed. Patients with symptomatic or primary orthostatic tremor were excluded. Eight patients were identified with idiopathic slow 4–8 Hz orthostatic tremor, which was associated with tremor and dystonia in cervical and upper limb musculature. Coherence analysis in two patients showed findings different to those seen in primary orthostatic tremor. Discussion: Slow orthostatic tremor may be associated with dystonia and dystonic tremor

Objective analysis of neck muscle boundaries for cervical dystonia using ultrasound imaging and deep learning

Objective: To provide objective visualization and pattern analysis of neck muscle boundaries to inform and monitor treatment of cervical dystonia. Methods: We recorded transverse cervical ultrasound (US) images and whole-body motion analysis of sixty-one standing participants (35 cervical dystonia, 26 age matched controls). We manually annotated 3,272 US images sampling posture and the functional range of pitch, yaw, and roll head movements. Using previously validated methods, we used 60-fold cross validation to train, validate and test a deep neural network (U-net) to classify pixels to 13 categories (five paired neck muscles, skin, ligamentum nuchae, vertebra). For all participants for their normal standing posture, we segmented US images and classified condition (Dystonia/Control), sex and age (higher/lower) from segment boundaries. We performed an explanatory, visualization analysis of dystonia muscle-boundaries. Results: For all segments, agreement with manual labels was Dice Coefficient (64±21%) and Hausdorff Distance (5.7±4 mm). For deep muscle layers, boundaries predicted central injection sites with average precision 94±3%. Using leave-one-out cross-validation, a support-vector-machine classified condition, sex, and age from predicted muscle boundaries at accuracy 70.5%, 67.2%, 52.4% respectively, exceeding classification by manual labels. From muscle boundaries, Dystonia clustered optimally into three sub-groups. These sub-groups are visualized and explained by three eigen-patterns which correlate significantly with truncal and head posture. Conclusion: Using US, neck muscle shape alone discriminates dystonia from healthy controls. Significance: Using deep learning, US imaging allows online, automated visualization, and diagnostic analysis of cervical dystonia and segmentation of individual muscles for targeted injection. The dataset is available (DOI: 10.23634/MMUDR.00624643)

A neurophysiological investigation of anticipation to pain in Parkinson's disease

Chronic pain is common in people with Parkinson's disease and is often considered to be caused by the motor impairments associated with the disease. Altered top‐down processing of pain characterises several chronic pain conditions and occurs when the cortex modifies nociceptive processing in the brain and spinal cord. This contrasts with bottom‐up modulation of pain whereby nociceptive processing is modified on its way up to the brain. Although several studies have demonstrated altered bottom‐up pain processing in Parkinson's, the contribution of enhanced anticipation to pain and atypical top‐down processing of pain has not been fully explored. During the anticipation to noxious stimuli, EEG source localisation reported an increased activation in the midcingulate cortex and supplementary motor area in the Parkinson's disease group compared to the healthy control group during mid [−1,500 –1,000]‐and late anticipation [−500 0], indicating enhanced cortical activity before noxious stimulation. The Parkinson's disease group was also more sensitive to the laser and required a lower voltage level to induce pain. This study provides evidence supporting the hypothesis that enhanced top‐down processing of pain may contribute to the development of chronic pain in Parkinson's. Additional research to establish whether the altered anticipatory response is unique to noxious stimuli is required as no control stimulus was used within the current study. With further research to confirm these findings, our results inform a scientific rationale for novel treatment strategies of pain in Parkinson's disease, including mindfulness, cognitive therapies and other approaches targeted at improving top‐down processing of pain

Increased Intraepidermal Nerve Fiber Degeneration and Impaired Regeneration Relate to Symptoms and Deficits in Parkinson's Disease

Background: Previous studies have shown cutaneous small fiber pathology in patients with Parkinson's disease (PD). These studies have focused on nerve degeneration, but recent reports suggest that nerve regeneration may also be important in PD pathology.Objective: To establish the extent of intraepidermal nerve fiber (IENF) degeneration and regeneration and its relationship to clinical and neurological deficits in Parkinson's disease (PD).Methods: Twenty-three PD patients and 10 age-matched controls underwent skin biopsy and assessment of somatic and autonomic symptoms and deficits. We have assessed Intraepidermal Nerve Fiber Density (IENFD) using standard PGP9.5 staining and GAP-43 to assess Mean Axonal Length (MAL) and Intraepidermal Total Nerve Fiber Length (IETNFL).Results: IENFD (p < 0.0001), MAL (p < 0.0001), IETNFL/Area (p = 0.009), and IETNFL/Length (p = 0.04) were significantly reduced in patients with PD compared to controls. IENFD correlated significantly with disease duration (p = 0.03), cumulative levodopa dose (p = 0.02), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (p = 0.01), Schwab and England Activities of Daily Living (ADL) (p = 0.03), NSP (p = 0.03), and 30:15 ratio (p = 0.03). IETNFL/Area correlated with the Autonomic Scale for Outcomes in Parkinson's Disease (SCOPA-AUT) (p = 0.03) and Diabetic Neuropathy Symptom score (DNS) (p = 0.04) and IETNFL/Length correlated with DNS (p = 0.03). MAL correlated with SCOPA-AUT (p = 0.01), DNS (p = 0.02), and DB-HRV (p = 0.02).Conclusion: Increased IENF degeneration and impaired regeneration correlates with somatic and autonomic symptoms and deficits in patients with PD

Corneal Confocal Microscopy Identifies Parkinson's Disease with More Rapid Motor Progression

From Wiley via Jisc Publications RouterHistory: received 2020-12-15, rev-recd 2021-03-11, accepted 2021-03-12, pub-electronic 2021-04-07, pub-print 2021-08Article version: VoRPublication status: PublishedFunder: Michael J Fox Foundation Trust (Grant ID 12059); Id: http://dx.doi.org/10.13039/100010269ABSTRACT: Background: Corneal confocal microscopy (CCM) is a noninvasive, reproducible ophthalmic technique to quantify corneal small nerve fiber degeneration. CCM demonstrates small nerve fiber damage in Parkinson's disease (PD), but its role as a longitudinal biomarker of PD progression has not been explored. Objective: The aim of this study was to assess corneal nerve morphology using CCM in relation to disease progression in PD. Methods: Sixty‐four participants with PD were assessed at baseline and at 12‐month follow‐up. Participants underwent CCM with automated corneal nerve quantification and assessment of Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, and Montreal Cognitive Assessment. Results: Corneal nerve fiber density (CNFD), corneal nerve branch density, corneal nerve fiber length, corneal total branch density, and corneal nerve fiber area were significantly lower in participants with PD compared with healthy control subjects. Worsening of Movement Disorder Society Unified Parkinson's Disease Rating Scale part III score over 12 months was significantly greater in participants with a CNFD in the lowest compared with the highest quartile at baseline (mean difference: 6.0; 95% CI: 1.0–10.9; P = 0.019). There were no significant changes in CNFD, corneal nerve branch density, corneal nerve fiber length, corneal total branch density, corneal nerve fiber area, or corneal nerve fiber width between baseline and 12‐month follow‐up. Conclusions: CCM identifies neurodegeneration in patients with PD, especially those who show the greatest progression in neurological disability. CCM may be a useful tool to help enrich clinical trials with those likely to exhibit more rapid progression and reduce required sample size and cost of studies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

A detailed clinical study of pain in 1957 participants with early/moderate Parkinson's disease

Introduction The causes of pain in early/moderate Parkinson's disease (PD) are not well understood. Although peripheral factors such as rigidity, reduced joint movements and poor posture may contribute towards the development of pain, central mechanisms including altered nociceptive processing may also be involved. Methods We performed a large clinical study to investigate potential factors contributing towards pain in early/moderate PD. We recruited 1957 PD participants who had detailed assessments of pain, motor and non-motor symptoms. The King's Parkinson's Pain scale was used to quantify different subtypes of pain. Results 85% of participants reported pain (42% with moderate to severe pain). Pain influenced quality of life more than motor symptoms in a multiple regression model. Factors predicting overall pain severity included affective symptoms, autonomic symptoms, motor complications, female gender and younger age, but not motor impairment or disease duration. There was negligible correlation between the severity of motor impairment and the severity of musculoskeletal or dystonic pain as well as between the severity of OFF period motor problems and the severity of OFF period pain or OFF period dystonic pain. Features of central sensitization, including allodynia and altered pain sensation were common in this population. The use of drugs targeting central pain was very low. Conclusions Pain in early/moderate PD cannot be explained by peripheral factors. Central causes may play a much more important role than previously considered. These results should lead to a major shift in the investigation and management of this common and disabling symptom

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials

The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based endpoint selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy and related disorders, to compare candidate clinical trial endpoints. In this multicentre United Kingdom study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and magnetic resonance imaging assessments at baseline, six and twelve-months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, progressive supranuclear palsy-subcortical (progressive supranuclear palsy-parkinsonism and progressive gait freezing subtypes), progressive supranuclear palsy-cortical (progressive supranuclear palsy-frontal, progressive supranuclear palsy-speech-and-language, and progressive supranuclear palsy-corticobasal syndrome subtypes), multiple system atrophy-parkinsonism, multiple system atrophy-cerebellar, corticobasal syndrome with and without evidence of Alzheimer’s disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling, and sample sizes for clinical trials of disease modifying agents, according to group and assessment type. Two hundred forty-three people were recruited (117 progressive supranuclear palsy, 68 corticobasal syndrome, 42 multiple system atrophy and 16 indeterminate; 138 [56.8%] male; age at recruitment 68.7 ± 8.61 years). One hundred fifty-nine completed six-month assessment (82 progressive supranuclear palsy, 27 corticobasal syndrome, 40 multiple system atrophy and 10 indeterminate) and 153 completed twelve-month assessment (80 progressive supranuclear palsy, 29 corticobasal syndrome, 35 multiple system atrophy and 9 indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for one-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease specific. In conclusion, phenotypic variance within progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial endpoints, from potential functional, cognitive, clinical or neuroimaging measures of disease progression