Generalized Dystonia Due to a Pathogenic THAP1 Variant Showing Sustained Response to Globus Pallidus Deep Brain Stimulation.

A 21-year-old woman of south Asian origin presented with cervical dystonia which had progressed over the previous three years. Her symptoms started as writer's cramp since the age of seven years. She did not respond to medications and needed botulinum toxin injection for generalised dystonia. Subsequent whole genome sequencing revealed a likely pathogenic c.98G>A p.(Cys33Tyr) heterozygous variant in the THAP1 gene. She underwent bilateral posteroventral globus pallidus interna (GPi) deep brain stimulation (Medtronic Activa PC) implantation at the age of thirty-one years. She responded well to the deep brain stimulation even after more than 8 years post-surgery though she needs botulinum toxin injection for her cervical dystonia.

Altered Pain Processing Associated with Administration of Dopamine Agonist and Antagonist in Healthy Volunteers.

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals' ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.

Real world use of a neurophysiology service for the differential diagnosis of hyperkinetic movement disorders.

INTRODUCTION: Clinical neurophysiology constitutes a potentially useful aid in differentiating hyperkinetic movement disorders (HMD). Parameters including presence of a Bereitschaftspotential on back-averaged electroencephalography (EEG) have been demonstrated to help distinguish between these disorders. In 2008, a Movement Disorder neurophysiology service was established in Greater Manchester to aid in the diagnostic process. METHODS: We retrospectively reviewed records of patients with HMD who underwent EEG back-averaging through this service from January 2009 until January 2018. The aim was (i) to characterise the clinical features of our patient cohort and (ii) to determine how frequently neurophysiological testing altered the final diagnosis. RESULTS: A total of 39 patients (23 females, 16 males), with a mean age at onset of 42.6 years and mean disease duration of 2.0 years underwent neurophysiological examination. The clinical diagnosis was changed in 16 cases (41%) and refined in a further seven. Distractibility (P = 0.001), variability (P = 0.002), the presence of a Bereitschaftspotential (P < 0.0001), and electromyography burst duration > 300 ms (P = 0.012) were more frequent in those with an eventual diagnosis of functional movement disorder (n = 24) compared to other HMDs (n = 15). CONCLUSION: Neurophysiology is an invaluable adjunct in complex HMD, altering the diagnosis and treatment options for a significant proportion of patients. Our data also demonstrate, consistent with previous studies, that the majority of patients referred for jerky HMDs to a tertiary movement disorder service have a functional movement disorder.

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.

Outcomes from deep brain stimulation targeting subthalamic nucleus and caudal zona incerta for Parkinson's disease.

Both subthalamic nucleus (STN) and caudal zona incerta (cZI) have been implicated as the optimal locus for deep brain stimulation (DBS) in Parkinson's disease (PD). We present a retrospective clinico-anatomical analysis of outcomes from DBS targeting both STN and cZI. Forty patients underwent bilateral DBS using an image-verified implantable guide tube/stylette technique. Contacts on the same quadripolar lead were placed in both STN and cZI. After pulse generator programming, contacts yielding the best clinical effect were selected for chronic stimulation. OFF-medication unified PD rating scale (UPDRS) part III scores pre-operatively and ON-stimulation at 1-2 year follow up were compared. Active contacts at follow-up were anatomically localised from peri-operative imaging. Overall, mean UPDRS part III score improvement was 55 ± 9% (95% confidence interval), with improvement in subscores for rigidity (59 ± 13%), bradykinesia (58 ± 13%), tremor (71 ± 24%) and axial features (36 ± 19%). Active contacts were distributed in the following locations: (1) within posterior/dorsal STN (50%); (2) dorsal to STN (24%); (3) in cZI (21%); and (4) lateral to STN (5%). When contacts were grouped by location, no significant differences between groups were seen in baseline or post-operative improvement in contralateral UPDRS part III subscores. We conclude that when both STN and cZI are targeted, active contacts are distributed most commonly within and immediately dorsal to STN. In a subgroup of cases, cZI contacts were selected for chronic stimulation in preference. Dual targeting of STN and cZI is feasible and may provide extra benefit compared with conventional STN DBS is some patients.

Parkinson's-adapted cognitive stimulation therapy: a pilot randomized controlled clinical trial.

Cognitive stimulation therapy (CST) is widely used with people with dementia, but there is no evidence of its efficacy in mild cognitive impairment or dementia in Parkinson's disease (PD-MCI; PDD) or dementia with Lewy bodies (DLB). We aimed to explore the impact of 'CST-PD', which is home-based, individualized CST adapted for this population. In a single-blind, randomized controlled exploratory pilot trial (RCT), we randomized 76 participant-dyads [PD-MCI (n = 15), PDD (n = 40), DLB (n = 21) and their care partners] to CST-PD or treatment as usual (TAU). CST-PD involves home-based cognitively stimulating and engaging activities delivered by a trained care partner. Exploratory outcomes at 12 weeks included cognition (Addenbrooke's Cognitive Evaluation; ACE-III), neuropsychiatric symptoms and function. In care partners, we assessed burden, stress and general health status. Relationship quality and quality of life were assessed in both dyad members. At 12 weeks, the ACE-III showed a nonstatistically significant improvement in the CST-PD group compared with the TAU group, although neuropsychiatric symptoms increased significantly in the former. In contrast, care partners' quality of life (d = 0.16) and relationship quality ('satisfaction', d = 0.01; 'positive interaction', d = 0.55) improved significantly in the CST-PD group, and care burden (d = 0.16) and stress (d = 0.05) were significantly lower. Qualitative findings in the CST-PD recipients revealed positive 'in the moment' responses to the intervention, supporting the quantitative results. In conclusion, care-partner-delivered CST-PD may improve a range of care-partner outcomes that are important in supporting home-based care. A full-scale follow-up RCT to evaluate clinical and cost effectiveness is warranted.

Parkinson's-adapted cognitive stimulation therapy: feasibility and acceptability in Lewy body spectrum disorders.

BACKGROUND: Drug-based therapeutic approaches for Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are moderately effective and not always tolerated. Tailoring psychosocial approaches in PDD and DLB may offer additional support and improve outcomes. We adapted home-based, care partner-delivered Cognitive Stimulation Therapy (CST) for individuals with PDD or DLB and their care partners (CST-PD). OBJECTIVES: To evaluate the feasibility, acceptability, and tolerability of CST-PD. METHODS: This randomised controlled trial used mixed methods, including a process evaluation. People with PDD, DLB or mild cognitive impairment in PD (PD-MCI) and their care partners were randomised to 12 weeks of treatment as usual (TAU) or CST-PD. Outcomes were feasibility of the study conduct (i.e., recruitment, retention rate) and acceptability and tolerability of the intervention. Measures included rating scales, researcher field notes, therapy diaries, and exploratory clinical and care partner efficacy measures. RESULTS: The recruitment target was met with 76 consenting participant-dyads. Retention in both arms was high at over 70%. More than 90% of dyads undertook discrete sessions greater than 20 min duration, but the average number of sessions completed was lower than the recommended dose. Acceptability ratings (i.e., interest, motivation and sense of achievement) of the intervention were high. Participants reported no serious adverse events related to the intervention. CONCLUSIONS: The field of psychosocial interventions for PDD and DLB is newly emerging, and we demonstrated that this type of intervention is acceptable and well tolerated. Evaluating its clinical effectiveness in a full-scale randomized controlled clinical trial is warranted. TRIAL REGISTRATION NUMBER: The trial is a psychosocial intervention with an allocated ISRCTN number 11455062.

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.

5-HT modulation of pain perception in humans.

INTRODUCTION: Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. OBJECTIVES: Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. METHODS: Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. RESULTS: Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. CONCLUSION: As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.

Psychosocial therapy for Parkinson's-related dementia: study protocol for the INVEST randomised controlled trial.

INTRODUCTION: Parkinson's disease (PD) with mild cognitive impairment (MCI-PD) or dementia (PDD) and dementia with Lewy bodies (DLB) are characterised by motor and 'non-motor' symptoms which impact on quality of life. Treatment options are generally limited to pharmacological approaches. We developed a psychosocial intervention to improve cognition, quality of life and companion burden for people with MCI-PD, PDD or DLB. Here, we describe the protocol for a single-blind randomised controlled trial to assess feasibility, acceptability and tolerability of the intervention and to evaluate treatment implementation. The interaction among the intervention and selected outcome measures and the efficacy of this intervention in improving cognition for people with MCI-PD, PDD or DLB will also be explored. METHODS AND ANALYSIS: Dyads will be randomised into two treatment arms to receive either 'treatment as usual' (TAU) or cognitive stimulation therapy specifically adapted for Parkinson's-related dementias (CST-PD), involving 30 min sessions delivered at home by the study companion three times per week over 10 weeks. A mixed-methods approach will be used to collect data on the operational aspects of the trial and treatment implementation. This will involve diary keeping, telephone follow-ups, dyad checklists and researcher ratings. Analysis will include descriptive statistics summarising recruitment, acceptability and tolerance of the intervention, and treatment implementation. To pilot an outcome measure of efficacy, we will undertake an inferential analysis to test our hypothesis that compared with TAU, CST-PD improves cognition. Qualitative approaches using thematic analysis will also be applied. Our findings will inform a larger definitive trial. ETHICS AND DISSEMINATION: Ethical opinion was granted (REC reference: 15/YH/0531). Findings will be published in peer-reviewed journals and at conferences. We will prepare reports for dissemination by organisations involved with PD and dementia. TRIAL REGISTRATION NUMBER: ISRCTN (ISRCTN11455062).

The perception of affective touch in Parkinson's disease and its relation to small fibre neuropathy.

Affective touch sensation is conducted by a sub-class of C-fibres in hairy skin known as C-Tactile (CT) afferents. CT afferents respond maximally to gentle skin stroking at velocities between 1 and 10 cm/s. Parkinson's disease (PD) is characterised by markedly reduced cutaneous C-fibres. It is not known if affective touch perception is influenced by C-fibre density and if affective touch is impaired in PD compared to healthy controls. We predicted that perceived pleasantness to gentle stroking in PD would correlate with C-afferent density and that affective touch perception would be impaired in PD compared to healthy controls. Twenty-four PD patients and 27 control subjects rated the pleasantness of brush stroking at an optimum CT stimulation velocity (3 cm/s) and two sub-optimal velocities (0.3 and 30 cm/s). PD patients underwent quantification of C-fibre density using skin biopsies and corneal confocal microscopy. All participants rated a stroking velocity of 3 cm/s as the most pleasant with significantly lower ratings for 0.3 and 30 cm/s. There was a significant positive correlation between C-fibre density and pleasantness ratings at 3 and 30 cm/s but not 0.3 cm/s. Mean pleasantness ratings were consistently higher in PD patients compared to control subjects across all three velocities. This study shows that perceived pleasantness to gentle touch correlates significantly with C-fibre density in PD. The higher perceived pleasantness in PD patients compared to controls suggests central sensitisation to peripheral inputs, which may have been enhanced by dopamine therapy.

Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study.

UNLABELLED: Autonomic and somatic denervation is well established in Parkinson's disease (PD). OBJECTIVES: (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD. METHODS: Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease - autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III "ON"] and cumulative Levodopa dose. RESULTS: PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction. CONCLUSION: CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD.

Pain in multiple system atrophy and progressive supranuclear palsy compared to Parkinson's disease.

BACKGROUND: Pain is a common nonmotor symptom in Parkinson's disease (PD). The pathophysiology of pain in PD is not well understood. Pain characteristics have rarely been studied in atypical parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP). AIM OF THE STUDY: We aimed to evaluate pain intensity, location, and associated symptoms in atypical parkinsonian disorders compared to PD. METHODS: Twenty-one patients with MSA, 16 patients with PSP, and 65 patients with PD were screened for pain using question 1.9 of the MDS-UPDRS. Pain intensity was quantified using the short form McGill Pain Questionnaire (SFMPQ). Pain locations were documented. Motor disability was measured using UPDRS-III. Affective symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). RESULTS: Pain was significantly more common and more severe in PD and MSA compared to PSP (P < 0.01). Pain locations were similar with limb pain being the most common followed by neck and back pain. Pain intensity correlated with HADS scores but not motor severity. CONCLUSIONS: Pain is more common and more intense in PD and MSA than PSP. Differences in distribution of neurodegenerative pathologies may underlie these differential pain profiles.

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.

Randomized clinical trial of topiramate for levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: The antiepileptic drug topiramate reduces levodopa-induced dyskinesia without exacerbating parkinsonism in animal models. We report a randomized, double-blind, placebo-controlled crossover trial in patients with Parkinson's disease and levodopa-induced dyskinesia. METHODS: Fifteen patients with Parkinson's disease and stable levodopa-induced dyskinesia were enrolled into the study, of whom 13 were randomized to topiramate or placebo. The study medication was titrated to 100 mg/day over four weeks, and assessments were carried out after a further two weeks. Dyskinesia severity assessed by a blinded rater from video recordings was the primary outcome measure. RESULTS: Seven patients (mean age 58.9 ± 12.8 years) completed the study. Patients taking topiramate vs. placebo showed a significant increase in dyskinesia severity compared to baseline (Wilcoxon signed rank test, P = 0.043). Five patients withdrew from the study whilst taking topiramate due to adverse effects. CONCLUSIONS: Topiramate tended to worsen dyskinesia in patients with Parkinson's disease, and was poorly tolerated.

Prominent Lower-Limb Involvement in a Family with Myoclonus-Dystonia.

We report on a large family with myoclonus-dystonia resulting from an epsilon-sarcoglycan mutation, with prominent early and late lower-limb involvement. The proband's condition has evolved to include marked lower-limb dystonia and dystonic gait impairment in the fourth decade. Other family members had evidence of prominent lower-limb involvement at presentation or a more typical phenotype of axial and upper-limb myoclonus and dystonia. Prominent lower-limb involvement developing late in the disease course is an atypical feature and exemplifies the wide phenotypic heterogeneity observed in people with myoclonus-dystonia.