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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.

We assessed small nerve fibre degeneration and regeneration in more and less affected sides in Parkinson’s disease (PD). Bilateral skin biopsies from 23 PD patients were immunostained for PGP9.5 for Intraepidermal Nerve Fibre Density (IENFD) and GAP-43 for mean axonal length (MAL), total epidermal (TNFL) and subepidermal nerve fibre length (SKTNFL). IENFD (p

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.

Deep brain stimulation of the subthalamic nucleus is an effective and established therapy for patients with advanced Parkinson’s disease improving quality of life, motor symptoms and non-motor symptoms. However, there is a considerable degree of interindividual variability for these outcomes, likely due to variability in electrode placement and stimulation settings. Here, we present probabilistic mapping data from a prospective, open-label, multicentre, international study to investigate the influence of the location of subthalamic nucleus deep brain stimulation on non-motor symptoms in patients with Parkinson’s disease. A total of 91 Parkinson’s disease patients undergoing bilateral deep brain stimulation of the subthalamic nucleus were included, and we investigated NMSScale, NMSQuestionnaire, Scales for Outcomes in Parkinson’s disease-motor examination, -activities of daily living, and -motor complications, and Parkinson’s disease Questionnaire-8 preoperatively and at 6-month follow-up after surgery. Leads were localized in standard space using the Lead-DBS toolbox and individual volumes of tissue activated were calculated based on clinical stimulation settings. Probabilistic stimulation maps and non-parametric permutation statistics were applied to identify voxels with significant above or below average improvement for each scale and analysed using the DISTAL atlas. All outcomes improved significantly at follow-up. Significant spatial distribution patterns of neurostimulation were observed for NMSScale total score and its mood/apathy and attention/memory domains. For both domains, voxels associated with below average improvement were mainly located dorsal to the subthalamic nucleus. In contrast, above average improvement for mood/apathy was observed in the ventral border region of the subthalamic nucleus and in its sensorimotor subregion and for attention/memory in the associative subregion. A trend was observed for NMSScale sleep domain showing voxels with above average improvement located ventral to the subthalamic nucleus. Our study provides evidence that the interindividual variability of mood/apathy, attention/memory, and sleep outcomes after subthalamic nucleus deep brain stimulation depends on the location of neurostimulation. This study highlights the importance of holistic assessments of motor and non-motor aspects of Parkinson’s disease to tailor surgical targeting and stimulation parameter settings to patients’ personal profiles.

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 mid-cingulate cortex and supplementary motor area in the Parkinson's disease group compared to the healthy control group during Mid [-1500 -1000] 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. This article is protected by copyright. All rights reserved.

[Image: see text] Parkinson’s disease (PD) is a progressive, neurodegenerative disease that presents with significant motor symptoms, for which there is no diagnostic chemical test. We have serendipitously identified a hyperosmic individual, a “Super Smeller” who can detect PD by odor alone, and our early pilot studies have indicated that the odor was present in the sebum from the skin of PD subjects. Here, we have employed an unbiased approach to investigate the volatile metabolites of sebum samples obtained noninvasively from the upper back of 64 participants in total (21 controls and 43 PD subjects). Our results, validated by an independent cohort (n=31), identified a distinct volatiles-associated signature of PD, including altered levels of perillic aldehyde and eicosane, the smell of which was then described as being highly similar to the scent of PD by our “Super Smeller”.

Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD-specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item-total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non-Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD. © 2015 International Parkinson and Movement Disorder Society. (Less)

Summary Background Deep brain stimulation (DBS) has been proposed as a treatment option for severe Tourette's syndrome on the basis of findings from open-label series and small double-blind trials. We aimed to further assess the safety and efficacy of bilateral globus pallidus internus (GPi) DBS in patient's with severe Tourette's syndrome. Methods In a randomised, double-blind, crossover trial, we recruited eligible patients (severe medically refractory Tourette's syndrome, age ≥20 years) from two clinics for tertiary movement disorders in the UK. Enrolled patients received surgery for GPi DBS and then were randomly assigned in a 1:1 ratio (computer-generated pairwise randomisation according to order of enrolment) to receive either stimulation on-first or stimulation off-first for 3 months, followed by a switch to the opposite condition for a further 3 month period. Patients and rating clinicians were masked to treatment allocation; an unmasked clinician was responsible for programming the stimulation. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) total score between the two blinded conditions, assessed with repeated measures ANOVA, in all patients who completed assessments during both blinded periods. After the end of the blinded crossover phase, all patients were offered continued DBS and continued to have open-label stimulation adjustments and objective assessments of tic severity until database lock 1 month after the final patient's final trial-related visit. This trial is registered with ClinicalTrials.gov, number NCT01647269. Findings Between Nov 5, 2009, and Oct 16, 2013, we enrolled 15 patients (11 men, four women; mean age 34·7 years [SD 10·0]). 14 patients were randomly assigned and 13 completed assessments in both blinded periods (seven in the on-first group, six in the off-first group). Mean YGTSS total score in these 13 patients was 87·9 (SD 9·2) at baseline, 80·7 (SD 12·0) for the off-stimulation period, and 68·3 (SD 18·6) for the on-stimulation period. Pairwise comparisons in YGTSS total scores after Bonferroni correction were significantly lower at the end of the on-stimulation period compared with the off-stimulation period, with a mean improvement of 12·4 points (95% CI 0·1–24·7, p=0·048), equivalent to a difference of 15·3% (95% CI 5·3–25·3). All 15 patients received stimulation in the open-label phase. Overall, three serious adverse events occurred (two infections in DBS hardware at 2 and 7 weeks postoperatively, and one episode of deep-brain-stimulation-induced hypomania during the blinded on-stimulation period); all three resolved with treatment. Interpretation GPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. Future research should concentrate on identifying the most effective target for DBS to control both tics and associated comorbidities, and further clarify factors that predict individual patient response. Funding UK National Health Service.

Background and purpose Non-motor symptoms (NMSs) occurring at an early stage of Parkinson's disease (PD) may impair quality of life more than motor symptoms. This study aimed to evaluate the severity of overall NMS profile and burden of NMSs in early PD patients, treated (time since confirmed diagnosis of 5 years or less) or drug naive (DN). Methods Cross-sectional data from an ongoing multicentre study (16 sites) were obtained and specifically an NMS data set from validated scales was analysed in treated and DN PD patients. Results A full data set was available in 234 unique early PD patients. Of them, there were 170 treated (63.5% males, mean age 68.2 years) and 64DN patients (64.1% males, mean age 66.5 years). Compared to DN patients the time since confirmed diagnosis was significantly longer in treated PD patients (1.9 years vs. 3.7 years, P

Introduction: Deep brain stimulation (DBS) markedly improves motor function in advanced Parkinson’s disease (PD), but its effect on sleep is less clear. Patients and methods: Forty PD patients who had subthalamic DBS (STN-DBS) were identified from an on-going non-motor naturalistic longitudinal study (NILS). All patients were followed up for at least 6 months, 26 patients had a 1 year follow-up. A total PDSS score of 100 or less, a score in any PDSS-item of 6 or less, and a Epworth score of 10 or more were classified as being significant. Results: Forty-five percent of patients reported significant improvement in the total PDSS score at 6 months, and 35% at 12 months. In terms of magnitude, the total PDSS score at 6 months was significantly improved from baseline while the improvement at 12 months was not statistically significant. The most frequently reported improvements were overall sleep quality and maintenance of sleep. Some patients reported worsening of the total PDSS score. More than half of the patients reporting daytime sleepiness at baseline had persistent sleepiness at 6 and 12 months. The mean Epworth Score did not improve because a significant number of patients without sleepiness at baseline reported new-onset sleepiness at 6 and 12 months. Neither medication changes nor motor improvement were consistently related to sleep changes after DBS. Conclusion: Subthalamic DBS is associated with a statistically and clinically significant, but variable, improvement in sleep as measured by the PDSS. The most frequent improvements were better overall sleep quality and better sleep maintenance., Deep brain stimulation: variable effects on sleep Subthalamic deep brain stimulation (DBS) improves sleep quality and maintenance in a subset of patients with Parkinson’s disease (PD). DBS is known to markedly improve motor function PD patients, but its effects on sleep are unclear. Most patients with advanced PD experience sleep problems that adversely affect their quality of life. Jonathan Ellenbogen, at Kings College Hospital in London, UK, and colleagues investigated the long-term effects of DBS on sleep in 40 patients using a PD-specific sleep symptom questionnaire. Eighteen patients (45%) reported a significant overall improvement in sleep quality and maintenance after 6 months, but three of them (7.5%) reported a worsening of sleep symptoms. There was no correlation between the improvement in motor function and sleep improvement following DBS indicating that further research is required to optimize the effects of DBS on sleep.

OBJECTIVE: The optimal timing of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) is a topic of ongoing debate. In patients with short disease duration an improvement of quality of life (QoL) has been demonstrated for patients aged younger than 61 years. However, this has not been systematically investigated in older patients yet. We hypothesized that patients aged 61 years or older experience a significant QoL improvement after STN-DBS with no difference in effect sizes for groups of patients with short and longer disease duration.MATERIALS AND METHODS: From four centers (Cologne, London, Manchester, Venice) we identified "older patients" aged 61 years or older with short (≤8 years) or longer disease duration and compared QoL, motor impairment, complications, medication requirements, and Mini-Mental State Examination (MMSE) on baseline and five months after surgery.RESULTS: Mean age/disease duration in 21 subjects with shorter disease duration were 65.5/6.3 years compared to 66.8/14.6 in 33 subjects with longer disease duration. The short disease duration group was affected by less baseline motor complications (p = 0.002). QoL in the short/longer disease duration group improved by 35/20% (p = 0.010/p = 0.006), motor complications by 40/44% (p = 0.018/p CONCLUSION: Patients aged 61 years or older benefited from STN-DBS regardless of short (≤8 years) or longer (>8 years) disease duration. Our results contribute to the debate about DBS selection criteria and timing and call for prospective confirmation in a larger cohort.

The purpose of this study was to investigate how quality of life outcome after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on age.In this prospective, open-label, multicenter study including 120 PD patients undergoing bilateral STN-DBS, we investigated the PDQuestionnaire-8 (PDQ-8), Unified PD Rating Scale-III, Scales for Outcomes in PD-motor examination, complications, activities of daily living, and levodopa equivalent daily dose preoperatively and at 5 months follow-up. Significant changes at follow-up were analyzed with Wilcoxon signed-rank test and Bonferroni correction for multiple comparisons. To explore the influence of age post hoc, the patients were classified into 3 age groups (≤59, 60-69, ≥70 years). Intragroup changes were analyzed with Wilcoxon signed-rank and intergroup differences with Kruskal-Wallis tests. The strength of clinical responses was evaluated using effect size.The PDQuestionnaire-8, Scales for Outcomes in PD-motor complications, activities of daily living, and levodopa equivalent daily dose significantly improved in the overall cohort and all age groups with no significant intergroup differences. However, PDQuestionnaire-8 effect sizes for age groups ≤59, 60 to 69, and ≥70 years, respectively, were strong, moderate, and small. Furthermore, PDQuestionnaire-8 domain analyses revealed that all domains except cognition and emotional well-being significantly improved in patients aged ≤59 years, whereas only communication, activities of daily living, and stigma improved in patients aged 60-69 years, and activities of daily living and stigma in patients aged ≥70 years.Although quality of life, motor complications, and activities of daily living significantly improved in all age groups after bilateral STN-DBS, the beneficial effect on overall quality of life was more pronounced and affected a wider range of quality of life domains in younger patients. © 2017 International Parkinson and Movement Disorder Society.

The objective of this study was to investigate 24-month of effects of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on nonmotor symptoms in Parkinson's disease (PD).In this prospective, observational, multicenter, international study including 67 PD patients undergoing bilateral STN-DBS, we examined the Non-motor Symptom Scale, Non-Motor Symptoms Questionnaire, Parkinson's Disease Questionnaire-8, Scales for Outcomes in Parkinson's Disease-motor examination, -activities of daily living, and -complications, and levodopa-equivalent daily dose preoperatively and at 5 and 24-month of follow-up. After checking distribution normality, longitudinal outcome changes were investigated with Friedman tests or repeated-measures analysis of variance and Bonferroni correction for multiple comparisons using multiple tests. Post hoc, Wilcoxon signed rank t tests were computed to compare visits. The strength of clinical responses was analyzed using effect size. Explorative Spearman correlations of change scores from baseline to 24-month follow-up were calculated for all outcomes.The Non-motor Symptom Scale and all other outcome parameters significantly improved from baseline to the 5-month follow-up. From 5 to 24-month, partial decrements in these gains were found. Nonetheless, comparing baseline with 24-month follow-up, significant improvements were observed for the Non-motor Symptom Scale (small effect), Scales for Outcomes in PD-motor examination showed a moderate effect, and Scales for Outcomes in Parkinson's Disease-complications and levodopa-equivalent daily dose showed large effects. Non-motor Symptom Scale change scores from baseline to 24-month follow-up correlated significantly with Parkinson's Disease Questionnaire-8, Scales for Outcomes in Parkinson's Disease-activities of daily living, and -motor complications change scores.This study provides evidence of beneficial effects of bilateral STN-DBS on nonmotor symptoms at 24-month follow-up. The extent of nonmotor symptom improvement was directly proportionate to improvements in quality of life, activities of daily living, and motor complications. This study underlines the importance of nonmotor symptoms for holistic assessments of DBS outcomes. © 2018 International Parkinson and Movement Disorder Society.

IntroductionAlthough 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.ObjectivesHere, 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.MethodsFifteen 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.ResultsOur 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.ConclusionAs far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.

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 1-10 cm/sec. 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 (3cm/sec) and two sub-optimal velocities (0.3cm/sec & 30cm/sec). PD patients underwent quantification of C-fibre density using skin biopsies and corneal confocal microscopy. All participants rated stroking velocity of 3cm/sec as the most pleasant with significantly lower ratings for 0.3cm/sec and 30cm/sec. There was a significant positive correlation between C-fibre density and pleasantness ratings at 3cm/sec and 30cm/sec but not 0.3cm/sec. 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 correlate 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. This article is protected by copyright. All rights reserved.

As well as being an effective treatment for well selected Parkinson’s disease patients, Deep Brain Stimulation (DBS) is also a beneficial treatment for Movement Disorders other than Parkinson’s disease. In the treatment of dystonia, the most common target is the internal globus pallidus (GPi). Focal and generalised primary dystonia will often respond extremely well to bilateral GPi DBS. More modest improvements can be seen in the management of secondary dystonia. In the treatment of Essential Tremor, the usual target is either the ventral intermediate nucleus of the thalamus (VIM) or the zona incerta (ZI). Bilateral VIM or ZI DBS is often a very effective treatment for Essential Tremor and other tremor syndromes. DBS is sometimes used to treat Tourette syndrome, chorea, myoclonus and tardive syndromes. Impressive results are often seen in these other conditions, although further research is needed to clarify which patients will benefit. DBS does not improve patients with Parkinson Plus disorders.

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.

Neurophysiology constitutes a potentially useful aid in differentiating hyperkinetic movement disorders (HMD). Parameters including presence of a Bereitschaftspotential on back-averaged 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.We retrospectively reviewed records of 39 patients with HMD who underwent EEG back-averaging through this service from January 2009 until January 2018. The aim was to determine how frequently neurophysiology altered the final diagnosis.We reviewed 39 patients (23 females, 16 males), with a mean age at onset of 42.6 years and mean disease duration of 2.0 years. The clinical diagnosis was altered in 23 cases (59%). Distractibility (P=0.001), variability (P=0.002), the presence of a Bereitschaftspotential (P 300 ms (P=0.012) were more frequent in those with a final diagnosis of functional movement disorder than other HMD.Neurophysiology is an invaluable adjunct in complex HMD, altering the diagnosis and treatment options for a significant proportion of patients. We hope these results will be beneficial for other units considering establishing this type of service.

We describe a method for evaluating facial expressivity in order to improve related clinical assessments of Parkinson’s Disease (PD). There is a controversial evidence in the literature that PD facial impairment can be detected on certain emotional expressions. This study aimed to investigate the feasibility of discriminative and quantitive measures of PD from the ability of a subject to express facial expressions. Video clips of 8 subjects (4 healthy controls and 4 with patients with PD) were recorded during daily sessions over several weeks. Observations covered emotion variation over one week for control subjects and six weeks for patients with PD. A statistical shape model was used to track facial expressions and to measure the amount of expressivity exhibited by each subject. The study suggests that measures of the amount of movement during happiness, disgust and anger expressions are the most discriminative, with PD patients exhibiting less movement than controls. This work demonstrates that it may be possible to measure day-to-day variations in symptoms of PD automatically.

Background: STN-DBS is well established to improve motor symptoms and quality of life in patients with PD. While non-motor symptoms are crucial for quality of life in these patients, only neuropsychiatric and neuropsychological symptoms have been systematically studied in a longitudinal design so far. However, these are only a part of the non-motor symptoms spectrum. Hypothesis: We hypothesized that STN-DBS is associated with a beneficial effect on a range of non-motor symptoms. Methods: In this multicenter, open, prospective, international study (EuroInf-study, UKCRN10084/DRKS00006735) we investigated non-motor effects of STN-DBS in "real-life" use. We evaluated Non-motor Symptom Scale, and Questionnaire, PD Questionnaire-8, Scales for Outcomes of PD motor examination and complications, and activities of daily living preoperatively and at 6 months follow-up in 60 consecutive patients (35 male, mean age: 61.6 ± 7.8 years, mean disease duration: 10.4 ± 4.2 years). Results: All outcomes improved significantly at 6 months follow-up (PD Questionaire-8, p = 0.006; activities of daily living, p = 0.012; all others, p < 0.001; Wilcoxon signed-rank, respectively paired t-test; Bonferroni-correction). Post-hoc analyses of Non-motor Symptom Scale domains showed a significant reduction of sleep/fatigue and miscellaneous domains (p ≤ 0.001), perceptual problems/hallucinations (p = 0.036), and urinary (p = 0.018) scores. Effect sizes were "moderate" for Non-motor Symptom Scale, and motor complications, "large" for motor examination, and "small" for other outcomes. Conclusions: This study provides evidence that bilateral STN-DBS improves non-motor burden in patients with PD and opens the door to a more balanced evaluation of DBS outcomes. Further randomized studies are needed to confirm these findings and compare DBS non-motor effects to other invasive therapies of advanced PD.

This article examines movement disorders other than Parkinson's disease, including ataxias and hyperkinetic movement disorders. Ataxias are caused by dysfunction of the cerebellum or its connections and cause irregular disordered movement. Hyperkinetic movement disorders involve involuntary movements that often interfere with normal movements. There are several different hyperkinetic movement disorders, which can usually be distinguished by clinical assessment: in chorea, the involuntary movements are random in nature; in dystonia, the movements are patterned; in tremor, the movements are rhythmic; in myoclonus, the movements are very brief, jerky and irregular; and in tics, the movements are suppressible and associated with an underlying urge sensation This article gives an approach to diagnosing patients with ataxic and hyperkinetic movement disorders, and discuss some of the more common and important associations. It also discusses treatment including using deep brain stimulation, which can be extremely effective in correctly selected patients.

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

Orolingual tremors include tremors of the jaw, tongue, pharynx, and face. There is currently no accepted classification scheme for such tremors. A proper classification scheme for orolingual tremors should aid in providing more accurate diagnoses and permit future research studies assessing important aspects such as pathogenesis or novel therapies using more uniformly defined and characterized populations. In this review, we propose a classification system for orolingual tremor based on the consensus statement of the Movement Disorder Society on tremor. We also present cases of orolingual tremor and include these cases in the classification system.

Current treatments for Parkinson's disease (PD) are plagued by motor complications. Here these underlying motor complications are briefly reviewed, and strategies to reduce them are discussed.The rationale behind the use of continuous dopaminergic stimulation is highlighted as this is a strategy that may reduce motor complications and improve the quality of life for patients with PD. Copyright © 2007 Wiley Interface Ltd

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

Long-term levodopa or dopamine agonist treatment in the MPTP-lesioned primate model of Parkinson's disease elicits dyskinesia, which is phenotypically similar to levodopa-induced dyskinesia in patients with Parkinson's disease. AMPA receptor antagonists have previously been shown to have both anti-parkinsonian and anti-dyskinetic actions in MPTP-lesioned primates, suggesting that AMPA receptor transmission is functionally overactive under these conditions. In this study, we investigated the level of striatal AMPA receptor binding in the MPTP lesioned primate using the selective AMPA ligand (3)H-(S)-5-fluorowillardiine. AMPA receptor binding was studied in non-parkinsonian, non-dyskinetic parkinsonian, and dyskinetic macaques. Striatal AMPA receptor binding was not different in any of the treatment groups (P > 0.05). Although AMPA receptor-mediated transmission is functionally overactive in Parkinson's disease and dyskinesia, changes in striatal AMPA receptor levels are not likely to be the cause of such movement disorders.

Introduction Parkinson9s 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 Parkinson9s-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).

Background Recent studies have demonstrated that, contrary to common perception non-motor symptoms (NMS) occur and may dominate early and untreated stage of Parkinson's disease (PD). Objective The aim of this ongoing study was to describe the overall NMS profile and burden in drug naive PD patients (DNPD) compared to a group of long-term PD patients (LTPD, disease duration ≥15 years). Methods Cross sectional UK data from a multicenter (16 sites) collaboration were obtained and specifically NMS dataset from validated scales were analysed in DNPD and LTPD patients. The NMS scale (NMSS) was used as the primary outcome variable. Results Out of a current database of 468 PD patients, 57 were DNPD (58% males, mean age 64.8 years, median Hoehn and Yahr stage 1) and 25 were LTPD (44%, mean age 67.6 years, median Hoehn and Yahr stage 3). DNPD patients had a significantly lower (p = 0.001) NMSS score (mean 45.5, range 1-150) compared to the LTPD patients (mean 74.0, range 6-155), but 26.3% had severe and 19.3% had very severe burden of NMSS using NMSS cutoff scores. In comparison, 20.0% of the LTPD patients had severe and 60.0% very severe burden of NMS (p = 0.003). Conclusions NMS are common in DNPD patients and over 45% may have severe to very severe burden of NMS, which is a key determinant of quality of life. In LTPD patients not only the burden of "very severe" NMS is significantly higher, but there are also differences in the profile of expression of NMS.

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.

Item does not contain fulltext BACKGROUND: Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. METHODS: In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. FINDINGS: Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1.8 points (95% CI 0.5-3.0, p=0.005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1.4 points (95% CI 0.0-2.9, p=0.05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0.03 (95% CI 0.01-0.05; p=0.0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0.81, 95% CI 0.61-1.08, p=0.14), admissions to institutions (0.86, 0.63-1.18; p=0.4), and death (0.85, 0.69-1.06, p=0.17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p

High levels of both endocannabinoids and endocannabinoid receptors are present in the basal ganglia. Attention has recently focused on the role of endocannabinoids in the control of movement and in movement disorders of basal ganglia origin such as Parkinson's disease. We investigated CB1 cannabinoid receptor mRNA expression in the reserpine-treated rat model of Parkinson's disease using in situ hybridization. Reserpine treatment caused a topographically organized reduction in CB1 receptor mRNA expression in the striatum (ranging from 11.6% medially to 53.6% laterally and dorsally). No change in CB1 receptor mRNA expression was observed in the cerebral cortex or septum. This reduction in CB1 receptor mRNA expression may be secondary to increased endocannabinoid stimulation of the receptor as increased basal ganglia endocannabinoid levels have been shown to occur in this model of Parkinson's disease. The data support the idea that cannabinoid receptor antagonists may provide a useful treatment for the symptoms of Parkinson's disease.

Introduction: Neuromelanin-sensitive (NM) magnetic resonance imaging visualizes dopaminergic neuronal loss in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD), and may be a useful diagnostic marker Methods: Fifty-five patients with early stage PD and 12 age-matched healthy volunteers (HV) underwent 3T MR scanning. SNc volumes were determined according to the threshold of background signal intensity+3SD. SNc volumes were also compared between HV and three PD sub-groups as divided by UPDRS 3 scores with tertile calculations, using analysis of covariance (ANCOVA), adjusting by regional volumes and age. Results: PD patients showed marked reductions of SNc volumes compared to HV (p

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379CT, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

The relevance of impaired neurovascular function in idiopathic Parkinson's disease (IPD) is unknown. Furthermore, it is unknown whether any such changes might contribute to, or be the effect of, neurodegeneration, or potentially reflect comorbid cerebrovascular disease (CVD). MRI arterial spin labelling (ASL) is a suitable, non-invasive tool for quantifying cerebral haemodynamics including measurements of cerebral blood flow (CBF) and arterial arrival time (AAT). Prolonged AAT has been attributed to increased collateral circulation, chronic vasodilatation and/or increased tortuosity of vessels.12 subjects with CVD (mean age 68.9±7.8), 19 tremor dominant (TD) IPD subjects (mean age 67.2±0.6), 17 postural instability and gait dominant (PIGD) IPD subjects (mean age 70.7±6.6) and 23 control subjects (mean age 65.1±5.7) completed a 3T MRI scanning protocol, including ASL. CVD subjects had significantly more cerebrovascular risk factors than the other groups. A significant widespread increase in baseline AAT was seen in IPD (both TD and PIGD) and CVD groups when compared to controls. Voxel-based analysis of CBF revealed significant focal hypoperfusion (predominantly posteriorly) in the TD, PIGD and the CVD groups when compared to controls.These novel findings suggesting similar alterations in cerebral haemodynamics in IPD and CVD groups merit further study.

To date, the lack of highly selective antagonists at the dopamine D(3) receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D(3) versus D(2) receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D(3)-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D(3) receptor stimulation. Indeed, stimulation of D(3) receptors may be detrimental to the anti-parkinsonian properties of D(2)/D(3) agonists. Selectivity for stimulation of D(2), over D(3), receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.