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Movement disorders: Pediatrics Trastornos del movimiento; Pediatría Trastorns del moviment; Pediatria Background The International Parkinson and Movement Disorders Society (MDS) set up a working group on pediatric movement disorders (MDS Task Force on Pediatrics) to generate recommendations to guide the transition process from pediatrics to adult health care systems in patients with childhood-onset movement disorders. Methods To develop recommendations for transitional care for childhood onset movement disorders, we used a formal consensus development process, using a multi-round, web-based Delphi survey. The Delphi survey was based on the results of the scoping review of the literature and the results of a survey of MDS members on transition practices. Through iterative discussions, we generated the recommendations included in the survey. The MDS Task Force on Pediatrics were the voting members for the Delphi survey. The task force members comprise 23 child and adult neurologists with expertise in the field of movement disorders and from all regions of the world. Results Fifteen recommendations divided across four different areas were made pertaining to: (1) team composition and structure, (2) planning and readiness, (3) goals of care, and (4) administration and research. All recommendations achieved consensus with a median score of 7 or greater. Conclusion Recommendations on providing transitional care for patients with childhood onset movement disorders are provided. Nevertheless several challenges remain in the implementation of these recommendations, related to health infrastructure and the distribution of health resources, and the availability of knowledgeable and interested practitioners. Research on the influence of transitional care programs on outcomes in childhood onset movement disorders is much needed. This study was funded by the International Parkinson's and Movement Disorders Society. The authors have no financial disclosures or conflicts of interest concerning the research related to the manuscript.

INTRODUCTION/AIMS Imbalance is a common feature of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Intravenous immunoglobulin (IVIg) exerts clinical benefit in CIDP, including improving balance, although objective markers of efficacy are lacking. Posturography is an established objective marker of balance; therefore, this study aimed to determine the utility of posturography as an objective marker of treatment efficacy in CIDP. METHODS Posturography was performed on 18 CIDP patients, established on IVIg infusions, and results were compared to age-matched healthy controls. CIDP patients were assessed just prior to IVIg infusion and at the mid-point of the cycle. Center of pressure (CoP) was measured and the total path traveled by CoP (Sway Path, SP) was calculated for five different conditions: feet placed in parallel 16 cm apart at the medial border with eyes open (16cmEO) and eyes closed (16cmEC); medial borders of the feet touching with eyes open (0cmEO) and eyes closed (0cmEC); and tandem stance. RESULTS The sway path (SP) was significantly increased in CIDP patients (mean SP 1191 ± 104 mm) when compared to healthy controls (mean SP 724 ± 26 mm, P

Cervical dystonia (CD) is a neurological movement disorder causing the neck to move involuntarily away from the neutral position. CD is a network disorder, involving multiple brain areas and, therefore, may impair movement in parts of the body other than the neck. This study used clinical assessments to investigate walking, balance and upper limb function (UL) in people with CD; the reliability of scoring these assessments and examined for relationship between CD severity, usual exercise and clinical assessments. We conducted a prospective observational cohort study of participants with isolated, focal, idiopathic CD. Participants were assessed by experienced physiotherapists and completed three questionnaires and eight clinical assessments of fear of falling, balance confidence, walking, balance, UL function and usual exercise. Results were compared to published data from healthy adults and other neurological populations. Twenty-two people with mild to moderate CD participated. Fear of falling, gross UL function and usual exercise were worse in people with CD compared with healthy adults, while walking, balance and distal UL function were similar to healthy populations. All assessments were reliably performed by physiotherapists, and we found no correlations between the severity of dystonia or usual exercise and performance on the physical assessments. Routine performance of clinical assessment of walking and balance are likely not required in people with mild to moderate CD; however, fear of falling and gross upper limb function should be assessed to determine any problems which may be amenable to therapy.

Summary Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879. Findings Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI –2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [–1·6 to 3·6], –0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related. Interpretation A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy. Funding AbbVie Inc.

Infusion of levodopa-carbidopa intestinal gel (LCIG; also designated carbidopa-levodopa enteral suspension) for 16 hours is a standard treatment for patients with advanced Parkinson’s disease, and clinical observations suggest that 24-hour LCIG infusion may further reduce symptoms. This review provides practical advice on the management of patients transitioning to 24-hour LCIG infusion. We review available clinical data for 24-hour infusion and discuss adjustments to dosing, recommendations for monitoring, and management of patient concerns, based on our clinical experience. Data from multiple studies suggest that LCIG may improve non-motor symptoms. Although few studies have examined 24-hour LCIG infusion, available data indicate that certain patients may benefit from around-the-clock treatment. Studies of 24-hour LCIG infusion are limited by small sample sizes and open-label study designs, which may hamper translation to clinical practice. In our experience, we have found that patients may benefit from 24-hour infusion when reductions in nocturnal symptoms and improvements to quality of sleep are needed. Levodopa-unresponsive freezing of gait or poorly controlled troublesome dyskinesias may also indicate a patient may benefit from 24-hour infusion. Dose adjustments, especially of the nocturnal rate, are typically necessary and, as with 16-hour infusion, patients should be monitored for autonomic dysfunction; overnight wearing off symptoms; weight changes; fluctuations in plasma levels of vitamins B6/B12, folate, and homocysteine; changes in sleep patterns; or worsening of hallucinations, delusions, and/or nightmares. Available data and our clinical experience suggest that 24-hour LCIG may be warranted among selected patients who have poorly controlled nocturnal fluctuations or early morning “off” symptoms.

Objective: Blepharospasm is a type of dystonia where the diagnosis is often delayed because its varied clinical manifestations are not well recognized. The purpose of this study was to provide a comprehensive picture of its clinical features including presenting features, motor features, and non-motor features.Methods: This was a two-part study. The first part involved a systematic literature review that summarized clinical features for 10,324 cases taken from 41 prior reports. The second part involved a summary of clinical features for 884 cases enrolled in a large multicenter cohort collected by the Dystonia Coalition investigators, along with an analysis of the factors that contribute to the spread of dystonia beyond the periocular region.Results: For cases in the literature and the Dystonia Coalition, blepharospasm emerged in the 50s and was more frequent in women. Many presented with non-specific motor symptoms such as increased blinking (51.9%) or non-motor sensory features such as eye soreness or pain (38.7%), photophobia (35.5%), or dry eyes (10.7%). Non-motor psychiatric features were also common including anxiety disorders (34–40%) and depression (21–24%). Among cases presenting with blepharospasm in the Dystonia Coalition cohort, 61% experienced spread of dystonia to other regions, most commonly the oromandibular region and neck. Features associated with spread included severity of blepharospasm, family history of dystonia, depression, and anxiety.Conclusions: This study provides a comprehensive summary of motor and non-motor features of blepharospasm, along with novel insights into factors that may be responsible for its poor diagnostic recognition and natural history.

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 (

Background The head retraction reflex (HRR) is characterized by the extension of the neck after percussion stimulation of the central facial region. It is either absent or habituates in normal individuals and can become exaggerated and persistent in certain pathological conditions, having been most commonly reported in hyperekplexia and stiff-person syndrome disorders. It has not, however, been reported in Niemann-Pick type C (NPC), a lipid storage disorder with a variety of neurologic and systemic manifestations. The diagnosis of NPC is often delayed because of the rarity of the condition and the subtlety of clinical signs. Cases We present 3 consecutive cases of genetically confirmed NPC with a pathological HRR, which was not present in controls. Neurophysiological analysis showed findings suggestive of myoclonus of brainstem origin. Conclusion We propose that the presence of a pathological HRR, an easily performed clinical test, may provide a clue to the diagnosis of NPC.

Introduction Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these “imaging pearls” into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

Carlos II of Spain (1661–1700), last of the Spanish Habsburgs, was known as The ‘Bewitched’ due to his multiple medical issues and feeble nature. He suffered from a range of ailments extending beyond the well-known Habsburg jaw, including developmental delay, intellectual disability, dysarthria, skeletal deformity, recurrent infections, epilepsy and infertility, among others. The Habsburg dynasty of Spain was characterised by marked inbreeding, and the male line died out with Carlos II. Various diagnoses have been proffered to explain Carlos II’s infirmity, though none have been full satisfactory to explain the full breadth of his ailments. As illustrated here, it may be that aspartylglucosaminuria, an autosomal recessively inherited lysosomal storage disorder, can account for both the characteristic facial features and the wide variety of other features exhibited by Carlos II.

Background Parkinson's disease is a common, progressive neurodegenerative disorder, the prevalence of which is on the rise. The diagnosis and management of Parkinson's disease is therefore likely to become increasingly frequent in general practice. Objective The aim of this article is to provide a practical overview for the general practitioner of the initial diagnosis and management of Parkinson's disease. Discussion Parkinson's disease is a multisystem disorder, and the way the diagnosis is delivered, as well as the early management, can have a lasting impact on the patient experience. In this article, the authors present their preferred approach to diagnosis and initial treatment, while highlighting common pitfalls and some useful simple strategies for communicating the diagnosis.

Introduction IgLON5 autoimmunity has four main clinical patterns; a sleep disorder, bulbar syndrome, PSP-like pattern and predominant cognitive impairment. Other manifestations include movement disorders, gait instability, dysautonomia and neuropsychiatric features [1-3]. Peripheral nervous system involvement has been occasionally reported [3,4]. We describe two cases of IgLON5 autoimmunity presenting with peripheral neuropathy. Cases A 72-year-old lady presented with progressive distal lower limb numbness, paraesthesia, incoordination and gait disturbance. Associated features included fluctuating facial numbness, limb and trunk fasciculations, upper limb tremor, anxiety, episodic hyperventilation, nocturnal myoclonus and vocalisations in sleep. Nerve conduction studies (NCS) demonstrated demyelinating features in the lower limbs. Anti-IgLON5 antibodies were detected in cerebrospinal fluid. She was treated with IVIg, oral prednisolone, azathioprine and plasma exchange. A 73-year-old man presented with worsening tremor. Evolving features included facial paraesthesia, imbalance, head ‘fogginess’, visual agnosia, constipation, insomnia, sleep utterances, somnambulism, nocturnal tremor and myoclonus. NCS showed a generalised demyelinating sensorimotor polyneuropathy. Neuropathy screen demonstrated anti-IgLON5 antibodies and IgG kappa paraprotein, leading to a new diagnosis of monoclonal gammopathy of undetermined significance (MGUS). IgLON5 autoimmunity was considered the likely explanation for the peripheral neuropathy, as sural nerve biopsy findings were not typical for MGUS-related neuropathy. He received IVIg, oral prednisolone, plasma exchange and Rituximab. During follow-up, he progressed to multiple myeloma and commenced lenalidomide and dexamethasone. Conclusion Our two cases and the few published reports suggest an association of peripheral neuropathy and IgLON5 autoimmunity. We recommend cases of IgLON5 autoimmunity undergo routine neurophysiological studies. References Sabater L, Gaig C, Gelpi E, et al. A novel NREM and REM parasomnia with sleep breathing disorder associated with antibodies against IgLON5: a case series, pathological features, and characterisation of the antigen. Lancet Neurology 2014;13:575–586. Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 2017;88:1736–1743. Honorat JA, Komorowski L, Josephs KA, et al. IgLON5 antibody: neurological accompaniments and outcomes in 20 patients. Neurol Neuroimmunol Neuroinflamm 2017;4:e385. doi: 10.1212/NXI.0000000000000385 Wenninger S. Expanding the clinical spectrum of IgLON5-syndrome. Journal of Neuromuscular Diseases 2017;4:337–339.

Introduction Raised intracranial pressure (ICP) headache is rarely caused by spinal cord lesions. We present two patients with rare presentations of uncommon malignancies surrounding the cauda equina resulting in raised ICP headache. Cases Patient 1, a 54-year-old man, presented with two months of headache, blurred vision and 9kg weight loss. Fundoscopy revealed papilloedema. Shortly after presentation he developed lower limb weakness with absent tendon reflexes. MRI brain was unremarkable. MRI spine showed diffuse nerve root thickening and effacement of the CSF spaces around the cauda equina. Patient 2, a 51-year-old man, presented with four months of headache and blurred vision, progressive lower limb weakness and 20kg weight loss over 12 months. MRI brain showed two small lesions insufficient to cause raised ICP. MRI spine showed extensive lower spinal cord infiltration with diffuse thickening of the cauda equina. Pathological assessments revealed malignant histiocytosis in patient 1 and primary leptomeningeal gliomatosis in patient 2. Discussion These cases demonstrate the rare presentation of raised ICP headache resulting from spinal lesions. In both cases the original presentation with raised ICP headache and absent lower limb signs led to diagnostic delay. Malignant lesions in the spinal column can increase ICP, though the mechanism is debated. These cases emphasise the importance of a broader search for the aetiology of raised ICP headache in the absence of a causative lesion on primary brain imaging. Further, these cases highlight rare presentations of two uncommon pathological entities.

Introduction Poor balance is a common and debilitating feature in patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Posturography is an objective method of assessing balance. Intravenous Immunoglobulin (IVIG) exerts clinical benefits in CIDP, including improving balance, although this is difficult to quantify. The present study used posturography as a biomarker for determining IVIG efficacy in CIDP. Methods Eighteen patients with CIDP established on IVIG were compared with healthy controls. Five conditions were used to assess balance: Feet 16cm apart with eyes open and closed, feet together with eyes open and closed (Romberg’s test), and tandem stance. Centre of pressure (COP) was sampled for 15 seconds at 100Hz using a Kistler force platform, and the total path travelled by the COP was calculated (sway path). Testing was performed on the day of IVIG, corresponding to a trough, and at the mid-point of treatment, corresponding to a peak. Results At baseline, there was a significant increase in the sway path in CIDP patients compared with healthy controls (average performance 1191 ± 104mm vs 724 ± 26mm, P Conclusion The present study shows that objective assessment of balance using posturography may serve as a biomarker of IVIG efficacy in patients with CIDP.

The links between the two archetypical basal ganglia disorders, dystonia and parkinsonism, are manifold and stem from clinical observations, imaging studies, animal models and genetics. The combination of both, i.e. the syndrome of dystonia-parkinsonism, is not uncommonly seen in movement disorders clinics and has a myriad of different underlying aetiologies, upon which treatment and prognosis depend. Based on a comprehensive literature review, we delineate the clinical spectrum of disorders presenting with dystonia-parkinsonism. The clinical approach depends primarily on the age at onset, associated neurological or systemic symptoms and neuroimaging. The tempo of disease progression, and the response to L-dopa are further important clues to tailor diagnostic approaches that may encompass dopamine transporter imaging, CSF analysis and, last but not least, genetic testing. Later in life, sporadic neurodegenerative conditions are the most frequent cause, but the younger the patient, the more likely the cause is unravelled by the recent advances of molecular genetics that are focus of this review. Here, knowledge of the associated phenotypic spectrum is key to guide genetic testing and interpretation of test results. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms. α-synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra-neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. There is evidence that pathological α-synuclein exhibits prion-like behaviour in its mode of transmission through the nervous system. The choice of initial dopaminergic treatments should be individually tailored but long term outcomes appear to be equivalent. There is level A evidence supporting the benefit of three different device-assisted therapies in treating troublesome motor fluctuations and dyskinesias. Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device-assisted therapies. New modes of treatment including active immunisation against oligomeric α-synuclein and drugs that alter cellular metabolism show some promise. The inability to effectively treat a range of non-motor, non-dopaminergic symptoms remains a major therapeutic challenge.

Background There are currently no standard diagnostic criteria for characterizing advanced Parkinson’s disease (APD) in clinical practice, a critical component in determining ongoing clinical care and therapeutic strategies, including transitioning to device-aided treatment. The goal of this analysis was to determine the proportion of APD vs. non-advanced PD (non-APD) patients attending specialist PD clinics and to demonstrate the clinical burden of APD. Methods OBSERVE-PD, a cross-sectional, international, observational study, was conducted with 2615 PD patients at 128 movement disorder centers in 18 countries. Motor and non-motor symptoms, activities of daily living, and quality-of-life end points were assessed. The correlation between physician’s global assessment of advanced PD and the advanced PD criteria from a consensus of an international group of experts (Delphi criteria for APD) were evaluated. Results According to physician’s judgment, 51% of patients were considered to have APD. There was a moderate correlation between physician’s judgment and Delphi criteria for APD (K = 0.430; 95% CI 0.406–0.473). Activities of daily living, motor symptom severity, dyskinesia duration/disability, “Off” time duration, non-motor symptoms, and quality-of-life scores were worse among APD vs. non-APD patients (p

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Dopamine agonists (DAs) are frequently used in the management of Parkinson's disease (PD), a complex multisystem disorder influenced substantially by age-related factors. Over 80% of PD patients present after age 60 years and may have clinical features exacerbated by age-related comorbidities or decline in physiological compensatory mechanisms. Pharmacotherapy for motor symptoms in older persons is more likely to involve exclusive use of levodopa combined with a peripheral decarboxylase inhibitor throughout the course of the illness. Non-ergot DAs, such as pramipexole, rotigotine and ropinirole, may be used as de novo monotherapy for the control of motor symptoms in older persons, although they are less efficacious than levodopa therapy. DAs may also be considered as adjunct therapy in older persons when motor symptoms are no longer adequately controlled by levodopa or when motor fluctuations and dyskinesia appear. DAs may be used cautiously in older persons with cognitive impairment and orthostatic hypotension but should be avoided when there is a history or risk of psychosis or impulse control disorders.

Growing evidence suggests that non-motor symptoms (NMS) in Parkinson's disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naïve and non-drug-naïve treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 ± 10.8 years, mean disease duration 6.3 ± 5.6 years, median Hoehn and Yahr stage was 2 (2-3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 ± 37.2. Differences in non-motor burden and patterns differed significantly between drug-naïve participants, those with a disease duration of less than five years, and those with a duration of five years or over (p ≤ 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 ± 36.3; Americas: 55.3 ± 42.8; Asia: 26.6 ± 25.1; p

BACKGROUND Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging. OBJECTIVE We sought to expand the catalogue of monogenic etiologies for isolated dystonia. METHODS After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles. RESULTS Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism. CONCLUSIONS Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Childhood-onset movement disorders represent a heterogenous group of conditions. Given the complexity of these disorders, the transition of care from pediatric to adult medicine is an important consideration. We performed a scoping review of the literature on transitional care in chronic neurological disease, exploring key transitional issues and proposed transitional care models. Our aim was to describe the current knowledge and gaps about the transition process of young adults with chronic neurological disorders, paying special attention to childhood onset movement disorders. A total of 64 articles were included in the qualitative synthesis; 56 articles reported on transitional care issues, and 8 articles reported on transitional care models. Only 2 articles included patients with movement disorders. The following 4 main transitional issues were identified following synthesis of the available literature: (1) inadequate preparation for the transition process, (2) inappropriate and inconsistent transition practices, (3) inadequate adult services, and (4) heightened emotional response surrounding transition. Of the reported transitional care models, multidisciplinary ambulatory care was the most common approach. In studies evaluating patient-related outcomes, positive health, educational, and vocational outcomes were found. The available literature provides insights on issues that can arise during transition that should be addressed to improve patient and caregiver comfort and satisfaction with care. Further research is needed to evaluate how transitional care programs affect outcomes and their cost effectiveness. More studies are required to determine the needs and outcomes specific to patients with childhood onset movement disorders. © 2020 International Parkinson and Movement Disorder Society.

Background Microscopic colitis is a form of inflammatory bowel disease characterized by profuse non-bloody watery diarrhea. Macroscopic abnormality is not present on colonoscopy, and it requires biopsy for diagnosis. Few cases have been attributed to levodopa/dopa-decarboxylase inhibitor therapy. Method A retrospective cohort study of 21 patients on levodopa/benserazide and one patient on levodopa-carbidopa intestinal gel with clinically suspected or biopsy proven microscopic colitis. Results All 21 patients on oral levodopa/benserazide had resolution of diarrhea with cessation of the medication. Four patients discontinued levodopa permanently. Two were rechallenged with levodopa/benserazide without symptom recurrence. One patient on oral levodopa/carbidopa developed diarrhea only with intermittent dispersible levodopa/benserazide. 14 were switched to levodopa/carbidopa with resolution of diarrhea in 9 but symptom recurrence in 5. One patient on oral levodopa/benserazide developed profuse diarrhea when switched to levodopa-carbidopa intestinal gel. Of 7/22 patients who had colonoscopy and biopsy, 5 had histopathological proven microscopic colitis. Conclusion levodopa/dopa-decarboxylase inhibitor induced microscopic colitis may be more common than previously suspected, with the potential to affect treatment compliance and therapeutic options.

ObjectiveTo better characterize oromandibular dystonia (OMD) to facilitate early diagnosis and test the hypothesis that botulinum toxin treatment alleviates symptoms, regardless of etiology, to provide guidance on treatment strategies.MethodsTo better characterize this condition we utilize a three-pronged approach. First, we provide a comprehensive summary of the world’s literature encompassing 1157 cases in 27 separate manuscripts. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter database. Finally, we provide details of the treatment approach and response from two expert centers where large numbers of OMD patients are followed. Cases from expert centers were utilized to analyze whether response to botulinum toxin varied by etiology of OMD.ResultsIn all cohorts, typical age at onset was in the 50s and approximately 70 % of cases were female. Although the literature OMD more commonly described as a focal dystonia, analysis of the DC database revealed it more commonly appears as part of a segmental dystonia. Expert center review of 173 cases revealed botulinum toxin injections improved symptom severity by more than 50% in approximately 78% of subjects. Among the patients at expert centers, analysis revealed that treatment response did not vary by etiology.ConclusionsBotulinum toxin injections are an effective treatment for OMD, regardless of etiology. By providing a more comprehensive description of OMD and the therapeutic efficacy of botulinum toxin for this type of dystonia, we hope to improve clinical recognition to aid in timely diagnosis and inform treatment strategies.

Introduction In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor. Methods 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3–10Hz and to calculate the tremor stability index (TSI). Results Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions. Conclusion These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Levodopa-carbidopa intestinal gel (LCIG) is effective for the control of motor fluctuations in Parkinson’s disease (PD). The objective of this study is to report the reduction of dyskinesias after transitioning from 16 to 24-h/day LCIG infusion. From a cohort of 74 PD patients treated with LCIG for motor fluctuations, we identified 12 patients that were treated with 24-h per day infusion with the aim to control troublesome daytime dyskinesia. Clinical, demographic, dyskinesia rating scales were evaluated. Daytime dyskinesia was reduced in 75% (9/12) patients following treatment with 24-h therapy, including 7 who were compared with 16-h therapy and 2 that were transitioned from oral dopaminergic therapy to 24-h LCIG. Combining the data from all 12 subjects, troublesome dyskinesias were reduced during 24-h LCIG; UPDRS 4.1 (time spent with dyskinesias) mean change was −1.5 ± 0.75, p = 0.010 (Wilcoxon signed-rank test) and UPDRS 4.2 (functional impact of dyskinesias) mean change was −1.7 ± 0.90, p = 0.016, without changing their UPDRS part 3 “ON” scores (p = 0.138) or H&Y (p = 0.157). In 5 patients, improvement in dyskinesia occurred despite an overall increase in the total daily levodopa dose. None of the patients had worsening of dyskinesia after a median follow-up of 28 months. 24-h per day infusion of LCIG may be a useful strategy in the management of troublesome dyskinesias in PD patients with disabling dyskinesias resistant to attempts to optimise 16-hours per day therapy. We postulate that this may be due to a pharmacodynamic as opposed to pharmacokinetic mechanism., Motor symptoms: the benefits of round-the-clock drug delivery Continuous 24-h intestinal administration of Parkinson’s disease (PD) drugs in a gel formulation helps control disabling dyskinesias in patients with advanced PD. Typically, patients treated with levodopa-carbidopa intestinal gel (LCIG) receive a continuous dose that is administered over 16 h. This regimen has been shown to efficiently and safely improve patients’ motor symptoms, although in some cases, daytime dyskinesias persist. Victor Fung at the University of Sydney, Australia, and colleagues examined whether 24-h LCIG infusion offers additional benefits for the treatment of dyskinesias. They found a significant decrease in the frequency and severity of daytime dyskinesia in nine out of twelve (75%) patients, and none of them experienced a worsening of dyskinesia. These results suggest that round-the-clock LCIG is a promising approach for treating troublesome dyskinesias that are resistant to 16-h therapy.

BACKGROUND Levodopa-carbidopa intestinal gel (designated as carbidopa-levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long-term safety and efficacy outcomes from an open-label phase 3 treatment program. METHODS PD patients (n = 262) who completed a 12-week double-blind study and its 52-week open-label extension or a separate 54-week open-label study were enrolled in this ongoing phase 3 open-label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months. RESULTS Mean total duration of exposure to levodopa-carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in "off" time and increases in mean "on" time without dyskinesia from initial levodopa-carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality-of-life assessments demonstrated significant improvements that persisted through the study. CONCLUSIONS This long-term study demonstrates sustained and clinically meaningful benefits from levodopa-carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device-related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.