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Introduction: Daytime sleepiness, reported in about 50 % of patients with Parkinson's disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and co-morbidites on this relationship is inadequate., Methods: Data were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was excessive daytime sleepiness (EDS), as measured by the Epworth Sleepiness Scale (ESS; ESS score > 10). The primary exposure variable was orthostatic hypotension (OH). Linear and logistic regression analyses followed by moderated graphical network analyses were conducted to explore the complex association between OH and ESS. Edge weight from graphical network analysis indicates the strength of the association., Results: Data on 453 subjects with PD were analyzed. Median disease duration was 5.8 years and nearly 90 % were H&Y stage <3. OH was not associated with EDS. OH was associated with depression (edge weight, 0.22) in cognitively impaired patients but not in cognitively normal patients. In addition, depression was associated with ESS (edge weight, 0.37; moderation weight, 0.22) in cognitively impaired patients to a greater extent than in cognitively normal patients (edge weight, 0.22)., Conclusions: OH is not directly associated with daytime sleepiness in early, treated PD. However, OH seems to be associated with ESS via depression in cognitively impaired patients. This complex relationship deserves additional study., Competing Interests: Declaration of competing interest All authors reports no relevant financial disclosures or conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing-WES; whole-genome sequencing-WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia., Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia., Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation., Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small., Conclusions: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Smartphone applications (apps) are instruments that assist with objective measurements during the clinical assessment of patients with movement disorders. We aim to test the hypothesis that Parkinson's disease (PD) patients will exhibit an increase in tapping variability and a decrease in tapping speed over a one-year period, compared to healthy controls (HC)., Methods: Data was prospectively collected from participants enrolled in our Cincinnati Cohort Biomarker Program, in 2021-2023. Participants diagnosed with PD and age-matched HC were examined over a one-year-interval with a tapping test performed with customized smartphone app. Tapping speed (taps/s), inter-tap intervals and variability (movement regularity), and sequence effect were measured., Results: We included 295 PD patients and 62 HC. At baseline, PD subjects showed higher inter-tap variability than HC (coefficient-of-variation-CV, 37 ms [22-64] vs 26 ms [8-51]) (p = 0.007). Conversely, there was no difference in inter-tap intervals (411 ms [199-593] in PD versus 478 ms [243-618] in HC) and tapping speed (3.42[2.70-4.76] taps/s in PD versus 3.21 taps/s [2.57-4.54] in HC) (p > 0.05). Only PD subjects (n = 135), at the one-year follow-up, showed a decreased tapping speed vs baseline (3.44 taps/s [2.86-4.81] versus 3.39 taps/s [2.58,4.30]) (p = 0.036), without significant changes in inter-tap variability (CV, 32 ms [18,55] baseline versus 34 ms [22,59] follow-up) (p = 0.142). No changes were found in HC at the one-year follow up (all p values>0.05)., Conclusions: Inter-tap variability (dysrhythmia) but no inter-tap intervals or tapping speed are reliably distinctive feature of an app-based bradykinesia assessment in PD., Competing Interests: Declaration of competing interest Dr. Luca Marsili has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support, and personal compensation as a consultant/scientific advisory board member for Acadia. Dr. Marsili has received a grant (collaborative research agreement) from the International Parkinson's and Movement Disorders Society for the MDS-UTRS Validation Program (Role: PI), Non-Profit. Dr. Alberto J. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion. Dr. Espay is cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies. Drs. Abanto, Mahajan, Duque, Chinchihualpa Paredes, Deraz, and Bologna report no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia., Methods: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year., Results: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). Higher GAD scores at baseline predicted lower HR-QoL related to general health, pain and emotional well-being, whereas higher SAD scores predicted higher pain-related QoL after 2 years (all p ≤ 0.006). Dystonia severity at baseline predicted social functioning (p = 0.002). Neither dystonic tremor, age, or sex predicted HR-QoL at 2 years. Two latent categories were revealed across the three-time points: Category 1 with higher total HR-QoL scores (mean HR-QoL = 74.4% ± 16.1), susceptible to symptoms of depression and SAD, and Category 2 with lower total HR-QoL scores (mean HR-QoL = 45.5% ± 17.6), susceptible to symptoms of GAD. HR-QoL improved over the course of 1 year irrespective of the use of BoNT., Conclusion: The longitudinal impact of psychiatric symptoms on HR-QoL emphasizes the importance of incorporating mental health treatment, in particular also the therapy of anxiety disorders, into treatment regimens for dystonia., (© 2023. The Author(s).)

Background: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies., Objective: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies., Methods: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration., Results: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05)., Conclusions: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Clinical trials of putative disease-modifying therapies in neurodegeneration have obeyed the century-old principle of convergence, or lumping, whereby any feature of a clinicopathologic disease entity is considered relevant to most of those affected. While this convergent approach has resulted in important successes in trials of symptomatic therapies, largely aimed at correcting common neurotransmitter deficiencies (e.g., cholinergic deficiency in Alzheimer's disease or dopaminergic deficiency in Parkinson's disease), it has been consistently futile in trials of neuroprotective or disease-modifying interventions. As individuals affected by the same neurodegenerative disorder do not share the same biological drivers, splitting such disease into small molecular/biological subtypes, to match people to therapies most likely to benefit them, is vital in the pursuit of disease modification. We here discuss three paths toward the splitting needed for future successes in precision medicine: (1) encourage the development of aging cohorts agnostic to phenotype in order to enact a biology-to-phenotype direction of biomarker development and validate divergence biomarkers (present in some, absent in most); (2) demand bioassay-based recruitment of subjects into disease-modifying trials of putative neuroprotective interventions in order to match the right therapies to the right recipients; and (3) evaluate promising epidemiologic leads of presumed pathogenetic potential using Mendelian randomization studies before designing the corresponding clinical trials. The reconfiguration of disease-modifying efforts for patients with neurodegenerative disorders will require a paradigm shift from lumping to splitting and from proteinopathy to proteinopenia., (Copyright © 2023 Elsevier B.V. All rights reserved.)

According to expert consensus, dystonia can be classified as focal, segmental, multifocal, and generalized, based on the affected body distribution. To provide an empirical and data-driven approach to categorizing these distributions, we used a data-driven clustering approach to compare frequency and co-occurrence rates of non-focal dystonia in pre-defined body regions using the Dystonia Coalition (DC) dataset. We analyzed 1,618 participants with isolated non-focal dystonia from the DC database. The analytic approach included construction of frequency tables, variable-wise analysis using hierarchical clustering and independent component analysis (ICA), and case-wise consensus hierarchical clustering to describe associations and clusters for dystonia affecting any combination of eighteen pre-defined body regions. Variable-wise hierarchical clustering demonstrated closest relationships between bilateral upper legs (distance = 0.40), upper and lower face (distance = 0.45), bilateral hands (distance = 0.53), and bilateral feet (distance = 0.53). ICA demonstrated clear grouping for the a) bilateral hands, b) neck, and c) upper and lower face. Case-wise consensus hierarchical clustering at k = 9 identified 3 major clusters. Major clusters consisted primarily of a) cervical dystonia with nearby regions, b) bilateral hand dystonia, and c) cranial dystonia. Our data-driven approach in a large dataset of isolated non-focal dystonia reinforces common segmental patterns in cranial and cervical regions. We observed unexpectedly strong associations between bilateral upper or lower limbs, which suggests that symmetric multifocal patterns may represent a previously underrecognized dystonia subtype., Competing Interests: JRY’s institution receives grant funding on his behalf from the National Institutes of Health (NIH). BB has received research grant support from the Dystonia Coalition (DC), the Parkinson’s Foundation (PF), the VCU School of Medicine, the Administration for Community Living, and the Dystonia Medical Research Foundation (DMRF). He has received honoraria from the International Parkinson and Movement Disorder Society (MDS) and serves on the medical advisory board of the Benign Essential Blepharospasm Research Foundation (BEBRF) and the National Spasmodic Torticollis Association. HJ has grant support (recent, active, or pending) from the US government (National Institutes of Health), private philanthropic organizations (Cure Dystonia Now), and industry (Addex, Aeon, Revance, Jazz) and has also served on advisory boards or as a consultant for Addex, Allergan, Apello, CoA Therapeutics, Cavion, Daiichi Sankyo, Ipsen, PureTech, Retrophin, Revance and Takaha/Ene. HJ has received honoraria or stipends for lectures or administrative work from the MDS and has also served on the Scientific Advisory Boards for several private foundations including the BEBRF, Cure Dystonia Now, the DMRF, the Tourette Association of America, and Tyler’s Hope for a Cure. JF is funded through an internal grant at the University of Colorado and through a philanthropic grant from the Mowry family. AW reports grant support from the NIH R01NS122943 as PI and RO1 NS121120-01 as a Co-I and reports past funding from BEBRF, DC, DMRF, and National Organization for Rare Disorders. AW has received consultant fees from Merz, Jazz and Acadia and is the current Vice President for the Tremor Research Group and recent advisor for Supernus and Biogen-Sage. AM has been funded by the DMRF, Sunflower Parkinson’s Disease Foundation and the PF. KD has received honoraria from the PF for web support. SP’s institution receives grant funding on her behalf from the NIH (P20 GM109899; U54 NS116025), Department of Defense (W81XWH-19-CTRR-CTA); Aeon, Scion, and she is a member of the Medical Scientific Advisory Committee for the DMRF and the BEBRF (uncompensated); she has received honoraria from American Academy of Neurology and the MDS for educational lectures. AD is funded by Teva (NCT04173260) and serves as site PI for trials from Cerevel, Teva, Lundbeck, and Annovis Bio. NS is an investigator in studies funded by F. Hoffmann-LaRoche Ltd., Neuraly, Inc., UCB Biopharma SPRL, Cerevel Therapeutics, Abbvie, Inc., Praxis Precision Medicines, Inc., DMRF, and NIH grant P50NS108675, and has been a consultant and received honoraria from The Huntington Study Group LTD., and PSG EARSTIM DSMB. SAN’s institution receives grant funding on his behalf from the NIH, DMRF, and Dysphonia International, and he is a member of the Medical Scientific Advisory Committee for the DMRF (uncompensated). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Movement disorders can be associated with anti-neuronal antibodies., Methods: We conducted a systematic review of cases with documented anti-neuronal antibodies in serum and/or cerebrospinal fluid published in PubMed before April 1, 2020. Only patients with at least one movement disorder were included. We used random forests for variable selection and recursive partitioning and regression trees for the creation of a data-driven decision algorithm, integrated with expert's clinical feedback., Results: Three hundred and seventy-seven studies met eligibility criteria, totaling 844 patients and 13 antibodies: amphiphysin, GAD, GlyR, mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, NMDAR, LGI-1, CRMP5/CV2, ANNA-1/Hu, IgLON5, and DPPX. Stiffness/rigidity/spasm spectrum symptoms were more frequently associated with amphiphysin, GAD, and GlyR; ataxia with mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, and ANNA-1/Hu; dyskinesia with NMDAR and paroxysmal movement with LGI1; chorea/choreoathetosis with CRMP5/CV2, IgLON5, and NMDAR; myoclonus with GlyR and DPPX; tremors with ANNA2/Ri and anti-DPPX; and parkinsonism with IgLON5 and NMDAR. Data-driven classification analysis determined the following diagnostic predictions (with probability selection): psychiatric symptoms and dyskinesia predicted NMDAR (71% and 87%, respectively); stiffness/rigidity/spasm and ataxia, GAD (67% and 47%, respectively); ataxia and opsoclonus, ANNA-2/Ri (68%); chorea/choreoathetosis, CRMP5/CV2 (41%). These symptoms remained the top predictors in random forests analysis. The integration with an expert opinion analysis refined the precision of the approach. Breast and lung tumors were the most common tumors. On neuroimaging, cerebellar involvement was associated with GAD and Yo/PCA-1; temporal involvement with Caspr2, LGI-1, ANNA-1/Hu., Conclusion: Selected movement disorders are associated with specific anti-neuronal antibodies. The combination of data-driven and expert opinion approach to the diagnosis may assist early management efforts., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Study Objectives: To evaluate the health-related quality of life (HRQoL) in patients with upper airway respiratory syndrome (UARS) and obstructive sleep apnea (OSA) compared to the general population (GP) in Lima, Peru, and to explore the variables associated with differences in HRQoL in patients with UARS., Methods: This was a retrospective study of medical and polysomnography records from 2009-2014 in a referral sleep medicine center for patients aged 18-64 years. UARS was defined by polysomnography as follows: apnea-hypopnea index < 5 events/h, oxygen saturation ≥ 92%, respiratory effort-related arousal index ≥ 5. HRQoL was assessed using the 36-Item Short Form Survey (version 1) questionnaire validated in Peru. The GP HRQoL was obtained from a population-based survey. Linear and logistic regression analyses were conducted., Results: We reviewed 1,329 polysomnograms and selected 888. UARS and OSA were diagnosed in 93 and 795 participants, respectively. The GP cohort consisted of 641 participants. Total HRQoL mean scores (95% confidence interval) in patients with UARS, patients with OSA, and the GP were 67.4 (63.7-71.1), 66.9 (65.4-68.4), and 82.9 (81.6-84.3), respectively. Patients with UARS and patients with OSA had a 5.5 times (95% confidence interval, 3.3-9.2) and 6.2 times (95% confidence interval, 4.6-8.4) greater probability of having a low total HRQoL score compared to patients in the GP, respectively. In patients with UARS, muscle pain, use of psychotropic medication, obesity, and depression were negatively correlated with the total HRQoL score., Conclusions: The impact of OSA and UARS on HRQoL is similar between disease groups and markedly worse when compared to the impact in the GP. In patients with UARS, the presence of muscle pain, obesity, female sex, depression, and use of psychotropic medication negatively impacted HRQoL., Citation: Vizcarra-Escobar D, Duque KR, Barbagelata-Agüero F, Vizcarra JA. Quality of life in upper airway resistance syndrome. J Clin Sleep Med. 2022;18(5):1263-1270., (© 2022 American Academy of Sleep Medicine.)

Long-read sequencing (LRS) technologies have been recently introduced to overcome intrinsic limitations of widely-used next-generation sequencing (NGS) technologies, namely the sequencing limited to short-read fragments (150-300 base pairs). Since its introduction, LRS has permitted many successes in unraveling hidden mutational mechanisms. One area in clinical neurology in need of rethinking as it applies to genetic mechanisms is essential tremor (ET). This disorder, among the most common in neurology, is a syndrome often exhibiting an autosomal dominant pattern of inheritance whose large phenotypic spectrum suggest a multitude of genetic etiologies. Exome sequencing has revealed the genetic etiology only in rare ET families ( FUS, SORT1, SCN4A, NOS3, KCNS2, HAPLN4/BRAL2 , and USP46 ). We hypothesize that a reason for this shortcoming may be non-classical genetic mechanism(s) underpinning ET, among them trinucleotide, tetranucleotide, or pentanucleotide repeat disorders. In support of this hypothesis, trinucleotide (e.g., GGC repeats in NOTCH2NLC ) and pentanucleotide repeat disorders (e.g., ATTTC repeats in STARD7 ) have been revealed as pathogenic in patients with a past history of what has come to be referred to as "ET plus," bilateral hand tremor associated with epilepsy and/or leukoencephalopathy. A systematic review of LRS in neurodegenerative disorders showed that 10 of the 22 (45%) genetic etiologies ascertained by LRS include tremor in their phenotypic spectrum, suggesting that future clinical applications of LRS for tremor disorders may uncover genetic subtypes of familial ET that have eluded NGS, particularly those with associated leukoencephalopathy or family history of epilepsy. LRS provides a pathway for potentially uncovering novel genes and genetic mechanisms, helping narrow the large proportion of "idiopathic" ET., Competing Interests: LM has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support. MK is an employee of the CONICET and has received grant support from the Ministry of Science and Technology of Argentina and the Ministry of Health of Buenos Aires. AE has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consult-ant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion. He is cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marsili, Duque, Bode, Kauffman and Espay.)

Introduction: Otological symptoms contribute to the disability of established Parkinson's disease (PD). We sought to evaluate whether prodromal onset may affect PD progression., Methods: A retrospective cohort design was used to compare time to advanced disease, defined as a Hoehn & Yahr stage ≥3 in consecutive PD patients with history of auditory and/or vestibular symptoms appearing before versus after PD onset. Time from PD onset to H&Y ≥ 3 was determined using Cox proportional hazards, with adjusted results summarized as hazards ratio (HR)., Results: After adjusting for age at PD onset, there was a lower risk of progression to advanced disease in patients with prodromal otological symptoms compared to those with otological symptoms after PD onset (HR = 0.34; 95%CI: 0.15-0.75, p = 0.008). This association remained significant after adjusting for age at PD onset and MDS-UPDRS III (HR = 0.25; 95% CI: 0.10-0.63, p = 0.003) and propensity score-adjusted analysis (HR = 0.46; 95% CI: 0.24-0.91, p = 0.025)., Conclusion: Prodromal otological symptoms might be associated with a reduced risk of motor progression in PD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia-ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann-Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6 , associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6 -encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

Background: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms., Objectives: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA)., Methods: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire., Results: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy., Conclusions: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: To evaluate the relationship between health-related quality of life (HR-QoL) and both physical and psychiatric factors in a large, international, multicentre cohort of patients with isolated dystonia, the Dystonia Coalition., Methods: Natural history data from 603 patients with isolated dystonia (median age 57 years (IQR: 48 to 64 years), 67.0% women) were prospectively acquired and analysed. HR-QoL (RAND 36-Item Health Survey), severity of depressive symptoms, generalised anxiety (Hospital Anxiety and Depression Scale) and social anxiety (Liebowitz Social Anxiety Scale) were assessed. Dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale) and dystonic tremor were examined. Statistical predictors of HR-QoL were calculated using saturated path analysis., Results: Reduced HR-QoL was strongly associated with the degree of depressive symptoms and generalised and social anxiety (8/8 RAND 36 subscales, p≤0.001). Increased dystonia severity was associated with worse physical functioning, physical and emotional role functioning and social functioning (all p≤0.001). The presence of tremor correlated with worse physical functioning and pain (all p≤0.006). Younger age was associated with reduced emotional well-being and vitality (all p≤0.006). There were no HR-QoL differences between sexes., Conclusion: HR-QoL in isolated dystonia is strongly associated with psychiatric and physical features. While current standard of care focus on motor aspects of dystonia, comprehensive care should address both physical and mental aspects of health., Competing Interests: Competing interests: BDB has received research grant support from the Dystonia Coalition (receives the majority of its support through NIH grant NS065701 from the Office of Rare Diseases Research in the National Center for Advancing Translational Science and National Institute of Neurological Disorders and Stroke), Benign Essential Blepharospasm Research Foundation, Colorado Clinical and Translational Science Institute and Center for Neuroscience, Tools4Patient, Parkinson’s Foundation and from Mary Rossick Kern and Jerome H. Kern. He is on the medical advisory board of the Benign Essential Blepharospasm Research Foundation and the National Spasmodic Torticollis Association. VB has received no financial or non-financial support relating to this project or the preparation of this paper. VB is currently receiving funding from the ROLI music company and Tourettes Action UK (TAPG2019) and the Academy of Medical Sciences Springboard Award. JSP has received research funding from National Institutes of Health (NCATS, NINDS, NIA), Michael J Fox Foundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Greater St Louis Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, the Murphy Fund, Huntington Disease Society of America and CHDI. He has received honoraria from CHDI, Huntington Disease Study Group, Parkinson Study Group, Beth Israel Hospital (Harvard group), U Pennsylvania, Stanford U. He also is co-director for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). Dr Perlmutter serves as Director of Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation, Chair of the Scientific Advisory Committee of the Parkinson Study Group, Chair of the Standards Committee of the Huntington Study Group, member of the Scientific Advisory Board of the APDA, Chair of the Scientific and Publication Committee for ENROLL-HD and member of the Education Committee of the Huntington Study Group. JJ has received research/training funding from: AbbVie Inc; Acadia Pharmaceuticals; Allergan, Inc; Biotek; Cerevel Therapeutics; CHDI Foundation; Dystonia Coalition; Emalex Biosciences, Inc; F Hoffmann-La Roche Ltd; Huntington Study Group; Medtronic Neuromodulation; Merz Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; National Institutes of Health; Neuraly, Inc; Neurocrine Biosciences; Parkinson’s Foundation; Parkinson Study Group; Prilenia Therapeutics; Revance Therapeutics, Inc; Teva Pharmaceutical Industries Ltd. IAM has participated in research funded by the Parkinson Foundation (PF), Tourette Association of America (TAA), Dystonia Coalition, AbbVie, Biogen, Boston Scientific, Eli Lilly, Impax, Neuroderm, Prilenia, Revance, Teva but has no owner interest in any pharmaceutical company. She is on the medical advisory board of the TAA. She has received travel compensation or honoraria from the TAA, PF, International Association of Parkinsonism and Related Disorders, Medscape and Cleveland Clinic, and royalties from Robert Rose publishers. AWS reports grants from the NIH and has received grant support from Benign Essential Blepharospasm Research Foundation, Dystonia Coalition, Dystonia Medical Research Foundation, National Organization for Rare Disorders and grant support from NIH (KL2 and K23 NS092957-01A1). Reports receiving honoraria from Acadia, Cavion, Elsevier and MJFF in past; Participates as a co-I for several NIH, foundation and industry sponsored trials over the years but has not received honoraria. SGR has active or recent grant support from NINDS and royalties from Springer and Informa. He has also served as a consultant for Best Doctors and as a reviewer for UpToDate. He serves on the Data Safety Monitoring Board for Enterin. AJE has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for AbbVie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, InTrance, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion; NP has received honoraria as a speaker for USWorldMed and Teva and consultant for Revance and Acorda pharmaceutical. ER served on scientific advisory boards for Orkyn, Aguettant, Merz-Pharma; received honoraria for speeches from Orkyn, Aguettant, Merz-Pharma, Everpharma, International Parkinson and Movement disorders Society; received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Everpharma, Fondation Desmarest, AMADYS, Fonds de Dotation Brou de Laurière, Agence Nationale de la Recherche; received travel grant from Vitalair, PEPS development, Aguettant, Merz-Pharma, Ipsen, Merck, Orkyn, Elivie, Adelia Medical, Dystonia Medical Research Foundation, International Parkinson and Movement disorders Society, European Academy of Neurology, International Association of Parkinsonism and Related Disorders; HAJ has active or recent grant support from the US government (National Institutes of Health), private philanthropic organisations (Cure Dystonia Now), academically-oriented institutions (the Dystonia Study Group), and industry (Cavion Therapeutics, Ipsen Pharmaceuticals, Retrophin Inc.). HJ has also served on advisory boards or as a consultant for Allergan Inc, CoA Therapeutics, Cavion Therapeutics and Retrophin Inc. He has received honoraria or stipends for lectures or administrative work from the American Academy of Neurology, the American Neurological Association, the Dystonia Medical Research Foundation, the International Neurotoxin Society and the International Parkinson’s Disease and Movement Disorders Society. HJ serves on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now, the Dystonia Medical Research Foundation, the Tourette Association of America and Tyler's Hope for a Cure. He also is principle investigator for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). The Dystonia Coalition has received additional material or administrative support from industry sponsors (Allergan Inc and Merz Pharmaceuticals) as well as private foundations (The American Dystonia Society, Beat Dystonia, The Benign Essential Blepharospasm Foundation, Cure Dystonia Now, Dystonia Europe, Dystonia Inc, Dystonia Ireland, The Dystonia Medical Research Foundation, The Foundation for Dystonia Research, The National Spasmodic Dysphonia Association and The National Spasmodic Torticollis Association). NB received speaker’s honoraria from Grünenthal, UCB, AbbVie and Teva. He served as consultant for Censa and Centogene. NB is funded by the DFG (BR4328.2-1, GRK1957)., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

We report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM&#95;001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations.

Background: Urinary dysfunction and constipation, manifestations of pelvic floor dysfunction are common sources of disability and impaired quality of life in women with Parkinson's disease (PD)., Objective: We sought to evaluate the pelvic floor health amongst women with PD and their reporting of bladder and bowel symptoms., Methods: We surveyed women with PD and age-matched controls about pelvic floor health using validated questionnaires. All participants completed the Pelvic Floor Disability Index (PFDI-20), the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Patient-Reported Outcomes Measurement Information System (PROMIS) short form version 2.0 Cognitive Function 8a. Additionally, PD patients underwent the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scale and the Montreal Cognition Assessment (MoCA)., Results: Women with PD (n = 59; age, 70.4±8.6 years, PROMIS cognitive score, 52.0±7.8) self-reported urinary symptoms to a greater extent than controls (n = 59; age, 70.2±8.7 years, PROMIS cognitive score, 51.0±10) (68% vs 43%, p < 0.01). The difference was mirrored by higher (worse) scores on both PFDI-20 (35.4 vs 15.6; p = 0.01) and PFIQ-7 (4.8 vs 0; p < 0.01) for PD women compared to controls. Only 63% of all participants with self-reported pelvic floor symptoms had previously reported these symptoms to a health care provider. There was no difference in utilization of specialty care between the two groups (30% vs 46%, p = 0.2)., Conclusion: Pelvic floor dysfunction, more common amongst women with PD, is underreported and undertreated. Our study identifies a key gap in care of women with PD.

Children in the Peruvian Amazon Basin are at risk of soil-transmitted helminths (STH) infections. This study aimed to determine the prevalence of STH infection in children from a rural Amazonian community of Peru and to elucidate epidemiological risk factors associated with its perpetuation while on a school-based deworming program with mebendazole. Stool samples of children aged 2-14 years and their mothers were analyzed through direct smear analysis, Kato-Katz, spontaneous sedimentation in tube, Baermann's method, and agar plate culture. A questionnaire was administered to collect epidemiological information of interest. Among 124 children, 25.8% had one or more STH. Individual prevalence rates were as follows: Ascaris lumbricoides , 16.1%; Strongyloides stercoralis , 10.5%; hookworm, 1.6%; and Trichuris trichiura , (1.6%). The prevalence of common STH ( A. lumbricoides , T. trichiura , and hookworm) was higher among children aged 2-5 years than older children (31.6% versus 12.8%; P = 0.01). In terms of sanitation deficits, walking barefoot was significantly associated with STH infection (OR = 3.28; CI 95% = 1.11-12.07). Furthermore, STH-infected children more frequently had a mother who was concomitantly infected by STH than the non-STH-infected counterpart (36.4% versus 14.1%, P = 0.02). In conclusion, STH infection is highly prevalent in children from this Amazonian community despite routine deworming. Institutional health policies may include hygiene and sanitation improvements and screening/deworming of mothers to limit the dissemination of STH. Further studies are needed to address the social and epidemiological mechanics perpetuating these infections.

Objective: To evaluate the combined prognostic value of neurological examination, head circumference and cranial ultrasound for neurodevelopmental delay (NDD) in very low birth weight (VLBW, <1500 g) preterm infants., Methods: Prospective follow-up study. Preterm infants with VLWB were assessed for NDD using the Mullen Scales of Early Learning test at 24 months of corrected age. Abnormal neurological examination (≥2 deviant items of Hammersmith neurological examination), microcephaly and major ultrasound abnormalities, each performed at term age, were evaluated as predictors of NDD in a multivariable Poisson model., Results: 35/132 infants (26.5%) had NDD. In the multivariable analysis, microcephaly (RR, 3.2; 95% CI, 1.6-6.7) and major ultrasound abnormalities (RR, 2.7; 95% CI, 1.3-5.7) were associated to NDD. The combination of the two tests showed the highest positive predictive value (100%; 95% CI, 51%-100%), while the combination of normal neurological examination, no major US findings and normal head size at term showed the highest negative predictive value (89%; 95% CI, 78%-95%). The maximum under receiver operating characteristic curve area was for microcephaly or major ultrasound abnormalities (AUC 0.74 (0.65-0.83))., Conclusion: The combination of head circumference, cranial ultrasound and neurological examination at term age is useful to predict NDD in VLBW preterm infants., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Discordances between imaging findings of parenchymal neurocysticercosis and seizure expression have been reported, and as such the possibility that neurocysticercosis and seizures may frequently coexist by chance has been raised. In this study, we evaluate the topographic relationship between seizure foci based on semiology and electroencephalography with the location of parenchymal neurocysticercotic lesions., Methods: Seizure information, neuroimaging (computed tomography and magnetic resonance imaging [MRI]) and electroencephalographic data from three randomized clinical trials of individuals with parenchymal neurocysticercosis and focal seizures were analyzed. Blinded epileptologists defined a potential seizure onset zone and a symptomatogenic zone for each individual based on semiology. The topographic relationship between semiology, either lesion location or areas of perilesional edema on baseline MRI, and electroencephalographic abnormalities were assessed., Results: Fifty-eight patients with one or two parenchymal neurocysticercotic lesions were included in this study. From them, 50 patients (86%; 95% CI, 75%-93%) showed a clinical-topography relationship with the potential seizure onset zone, and 44 (76%) also with the symptomatogenic zone. From the eight patients with no topographic relationship, five had focal seizures 30 days before or after the baseline MRI and showed perilesional edema. All of these five patients showed a clinical-topography relationship between such seizures and an area of perilesional edema, making a total of 55 patients (95%; 95% CI, 85%-99%) with clinical-topography relationship when perilesional edema is considered. Most patients with focal epileptiform discharges (7/8, 88%) had a topographic association between electroencephalographic focality, the potential seizure onset zone and a cysticercotic lesion., Conclusion: Seizure semiology and focal epileptiform discharges are topographically related to neurocysticercotic lesions in most patients. These data strongly support seizure origin in the cortex surrounding these lesions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system and a major risk factor for seizures and epilepsy. Seizure types in NCC vary largely across studies and seizure semiology is poorly understood. We discuss here the studies regarding seizure types and seizure semiology in NCC, and examine the clinical presentation in patients with NCC and drug-resistant epilepsy. We also provide evidence of the role of MRI and EEG in the diagnosis of NCC-related epilepsy. Focal seizures are reported in 60-90% of patients with NCC-related epilepsy, and around 90% of all seizures registered prospectively are focal not evolving to bilateral tonic-clonic seizures. A great number of cases suggest that seizure semiology is topographically related to NCC lesions. Patients with hippocampal sclerosis and NCC have different clinical and neurophysiological characteristics than those with hippocampal sclerosis alone. Different MRI protocols have allowed to better differentiate NCC from other etiologies. Lesions' stages might account on the chances of finding an interictal epileptiform discharge. Studies pursuing the seizure onset in patients with NCC are lacking and they are specially needed to determine both whether the reported events of individual cases are seizures, and whether they are related to the NCC lesion or lesions. This article is part of a Special Issue entitled "Neurocysticercosis and Epilepsy"., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Abstract: Cyclic alternating pattern (CAP) is widely recognized as an expression of sleep instability in electroencephalogram activity during non-rapid eye movement sleep. We report a case with sequences of CAP followed by bruxism and catathrenia in a 10-y-old male patient with a diagnosis of attention deficit hyperactivity disorder in treatment with methylphenidate. We found CAP in 83.1% of all episodes of catathrenia, and the CAP rate was 12.8%. We propose to consider catathrenia as one of the sleep disorders that may be accompanied by CAP., (© 2017 American Academy of Sleep Medicine)