Towards multimodal cognition-based treatment for cognitive impairment in Parkinson's disease: drugs, exercise, non-invasive brain stimulation and technologies.

PURPOSE OF REVIEW: Cognitive impairment is one of the most challenging non-motor symptoms of Parkinson's disease (PD) and may occur during all PD stages. There are no established pharmacological treatments for PD-related cognitive impairment, which may be improved by cognition-based interventions (i.e., cognitive stimulation, cognitive training, cognitive rehabilitation). Multimodal cognition-based interventions by adjunctive drugs, exercise, non-invasive brain stimulation and technologies may be effective in PD. RECENT FINDINGS: Exercise combined with cognitive training may enhance global, memory, visuospatial and executive functioning, transcranial direct current stimulation delivered alongside cognitive training may improve attention and executive functioning, and exergames, semi-immersive virtual reality (VR) and telerehabilitation plus non-immersive VR combined with cognitive training may ameliorate global and executive functioning in PD patients. SUMMARY: The evidence reviewed here, despite preliminary, is very encouraging and suggests strong rationale for combining pharmacological and non-pharmacological interventions with cognition-based treatments in PD. To overcome limitations of current studies, we propose some recommendations for future trials on drugs, exercise, non-invasive brain stimulation and technologies combined with cognition-based treatments for cognitive impairment in PD.

Functional Movement Disorder as a Prodromal Symptom of Parkinson's Disease-Clinical and Pathophysiological Insights.

Functional movement disorder (FMD) is a common manifestation of functional neurological disorder. FMD can occur alongside other neurological conditions, but especially in patients with established Parkinson's disease (PD). An interesting observation emerging across cohort studies and case series is that FMD can precede the diagnosis of PD, suggesting that FMD may itself be a prodromal symptom of neurodegeneration. Such a notion would have significant clinical implications for the assessment and management of people with FMD, particularly with respect to decisions around the use of auxiliary investigations, counselling, and follow-up. In this Viewpoint we review the evidence concerning the temporal relationship between FMD and PD. We discuss the potential explanations and mechanisms for FMD as a prodromal symptom of PD, and highlight clinical considerations and important outstanding questions in the field. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abnormalities of the Descending Inhibitory Nociceptive Pathway in Functional Motor Disorders.

BACKGROUND: Pain is a common disabling non-motor symptom affecting patients with functional motor disorders (FMD). OBJECTIVE: We aimed to explore ascending and descending nociceptive pathways with laser evoked potentials (LEPs) in FMD. METHODS: We studied a "bottom-up and top-down" noxious paradigm applying a conditioned pain modulation (CPM) protocol and recorded N2/P2 amplitude in 21 FMD and 20 controls following stimulation of both right arm and leg at baseline (BS) (bottom-up), during heterotopic noxious conditioning stimulation (HNCS) with ice test (top-down) and post-HNCS. RESULTS: We found a normal ascending pathway, but reduced CPM response (lower reduction of the N2/P2 amplitude) in FMD patients, by stimulating both upper and lower limbs. The N2/P2 amplitude ratio*100 (between the HNCS and BS) was significantly higher in patients with FMD than HC. CONCLUSIONS: Our results suggest that pain in FMD possibly reflects a descending pain inhibitory control impairment, therefore, providing a novel venue to explore the pathophysiology of pain in FMD. © 2024 International Parkinson and Movement Disorder Society.

Unraveling the mechanisms of high-level gait control in functional gait disorders.

Functional gait disorders (FGDs) are a disabling subset of Functional Neurological Disorders in which presenting symptoms arise from altered high-level motor control. The dual-task paradigm can be used to investigate mechanisms of high-level gait control. The study aimed to determine the objective measures of gait that best discriminate between individuals with FGDs and healthy controls and the relationship with disease severity and duration. High-level spatiotemporal gait outcomes were analyzed in 87 patients with FGDs (79.3% women, average age 41.9±14.7 years) and 48 healthy controls (60.4% women, average age 41.9±15.7 years) on single and motor, cognitive, and visual-fixation dual tasks. The area under the curve (AUC) from the receiver operator characteristic plot and the dual-task effect (DTE) were calculated for each measure. Dual-task interference on the top single-task gait characteristics was determined by two-way repeated measures ANOVA. Stride time variability and its standard deviation (SD) failed to discriminate between the two groups in single and dual-task conditions (AUC<0.80 for all). Significant group x task interactions were observed for swing time SD and stride time on the cognitive dual tasks (p<0.035 for all). Longer disease duration was associated with poor gait performance and unsteadiness in motor and cognitive DTE (p<0.003) but improvement in stride length and swing time on the visual dual tasks (p<0.041). Our preliminary findings shed light on measures of gait automaticity as a diagnostic and prognostic gait biomarker and underline the importance of early diagnosis and management in individuals with FGDs.

Sex-based disparities in dopamine agonist response in patients with restless legs syndrome.

This study aimed to investigate sex-related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug-free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self-evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex-related expression of dopamine receptors, especially D3, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex-specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males.

Functional neurological disorder in Europe: regional differences in education and health policy.

BACKGROUND: Functional neurological disorder (FND) is a common cause of neurological disability. Despite recent advances in pathophysiological understanding and treatments, application of this knowledge to clinical practice is variable and limited. OBJECTIVE: Our aim was to provide an expert overview of the state of affairs of FND practice across Europe, focusing on education and training, access to specialized care, reimbursement and disability policies, and academic and patient-led representation of people with FND. METHODS: We conducted a survey across Europe, featuring one expert per country. We asked experts to compare training and services for people with FND to those provided to people with multiple sclerosis (MS). RESULTS: Responses from 25 countries revealed that only five included FND as a mandatory part of neurological training, while teaching about MS was uniformly included. FND was part of final neurology examinations in 3/17 countries, unlike MS that was included in all 17. Seventeen countries reported neurologists with an interest in FND but the estimated mean ratio of FND-interested neurologists to MS neurologists was 1:20. FND coding varied, with psychiatric coding for FND impacting treatment access and disability benefits in the majority of countries. Twenty countries reported services refusing to see FND patients. Eight countries reported an FND special interest group or network; 11 reported patient-led organizations. CONCLUSIONS: FND is largely a marginal topic within European neurology training and there is limited access to specialized care and disability benefits for people with FND across Europe. We discuss how this issue can be addressed at an academic, healthcare and patient organization level.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Long-term effects of SARS-CoV-2 infection in patients with and without chemosensory disorders at disease onset: a psychophysical and magnetic resonance imaging exploratory study.

A preserved sense of smell and taste allows us to understand many environmental "messages" and results in meaningfully improvements to quality of life. With the COVID-19 pandemic, it became clear how important these senses are for social and nutritional status and catapulted this niche chemosensory research area towards widespread interest. In the current exploratory work, we assessed two groups of post-COVID-19 patients who reported having had (Group 1) or not (Group 2) a smell/taste impairment at the disease onset. The aim was to compare them using validated smell and taste tests as well as with brain magnetic resonance imaging volumetric analysis. Normative data were used for smell scores comparison and a pool of healthy subjects, recruited before the pandemic, served as controls for taste scores. The majority of patients in both groups showed an olfactory impairment, which was more severe in Group 1 (median UPSIT scores: 24.5 Group 1 vs 31.0 Group 2, p = 0.008), particularly among women (p = 0.014). No significant differences emerged comparing taste scores between Group 1 and Group 2, but dysgeusia was only present in Group 1 patients. However, for taste scores, a significant difference was found between Group 1 and controls (p = 0.005). No MRI anatomical abnormalities emerged in any patients while brain volumetric analysis suggested a significant difference among groups for the right caudate nucleus (p = 0.028), although this was not retained following Benjamini-Hochberg correction. This exploratory study could add new information in COVID-19 chemosensory long-lasting impairment and address future investigations on the post-COVID-19 patients' research.

Functional neurological disorder: a comparative analysis of experience of Czech, Slovak, and Italian neurologists.

AIM OF STUDY: We aimed to compare knowledge, opinions, and clinical experiences among Czech, Slovak, and Italian neurologists to identify potential educational gaps and unify understanding. CLINICAL RATIONALE FOR STUDY: Functional neurological disorder (FND) is a disabling condition characterised by motor, sensory, or cognitive symptoms which are incompatible with other neurological disorders. Novel diagnostic and treatment approaches have improved FND management. However, the extent of their adoption, and any differences or similarities across European communities, remain to be established. MATERIAL AND METHODS: Members of the Czech and Slovak Neurological Societies were invited via e-mail to participate in a 14- -item web-based survey investigating their approach to FND. This data was compared to results from a previous study involving 492 Italian neurologists. RESULTS: 232 questionnaires were completed by Czech and Slovak neurologists (CZ-SK). Similarities were found between CZ- -SK and Italian neurologists in their preference for the term 'FND' over other psychological-related terms and in explaining symptoms as due to abnormal functioning of the nervous system rather than attributing them to mental illness. However, only fewer than 5% in both groups thought that simulation was highly unlikely. Both groups reported relying on positive signs (e.g. inconsistency, distractibility) according to the current diagnostic criteria, but also a tendency to perform additional tests to exclude other causes. However, some differences were observed: Italian neurologists placed a greater emphasis on psychological factors including litigation. CZ-SK neurologists were more likely to suggest physiotherapy as a treatment option and to provide educational intervention for patients and their relatives. CONCLUSIONS: Overall, our findings suggest that although Czech, Slovak, and Italian neurologists have adopted some new developments in the field of FND, significant gaps still exist in their understanding and common practices regarding conceptualisation, diagnosis, and treatment. CLINICAL IMPLICATIONS: Our results suggest that promoting knowledge through postgraduate curricula and teaching courses for neurologists is necessary to optimise patient management in various European countries.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

BACKGROUND: Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. OBJECTIVES: To assess the descending diffuse noxious inhibitory control in RLS patients. METHODS: Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. RESULTS: N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 µV; HC, 10.1 µV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). CONCLUSIONS: The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder.

BACKGROUND: Heterozygous NKX2-1 loss-of-function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood-onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease-causing structural variants whose detection in routine diagnostics remains challenging. OBJECTIVE: To establish the molecular diagnosis of two first-degree relatives with clinically suspected NKX2-1-related disorder who had negative NKX2-1 Sanger (SS), whole-exome (WES), and whole-genome (WGS) sequencing. METHODS: The proband's WES was analyzed for MEIs. A candidate MEI in NKX2-1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2-1 haploinsufficiency at RNA and protein levels were performed. RESULTS: A 347-bp AluYa5 insertion with a 65-bp poly-A tail followed by a 16-bp duplication of the pre-insertion wild-type sequence in exon 3 of NKX2-1 (ENST00000354822.7:c.556_557insAlu541_556dup) segregated with the disease phenotype. CONCLUSIONS: We identified a de novo exonic AluYa5 insertion causing NKX2-1-related disorder in SS/WES/WGS-negative cases, suggesting that MEI analysis of short-read sequencing data or targeted long-read sequencing could unmask the molecular diagnosis of unsolved MD cases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Axial postural abnormalities and pain in Parkinson's disease.

Axial postural abnormalities and pain are two main determinants of poor quality of life in patients with Parkinson's disease (PD). Indeed, a detailed characterization of pain and other non-motor symptoms in patients with PAs has not been provided yet. The aim of this study is to assess the phenomenology of pain and other non-motor symptoms in PD patients with Pisa syndrome and camptocormia compared to PD patients without axial postural abnormality. Forty-five PD participants were equally distributed in three groups: patients with Pisa syndrome (PS), patients with Camptocormia (CC), and patients without postural abnormalities (PD). Pain characteristics were assessed by Kings Parkinson's Pain Scale (KPPS), brief pain inventory (BPI), and numeric pain rating scale (NRS). All participants completed clinical assessments by non-motor symptom scale (NMSS), and movement disorder society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II-III. Patients with and without axial postural abnormalities showed one or more types of pain, being fluctuation, nocturnal, chronic, and musculoskeletal the most frequently reported in Pisa Syndrome and camptocormia. PD group compared with PS and CC groups showed differences in the KPPS, NMSS, BPI pain severity and interference, and NRS total scores. No significant differences were found between PS group compared with CC group with exception of the NMSS total scores. PD patients with Pisa syndrome or camptocormia have a higher burden of musculoskeletal, chronic and fluctuation pain than PD patients without axial postural abnormalities, suggesting different etiologies of pain and possible different treatments.

Performance validity tests in nonlitigant patients with functional motor disorder.

BACKGROUND AND PURPOSE: Performance validity tests (PVTs) are used in neuropsychological assessments to detect patterns of performance suggesting that the broader evaluation may be an invalid reflection of an individual's abilities. Data on functional motor disorder (FMD) are currently poor and conflicting. We aimed to examine the rate of failure on three different PVTs of nonlitigant, non-compensation-seeking FMD patients, and we compared their performance to that of healthy controls and controls asked to simulate malingering (healthy simulators). METHODS: We enrolled 29 nonlitigant, non-compensation-seeking patients with a clinical diagnosis of FMD, 29 healthy controls, and 29 healthy simulators. Three PVTs, the Coin in the Hand Test (CIH), the Rey 15-Item Test (REY), and the Finger Tapping Test (FTT), were employed. RESULTS: Functional motor disorder patients showed low rates of failure on the CIH and REY (7% and 10%, respectively) and slightly higher rates on the FTT (15%, n = 26), which implies a motor task. Their performance was statistically comparable to that of healthy controls but statistically different from that of healthy simulators (p < 0.001). Ninety-three percent of FMD patients, 7% of healthy simulators, and 100% of healthy controls passed at least two of the three tests. CONCLUSIONS: Performance validity test performance of nonlitigant, non-compensation-seeking patients with FMD ranged from 7% to 15%. Patients' performance was comparable to that of controls and significantly differed from that of simulators. This simple battery of three PVTs could be of practical utility and routinely used in clinical practice.

Placebo effect on gait: a way to reduce the dual-task cost in older adults.

The ability to perform two tasks simultaneously is essential for daily activities. In older adults, this ability is markedly reduced, as evidenced by the dual-task cost on gait. Preliminary evidences indicate that the dual-task cost can be influenced by different types of manipulations. Here, we explored the effectiveness of a new approach to reduce the dual-task cost, based on the placebo effect, a psychobiological phenomenon whereby a positive outcome follows the administration of an inert device thought to be effective. Thirty-five healthy older adults were asked to walk on a sensorized carpet (single-task condition) and to walk while counting backward (dual-task condition) in two sessions (pre-test and post-test). A placebo group, randomly selected, underwent sham transcranial direct current stimulation over the supraorbital areas between sessions, along with information about its positive effects on concentration and attention. A control group did not receive any intervention between sessions. The dual-task cost was significantly reduced in the placebo group at the post-test session compared to the pre-test for several gait parameters (Cohen's d > 1.43). At the post-test session, the dual-task cost was also lower in the placebo group than in the control group (d > 0.73). Cognitive (number of subtractions and number of errors) and subjective (perceived mental fatigability) variables remained stable across sessions. The reduced dual-task cost in the placebo group could indicate the ability to re-establish the allocation of attentional resources between tasks. These findings could contribute to the development of cognitive strategies that leverage positive expectations to boost motor control in older adults.

Camera- and Viewpoint-Agnostic Evaluation of Axial Postural Abnormalities in People with Parkinson's Disease through Augmented Human Pose Estimation.

Axial postural abnormalities (aPA) are common features of Parkinson's disease (PD) and manifest in over 20% of patients during the course of the disease. aPA form a spectrum of functional trunk misalignment, ranging from a typical Parkinsonian stooped posture to progressively greater degrees of spine deviation. Current research has not yet led to a sufficient understanding of pathophysiology and management of aPA in PD, partially due to lack of agreement on validated, user-friendly, automatic tools for measuring and analysing the differences in the degree of aPA, according to patients' therapeutic conditions and tasks. In this context, human pose estimation (HPE) software based on deep learning could be a valid support as it automatically extrapolates spatial coordinates of the human skeleton keypoints from images or videos. Nevertheless, standard HPE platforms have two limitations that prevent their adoption in such a clinical practice. First, standard HPE keypoints are inconsistent with the keypoints needed to assess aPA (degrees and fulcrum). Second, aPA assessment either requires advanced RGB-D sensors or, when based on the processing of RGB images, they are most likely sensitive to the adopted camera and to the scene (e.g., sensor-subject distance, lighting, background-subject clothing contrast). This article presents a software that augments the human skeleton extrapolated by state-of-the-art HPE software from RGB pictures with exact bone points for posture evaluation through computer vision post-processing primitives. This article shows the software robustness and accuracy on the processing of 76 RGB images with different resolutions and sensor-subject distances from 55 PD patients with different degrees of anterior and lateral trunk flexion.

Chromatic Pupillometry in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies. OBJECTIVES: To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls. METHODS: iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy. RESULTS: We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls. CONCLUSION: The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.

BACKGROUND: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration. OBJECTIVES: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. METHODS: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. RESULTS: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology. CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Do demographic and clinical features and comorbidities affect the risk of spread to an additional body site in functional motor disorders?

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

Shoulder-Touch test to reveal incongruencies in persons with functional motor disorders.

BACKGROUND AND PURPOSE: Clinical experience suggests that many patients with functional motor disorders (FMD), despite reporting severe balance problems, typically do not fall frequently. This discrepancy may hint towards a functional component. Here, we explored the role of the Shoulder-Touch test, which features a light touch on the patient's shoulders, to reveal a possible functional etiology of postural instability. METHODS: We enrolled consecutive outpatients with a definite diagnosis of FMD. Patients with Parkinson's disease (PD) or progressive supranuclear palsy (PSP) with postural instability served as controls. Each patient underwent a clinical evaluation including testing for postural instability using the retropulsion test. Patients with an abnormal retropulsion test (score ≥ 1) also received a light touch on their shoulders to explore the presence (S-Touch+) or absence (S-Touch-) of an incongruent, exaggerated postural response, defined as taking three or more steps to recover or a fall if not caught by the examiner. RESULTS: From a total sample of 52 FMD patients, 48 patients were recruited. Twenty-five patients (52%) had an abnormal retropulsion test. Twelve of these 25 patients (48%) had an S-Touch+, either because of need to take two or more steps (n = 4) or a fall if not caught by the examiner (n = 8). None of the 23 PD/PSP patients manifested S-Touch+. The sensitivity of the S-Touch test was 48%, whereas its specificity was 100%. CONCLUSION: The S-Touch test has a high specificity, albeit with a modest sensitivity, to reveal a functional etiology of postural instability in persons with FMD.