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Introduction: CACNA1A gene variants are correlated with different disorders, including episodic ataxia type 2, spinocerebellar ataxia type 6, and familial hemiplegic migraine type 1. Despite dystonia not being a typical manifestation of CACNA1A variants, there are reports indicating a link between this gene mutation and dystonic features., Methods: We report the case of a patient with a novel missense variant of the CACNA1A gene presenting headache, head and arm tremor, dystonia, episodic painful focal dystonic attacks, and unexplained falls., Results:  A 57-year-old woman presented with a history of neck dystonia, head and arm tremor, and headaches since age 15. In 2017, she progressively developed dystonic tremor of the head and arms with an unremarkable brain MRI. In 2018 she experienced worsening of tremor and developed painful dystonic attacks, resistant to treatments including clonazepam, trihexyphenidyl, baclofen, and levodopa/benserazide. Botulinum toxin injections for neck dystonia provided limited benefit. The next-generation sequencing exam revealed a CACNA1A gene missense variant (NM_023035.2:c.1630C > T; p.Arg544Trp). In 2021 we observed a worsening of dystonia, accompanied by weight loss, mood changes, and unexplained falls. Deep brain stimulation was considered but ruled out due to cortical atrophy and mild cognitive deficits revealed by the neuropsychological examination., Discussion: Only a few studies reported dystonia as part of the clinical features in carriers of CACNA1A mutations. This case points out the relevance of a need to expand the literature on voltage-dependent P/Q-type Ca2 + channels' role in dystonia's pathogenesis and stresses the complex phenotype-genotype presentation of CACNA1A mutation., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Non-motor symptoms and non-motor fluctuations (NMF) in Parkinson's disease (PD) strongly affect health-related quality of life (HRQoL) and disability. The impact of deep brain stimulation (DBS) on NMF remains an area of uncertainty. The aim is to evaluate the impact of DBS on NMF, using the recently validated Non-Motor Fluctuation Assessment (NoMoFa), and to explore the correlation between NMF and motor symptoms, motor complications (MC), and HRQoL post-surgical improvement., Methods: We prospectively evaluated consecutive patients undergoing subthalamic DBS (STN-DBS), at baseline and 6-months after surgery. Assessments included the NoMoFa questionnaire, the MDS-sponsored Unified Parkinson's Disease Rating Scale, and the 39-Item Parkinson's Disease Questionnaire. Pre- and post-surgical NoMoFa scores were compared using the Wilcoxon Signed rank-test. Linear regression analysis evaluated: a) the correlation between NoMoFa scores, motor and MC improvement, correcting for age, disease duration, and dopaminergic therapy reduction; b) the correlation between HRQoL and NMF improvement, correcting for age, disease duration, motor and MC improvement., Results: Twenty patients were evaluated. Total NMF score significantly improved (44.6 %, [IQR = 18.3-100]; p = 0.022), particularly in Off condition (52.0 %, [IQR = 25.4-100]; p = 0.009); we observed strong correlation between NMF and MC improvement (Beta = 0.728; p = 0.006), mainly driven by the mitigation of unpredictable Off (Beta = 0.905; p < 0.001). Even after adjusting for potential confounders, the reduction of NMF independently correlated with increased HRQoL (Beta = 0.714; p = 0.010)., Conclusions: STN-DBS demonstrated strong beneficial effect on NMF, resulting in significant improvement of HRQoL. This underlines the importance of recognizing NMF as a significant factor to be considered in the selection of patients eligible for STN-DBS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Neurogenic orthostatic hypotension (nOH) and gait impairment are frequent sources of disability in Parkinson's disease (PD). However, the impact of nOH on balance and gait features remains unclear. This cross-sectional study aimed to assess the influence of nOH on postural and gait parameters in a cohort of patients with PD by means of wearable inertial sensors., Methods: Gait and balance were assessed using Opal inertial sensors. nOH was defined as sustained systolic blood pressure (BP) drop ≥ 20 mmHg or diastolic BP drop ≥ 10 mmHg within 3 min of standing, with a ΔHR/ΔSBP ratio ≤ 0.5 bpm/mmHg. Analysis of covariance was performed to evaluate differences in gait/balance features between patients with and without nOH, adjusting for age, cognitive status, and motor disability. Moreover, we performed the same analysis considering the presence of hemodynamically relevant nOH (orthostatic mean BP ≤ 75 mmHg)., Results: A total of 82 patients were enrolled, 26 with nOH (31.7%), of which 13 presented with hemodynamically relevant nOH. After correcting for confounders, nOH was independently associated with lower gait speed (p = 0.027), shorter stride length (p = 0.033), longer time for postural transitions (p = 0.004), and increased postural sway (p = 0.019). These differences were even more pronounced in patients with hemodynamically relevant nOH. Higher postural sway was associated with a 7.9-fold higher odds of falls (p = 0.040)., Conclusions: Our study presents an objective demonstration of the independent negative impact of nOH on gait and balance in PD, emphasizing the need for careful detection and management of nOH to mitigate gait and balance disturbances in PD., (© 2024. The Author(s).)

Background: In spite of being considered the gold-standard of care, little is known about the real-life use of in-home and multidisciplinary care in atypical parkinsonism., Objective: Primary: Examine real-life multidisciplinary care use for Progressive Supranuclear Palsy (PSP). Secondary: a) Compare PSP care to advanced Parkinson's disease (APD) care; (b) Explore demographic and clinical variables associated with care needs in both groups., Methods: A cross-sectional multicenter observational study enrolled 129 PSP patients and 65 APD patients (Hoehn and Yahr ≥3), matched for sex and age. Univariate and multivariate regression analysis were performed., Results: Over the previous year, 40 % of PSP patients did not encounter a physical therapist, while only one-third met a speech and language therapist and 5 % an occupational therapist. More than 20 % received in-home care and 32 % needed home structural changes. Compared to APD, PSP patients required more day-time, night-time and home structural changes. When considering both PSP and APD in multivariate analysis, reduced functional autonomy and living without a family caregiver were both related to day-time home assistance and to the need of at least one home care service. A PSP diagnosis compared to APD was a risk factor for having at least four multidisciplinary visits in a year. Finally, PSP diagnosis and being from the Northern Italy were significantly related with home structural changes., Conclusions: There's a significant gap in providing multidisciplinary care for PSP patients. Our findings emphasize the need for a shared, integrated care plan at a national level for patients with atypical parkinsonism., Competing Interests: Declaration of competing interest The present work was supported by the Fondazione LIMPE which provided administrative support to Marina Picillo, MD, PhD (corresponding author). None of the authors report any financial interests or professional relationship related to the subject matter but not directly to this manuscript for the last 3 years. There are no patents or copyrights licensed to the authors that are relevant to the work submitted for publication. There are no additional relationships or activities to declare that may be perceived to have influenced the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread., Objective: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD., Methods: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed., Results: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia., Conclusions: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Gaucher disease (GD) is classically divided into three types, based on the presence or absence of neurological signs and symptoms. However, presentation can be highly variable in adulthood, and this aspect has not been adequately addressed in the literature so far. We performed a systematic literature review to analyze the entire spectrum of neurological manifestations in adult patients previously classified as GD type I, II, or III, evaluating the role of variants in different neurological manifestations., Methods: We searched databases for studies reporting clinical data of adult GD patients (age ≥ 18). Data extraction included GD types, GBA1 variants, age at disease onset and diagnosis, duration of GD, and age at onset and type of neurological symptoms reported., Results: Among 4190 GD patients from 85 studies, 555 exhibited neurological symptoms in adulthood. The median age at evaluation was 46.8 years (IQR 26.5), age at neurological symptoms onset was 44 years (IQR 35.1), and age at GD clinical onset was 23 years (IQR 23.4). Parkinsonism, including Parkinson's disease and Lewy Body dementia, was the most reported neurological manifestation. Other symptoms and signs encompassed oculomotor abnormalities, peripheral neuropathy, seizures, myoclonus, and cerebellar, cognitive and psychiatric symptoms. The genotype N370S/N370S mostly presented with Parkinsonism and the L444P variant with severe and earlier neurological symptoms., Conclusion: The findings of this systematic review highlight: (1) the relevance of a comprehensive neurological assessment in GD patients, and (2) the importance of considering possible undiagnosed GD in adult patients with mild systemic symptoms presenting unexplained neurological symptoms., (© 2024. The Author(s).)

Background: Axial postural abnormalities (PA) are invalidating symptoms of Parkinson's disease (PD). Risk factors for PA are unknown., Objectives: We sought to evaluate PA incidence and risk factors over the first 4-6 years of PD., Methods: We included 441 PD patients from the Parkinson's Progression Markers Initiative (PPMI) cohort with data at diagnosis and after 4-year follow-up. PA was defined according to a posture item ≥ 2 at the Movement Disorder Society-sponsored-revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) in Off therapeutic condition. The Kruskal-Wallis test was used to compare characteristics of patients without PA ('no-PA'), with PA at disease onset ('baseline-PA'), and PA developed during follow-up ('develop-PA'). To identify predictors of PA development, univariate and multivariate Cox regression analyses were performed considering demographic, clinical and therapeutic variables., Results: 10.9% of patients showed PA at baseline and 23.7% developed PA within the first 4-6 years since diagnosis. Older age, malignant phenotype, higher MDS-UPDRS part III, Hoehn & Yahr, and dysautonomia (SCOPA-AUT) score, and lower levels of physical activity were predictors of PA development at the univariate analysis. Older age (Hazard ratio [HR] per year: 1.041) and higher MDS-UPDRS part III score (HR per point: 1.035) survived as PA development predictors in the multivariate analysis., Conclusions: PPMI cohort data show that > 30% of PD patients present PA within the first 4-6 years of disease. Older age at onset and higher motor burden are associated with a higher risk for PA development. The protective role of physical activity merits to be further investigated., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients., Methods: Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness-EDS). Binary logistic regression analysis, adjusting for age, sex, disease duration, motor impairment, and sleep drugs, was employed to evaluate the association between dopaminergic therapy and PDSS-2 and ESS scores. Analysis of covariance assessed differences in PDSS-2 and ESS scores between patients without DA, and between patients treated with low or high doses of DA (cut-off: DA-LEDD = 180 mg)., Results: In a cohort of 281 patients, 66.2% reported poor sleep quality, and 34.5% reported EDS. DA treatment demonstrated twofold lower odds of reporting relevant sleep disturbances (OR 0.498; p = 0.035), while DA-LEDD, levodopa-LEDD, total LEDD, and extended-release levodopa were not associated with disturbed sleep. EDS was not influenced by dopaminergic therapy. Patients with DA intake reported significant lower PDSS-2 total score (p = 0.027) and "motor symptoms at night" domain score (p = 0.044). Patients with higher doses of DA showed lower PDSS-2 total score (p = 0.043)., Conclusion: Our study highlights the positive influence of DA add-on treatment on sleep quality in this group of advanced fluctuating PD patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Axial postural abnormalities (APAs), characterized by their frequency, disabling nature, and resistance to pharmacological treatments, significantly impact Parkinson's disease and atypical Parkinsonism patients. Despite advancements in diagnosing, assessing, and understanding their pathophysiology, managing these complications remains a significant challenge. Often underestimated by healthcare professionals, these disturbances can exacerbate disability. This systematic review assesses botulinum toxin treatments' effectiveness, alone and with rehabilitation, in addressing APAs in Parkinson's disease, utilizing MEDLINE (PubMed), Web of Science, and SCOPUS databases for source material. Of the 1087 records retrieved, 16 met the selection criteria. Most research has focused on botulinum toxin (BoNT) as the primary treatment for camptocormia and Pisa syndrome, utilizing mostly observational methods. Despite dose and injection site variations, a common strategy was using electromyography-guided injections, occasionally enhanced with ultrasound. Patients with Pisa syndrome notably saw consistent improvements in APAs and pain. However, studies on the combined effects of botulinum toxin and rehabilitation are limited, and antecollis is significantly under-researched. These findings recommend precise BoNT injections into hyperactive muscles in well-selected patients by skilled clinicians, avoiding compensatory muscles, and underscore the necessity of early rehabilitation. Rehabilitation is crucial in a multidisciplinary approach to managing APAs, highlighting the importance of a multidisciplinary team of experts.

Background: Dyskinesias and freezing of gait are episodic disorders in Parkinson's disease, characterized by a fluctuating and unpredictable nature. This cross-sectional study aims to objectively monitor Parkinsonian patients experiencing dyskinesias and/or freezing of gait during activities of daily living and assess possible changes in spatiotemporal gait parameters., Methods: Seventy-one patients with Parkinson's disease (40 with dyskinesias and 33 with freezing of gait) were continuously monitored at home for a minimum of 5 days using a single wearable sensor. Dedicated machine-learning algorithms were used to categorize patients based on the occurrence of dyskinesias and freezing of gait. Additionally, specific spatiotemporal gait parameters were compared among patients with and without dyskinesias and/or freezing of gait., Results: The wearable sensor algorithms accurately classified patients with and without dyskinesias as well as those with and without freezing of gait based on the recorded dyskinesias and freezing of gait episodes. Standard spatiotemporal gait parameters did not differ significantly between patients with and without dyskinesias or freezing of gait. Both the time spent with dyskinesias and the number of freezing of gait episodes positively correlated with the disease severity and medication dosage., Conclusions: A single inertial wearable sensor shows promise in monitoring complex, episodic movement patterns, such as dyskinesias and freezing of gait, during daily activities. This approach may help implement targeted therapeutic and preventive strategies for Parkinson's disease., Competing Interests: The authors declare no conflicts of interest.

Background: Levodopa-carbidopa intestinal gel infusion (LCIG) is a therapeutic option for advanced Parkinson disease (PD) patients with troublesome motor complications, unresponsive to conventional oral treatment. There is some evidence to suggest that the genetic background may influence the clinical presentation and rate of progression of PD. Whether the genetic background influences the outcome of device-assisted therapies is currently debated. Some studies have investigated the effectiveness of deep brain stimulation (DBS) in PD patients with different genetic background, while evidence is lacking regarding LCIG., Methods: A cohort of LCIG patients underwent genetic testing. The motor and neuropsychological outcomes of LCIG were retrospectively analyzed., Results: Fifty-six patients were analyzed, nine of them (15%) had at least one mutation/variant in a PD-associated gene: five GBA1, two SNCA, one LRRK2, one PRKN; 13 (23%) carried the BDNF Val66Met polymorphism. The mean duration of follow-up was 4.9 ± 2.6 years. There were no significant differences in motor or neuropsychological outcomes between patients with and without these gene mutations/variants. No cognitive worsening was observed at follow-up among GBA-PD patients, and they responded well to LCIG in terms of motor symptoms., Conclusions: Overall, we observed a significant benefit in terms of motor complications in our cohort, including patients carrying genetic mutations/variants. Due to the small sample and limited number of patients carrying genetic mutations/variants, no definitive conclusions can be drawn yet on the genotype impact on LCIG outcome. A careful selection of patients, regardless of the genetic background, is pivotal for an optimal outcome of LCIG., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce., Objective: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort., Methods: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS., Results: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up., Conclusions: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: As the most common cause of autosomal recessive early onset Parkinson's disease (EOPD), parkin type Parkinson's disease (PRKN-PD) may affect female patients in childbearing age. Accordingly, issues related to fertility must be adequately addressed. Here, we landscaped fertile life factors and pregnancy course of a PRKN-PD cohort, including both novel cases directly observed at our center and published ones., Methods: Six patients with confirmed PRKN-PD were examined by a structured interview on reproductive factors and associated modifications of PD disturbances, including one case followed up throughout pregnancy which was described in greater detail. Six studies reporting fertile life factors of nine PRKN-PD patients were reviewed collecting homogeneous data on fertile life and pregnancy course., Results: PRKN-PD female patients experienced motor fluctuations with the menstrual cycle, pregnancy, and puerperium, which suggests a role for sex hormones in PD clinical burden. In some cases, abortion and miscarriages occurred during the organogenesis phase in patients receiving oral antiparkinsonian therapy; however, levodopa/benserazide monotherapy resulted to be the safest choice in pregnancy., Conclusion: Collectively these data disclose the importance of pre-conception counseling in childbearing age PRKN-PD patients and EOPD in general., (© 2023. The Author(s).)

Background: Gait issues, including reduced speed, stride length and freezing of gait (FoG), are disabling in advanced phases of Parkinson's disease (PD), and their treatment is challenging. Levodopa/carbidopa intestinal gel (LCIG) can improve these symptoms in PD patients with suboptimal control of motor fluctuations, but it is unclear if continuous dopaminergic stimulation can further improve gait issues, independently from reducing Off-time., Objective: To analyze before (T0) and after 3 (T1) and 6 (T2) months of LCIG initiation: a) the objective improvement of gait and balance; b) the improvement of FoG severity; c) the improvement of motor complications and their correlation with changes in gait parameters and FoG severity., Methods: This prospective, longitudinal 6-months study analyzed quantitative gait parameters using wearable inertial sensors, FoG with the New Freezing of Gait Questionnaire (NFoG-Q), and motor complications, as per the MDS-UPDRS part IV scores., Results: Gait speed and stride length increased and duration of Timed up and Go and of sit-to-stand transition was significantly reduced comparing T0 with T2, but not between T0-T1. NFoG-Q score decreased significantly from 19.3±4.6 (T0) to 11.8±7.9 (T1) and 8.4±7.6 (T2) (T1-T0 p = 0.018; T2-T0 p < 0.001). Improvement of MDS-UPDRS-IV (T0-T2, p = 0.002, T0-T1 p = 0.024) was not correlated with improvement of gait parameters and NFoG-Q from T0 to T2. LEDD did not change significantly after LCIG initiation., Conclusion: Continuous dopaminergic stimulation provided by LCIG infusion progressively ameliorates gait and alleviates FoG in PD patients over time, independently from improvement of motor fluctuations and without increase of daily dosage of dopaminergic therapy.

Deep brain stimulation (DBS) is an established therapeutic option for Parkinson's disease (PD) patients; however, a clear-cut definition of subthalamic (STN) DBS predictors in PD is lacking. We analyzed a cohort of 181 STN-treated PD patients and compared pre- vs. 1-year post-surgical motor, dyskinesia, Off time, and daily-life activities (ADL) scores. A multivariate linear regression analysis was used to evaluate the association between clinical/demographic characteristics and the extent of STN-DBS response for outcomes proving a significant change after surgery. After STN-DBS, we observed a significant improvement of motor symptoms (P < 0.001), dyskinesia (P < 0.001), and daily Off time (P < 0.001). Sex, PD duration, cognitive status, and the motor and axial response to levodopa significantly explained the motor improvement (R = 0.360, P = 0.002), with presurgical response of axial symptoms (Beta = 0.203, P = 0.025) and disease duration (Beta = 0.205, P = 0.013) being the strongest predictors. Considering the daily Off time improvement, motor and axial response at the levodopa challenge test and disease duration explained 10.6% of variance (R = 0.326, p < 0.001), with disease duration being the strongest predictor of improvement (Beta = 0.253, p: 0.001) and axial levodopa response showing a trend of significance in explaining the change (Beta = 0.173, p: 0.056). Dyskinesia improvement was not significantly explained by the model. Our findings highlight the emerging role of axial symptoms in PD and their response to levodopa as potentially pivotal also in the DBS selection process., Competing Interests: Declaration of Competing Interest Carlo Alberto Artusi: received travel grants from Zambon and AbbVie, and speaker grants from Zambon, Bial and Lusofarmaco. Claudia Ledda: received travel grants from Bial, Lusofarmaco, AbbVie and Merz. Domiziana Rinaldi: received travel grants from AbbVie. Elisa Montanaro: received travel grant from Ralpharma. Alberto Romagnolo: received grant support and speaker honoraria from AbbVie, speaker honoraria from Bial and Chiesi Farmaceutici and travel grants from Lusofarmaco, Chiesi Farmaceutici, Medtronic, and UCB Pharma. Gabriele Imbalzano: received travel grants from Bial and AbbVie. Mario Giorgio Rizzone: received grant support and speaker honoraria from Medtronic and UCB. Maurizio Zibetti: received honoraria from Medtronic, Zambon Pharma and AbbVie. Leonardo Lopiano: received honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. Marco Bozzali: received honoraria for lecturing from Biogen Pharma; he is member of the Advisory board of Roche Pharmaceuticals., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Postural abnormalities involving the trunk are referred to as axial postural abnormalities and can be observed in over 20% of patients with Parkinson's disease (PD) and in atypical parkinsonism. These symptoms are highly disabling and frequently associated with back pain and a worse quality of life in PD. Despite their frequency, little is known about the pathophysiology of these symptoms and scant data are reported about their clinical predictors, making it difficult to prompt prevention strategies., Objectives: We conducted a scoping literature review of clinical predictors and pathophysiology of axial postural abnormalities in patients with parkinsonism to identify key concepts, theories and evidence on this topic., Methods: We applied a systematic approach to identify studies, appraise quality of evidence, summarize main findings, and highlight knowledge gaps., Results: Ninety-two articles were reviewed: 25% reported on clinical predictors and 75% on pathophysiology. Most studies identified advanced disease stage and greater motor symptoms severity as independent clinical predictors in both PD and multiple system atrophy. Discrepant pathophysiology data suggested different potential central and peripheral pathogenic mechanisms., Conclusions: The recognition of clinical predictors and pathophysiology of axial postural abnormalities in parkinsonism is far from being elucidated due to literature bias, encompassing different inclusion criteria and measurement tools and heterogeneity of patient samples. Most studies identified advanced disease stage and higher burden of motor symptoms as possible clinical predictors. Pathophysiology data point toward many different (possibly non-mutually exclusive) mechanisms, including dystonia, rigidity, proprioceptive and vestibular impairment, and higher cognitive deficits., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Lateral trunk flexion (LTF) and its severe form, called Pisa syndrome (PS), are highly invalidating axial postural abnormalities associated with Parkinson's disease (PD). Management strategies for LTF lack strong scientific evidence. We present a real-life, longitudinal study evaluating long-term efficacy of botulinum toxin (BoNT) injections in axial muscles to reduce LTF and PS in PD. A total of 13 PD patients with LTF > 5° received ultrasound- and electromyography-guided BoNT injections every 4 months. Seven untreated matched PD patients with LTF served as controls and their changes in posture after 18 months were compared with those of seven patients continuing BoNT over 12 months. 53.8% of patients continued the BoNT injections for at least 12 months. Various individual LTF responses were observed. Overall, BoNT-treated patients obtained a not statistically significant improvement of LTF of 17 ± 41% ( p = 0.237). In comparison, the seven untreated PD patients suffered a deterioration in LTF over 12 months by 36 ± 45% ( p = 0.116), showing a significantly different trajectory of posture change ( p = 0.026). In conclusion, repeated BoNT injections in axial muscles showed varying effects in managing PD-associated LTF, suggesting that: (a) a relevant number of patients with LTF can benefit from BoNT; (b) long-term treatment could prevent LTF worsening; (c) an instrumented, personalized approach is important; and (d) there is a need for prospective, long-term studies.

Introduction: Parkinson's Disease (PD) patients with Parkin gene (PRKN) mutations show good response to subthalamic deep brain stimulation (STN-DBS). Currently, the longest follow-up available of these patients is 6 years. We report a very long-term outcome (more than 15 years) of a STN-DBS-treated patient with a compound heterozygous deletion of exons 3 and 11 of the PRKN gene., Case Report: In 1993, a 39-year-old male was diagnosed with PD after the onset of resting tremor. Levodopa was started, and during the following 10 years, he reported good motor symptoms control, with only mild modification of levodopa intake and pramipexole introduction. In 2005, he developed disabling motor fluctuations and dyskinesia. In 2007, he underwent bilateral STN-DBS, with a marked improvement of motor symptoms and fluctuations during the following years. After 6 years, he reported mild motor fluctuations, improved after stimulation and treatment modifications. After 10 years he showed diphasic dyskinesias, feet dystonia, postural instability, and gambling (resolved after pramipexole discontinuation). In 2018, he developed a non-amnestic single-domain mild cognitive impairment (MCI). In 2023, after more than 15 years of STN-DBS, motor symptoms and fluctuations are still well controlled. He reports mild dysphagia, mild depression, and multiple-domain MCI. His quality of life is better than before surgery, and he still reports a subjective significant improvement from STN-DBS., Conclusion: Confirming the very long-term efficacy of STN-DBS in PRKN-mutated patients, our case report underlines their peculiar suitability for surgical treatment., (© 2023. Fondazione Società Italiana di Neurologia.)

Parkinson's disease (PD) patients who are carriers of glucosylceramidase β1 (GBA1) gene mutations typically have an earlier age at onset and a more aggressive disease course, with a higher burden of neuropsychological issues. The use of deep brain stimulation (DBS) in PD patients with disabling motor fluctuations and absence of dementia is a widespread therapeutic option, often with good results in terms of improvement in activities of daily living and quality of life. Although all PD patients, when fulfilling the common selection criteria for DBS, can benefit from this intervention, some studies have raised attention toward the fact that PD patients who are carriers of GBA1 variants may have a worse DBS outcome possibly due to an accelerated progression of cognitive decline. From this viewpoint, we summarize the current literature, highlighting the knowledge gaps and proposing suggestions for further research as well as for clinical practice in this timeframe of uncertainty related to using DBS in PD patients who are carriers of GBA1 variants., Competing Interests: The 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 © 2023 Artusi and Lopiano.)

Background: Dysphagia is common in advanced phases of Parkinson disease (PD), and is a risk factor for aspiration pneumonia. Nonetheless, dysphagia has been poorly investigated in PD patients treated with levodopa-carbidopa intestinal gel (LCIG). We aimed to analyze the impact of dysphagia on mortality in LCIG treated patients and its relationship with other PD disability milestones., Methods: We retrospectively evaluated 95 consecutive PD patients treated with LCIG. Kaplan-Meier and log-rank test were used to compare mortality in patients with dysphagia from others. Cox regression was used to estimate the impact of dysphagia, age, disease duration, and Hoehn and Yahr (H&Y) on mortality in the entire cohort. Finally, univariate and multivariate regression analyses were used to estimate the association between dysphagia and age, disease duration, H&Y, hallucinations, and dementia., Results: A significantly higher mortality rate was observed in patients with dysphagia. In the Cox model, dysphagia was the only feature significantly associated with mortality (95%CI 2.780-20.609; p < 0.001). Univariate analyses showed a significant correlation between dysphagia and dementia (OR: 0.387; p:0.033), hallucinations (OR: 0.283; p:0.009), and H&Y score (OR: 2.680; p < 0.001); in the multivariate analysis, only the H&Y stage was associated with the presence of dysphagia (OR: 2.357; p:0.003)., Conclusion: Dysphagia significantly increased the risk of death in our cohort of LCIG-treated patients, independently from other relevant features such as age, disease duration, dementia, and hallucinations. These findings support the management of this symptom as a priority in the advanced PD stages, even in people treated with LCIG., Competing Interests: Declaration of competing interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. DR received travel grants from Abbvie and Zambon. GI received travel grants from Lusofarmaco and Abbvie. SG reports no financial disclosures. EB reports no financial disclosures. LDC reports no financial disclosures. CL received travel grants from Bial and Merz. MZ received honoraria for lecturing and travel grants from Medtronic, Bial Pharma, and AbbVie. LL received honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. FEP received honoraria for lecturing from Abbvie, Bial, and Zambon, and a research grant from Lundbeck. CAA received honoraria from Ralpharma and Zambon for scientific support, and speaker honoraria from Ecupharma and Bial., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.

Background: Software-based measurements of axial postural abnormalities in Parkinson's disease (PD) are the gold standard but may be time-consuming and not always feasible in clinical practice. An automatic and reliable software to accurately obtain real-time spine flexion angles according to the recently proposed consensus-based criteria would be a useful tool for both research and clinical practice., Objective: We aimed to develop and validate a new software based on Deep Neural Networks to perform automatic measures of PD axial postural abnormalities., Methods: A total of 76 pictures from 55 PD patients with different degrees of anterior and lateral trunk flexion were used for the development and pilot validation of a new software called AutoPosturePD (APP); postural abnormalities were measured in lateral and posterior view using the freeware NeuroPostureApp (gold standard) and compared with the automatic measurement provided by the APP. Sensitivity and specificity for the diagnosis of camptocormia and Pisa syndrome were assessed., Results: We found an excellent agreement between the new APP and the gold standard for lateral trunk flexion (intraclass correlation coefficient [ICC] 0.960, IC95% 0.913-0.982, P  < 0.001), anterior trunk flexion with thoracic fulcrum (ICC 0.929, IC95% 0.846-0.968, P  < 0.001) and anterior trunk flexion with lumbar fulcrum (ICC 0.991, IC95% 0.962-0.997, P  < 0.001). Sensitivity and specificity were 100% and 100% for detecting Pisa syndrome, 100% and 95.5% for camptocormia with thoracic fulcrum, 100% and 80.9% for camptocormia with lumbar fulcrum., Conclusions: AutoPosturePD is a valid tool for spine flexion measurement in PD, accurately supporting the diagnosis of Pisa syndrome and camptocormia., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Purpose: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition., Methods: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed., Results: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate., Conclusions: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy., Methods: Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m 2 . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment., Results: At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%)., Conclusions: This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Gait and axial postural abnormalities (PA) are common and disabling symptoms of Parkinson's disease (PD). The interplay between them has been poorly explored., Methods: A standardized protocol encompassing videos and photos for posture and gait analysis of PD patients with a clinically defined PA (MDS-UPDRS-III item 3.13 > 0) was used in 6 movement disorder centers. A comprehensive evaluation was performed to clarify the association between gait performance and the presence and severity of PA., Results: 225 PD patients were enrolled: 57 had severe PA, 149 mild PA, and 19 did not meet criteria for PA, according to a recent consensus agreement on PA definition. PD patients with severe PA were significantly older (p:0.001), with longer disease duration (p:0.007), worse MDS-UPDRS-II and -III scores and axial sub-scores (p < 0.0005), higher LEDD (p:0.002) and HY stage (p < 0.0005), and a significantly lower velocity (p < 0.001) and cadence (p:0.021), if compared to mild PA patients. The multiple regression analysis evaluating gait parameters and degrees of trunk/neck flexion showed that higher degrees of lumbar anterior trunk flexion were correlated with lower step length (OR -0.244; p:0.014) and lower velocity (OR -0.005; p:0.028)., Conclusions: Our results highlight the possible impact of severe anterior trunk flection on PD patients' gait, with a specific detrimental effect on gait velocity and step length. Personalized rehabilitation strategies should be elaborated based on the different features of PA, aiming to target a combined treatment of postural and specifically related gait pattern alterations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: We sought to estimate the impact of cardiovascular autonomic neuropathy (cAN) on informal caregivers of patients with Parkinson's disease (PD), defined as individuals providing regular care to a friend, partner, or family member with PD, and to evaluate the mutual relationship between caregiver burden and patient health-related quality of life (HRQoL)., Methods: We enrolled 36 consecutive patients with PD and their informal caregivers. Patients underwent a detailed motor, autonomic, cognitive, and functional assessment. Caregivers were assessed using the Zarit Burden Interview (ZBI). Differences in caregiver burden, expressed by the ZBI score, and strength of association between caregiver burden, cAN, and HRQoL were assessed using analysis of covariance (ANCOVA), logistic regression, and linear regression analyses. Analyses were adjusted for patients' age, PD duration, and motor and cognitive disability, as well as caregivers' age., Results: Moderate-severe caregiver burden was reported in 41.7% of PDcAN + versus 8.7% of PDcAN - (p < 0.001). The ZBI score was increased in PDcAN + versus PDcAN - (31.5 ± 3.4 versus 15.2 ± 2.3; p < 0.001), with tenfold higher odds (p = 0.012) of moderate-severe caregiver burden in PDcAN + , even after adjusting for potential confounders. The ZBI score correlated with cAN severity (p = 0.005), global autonomic impairment (p = 0.012), and HRQoL impairment (p < 0.001)., Conclusion: These results highlight the significant impact of cAN on PD caregivers and the need for targeted interventions addressing this frequently overlooked and insufficiently treated source of nonmotor disability in PD., (© 2022. The Author(s).)

Background: Pisa syndrome (PS) and camptocormia (CC) are postural abnormalities frequently associated with Parkinson's disease (PD). Their pathophysiology remains unclear, but the role of cognitive deficits has been postulated., Objectives: To identify differences in the neuropsychological functioning of patients with PD with PS or CC compared with matched patients with PD without postural abnormalities., Methods: We performed a case-control study including 57 patients with PD with PS (PS+) or CC (CC+) and 57 PD controls without postural abnormalities matched for sex, age, PD duration, phenotype, and stage. Patients were divided into four groups: PS+ (n = 32), PS+ controls (PS-, n = 32), CC+ (n = 25), and CC+ controls (CC-, n = 25). We compared PS+ versus PS- and CC+ versus CC- using a neuropsychological battery assessing memory, attention, executive functions, visuospatial abilities, and language. Subjective visual vertical (SVV) perception was assessed by the Bucket test as a sign of vestibular function; the misperception of trunk position, defined as a mismatch between the objective versus subjective evaluation of the trunk bending angle >5°, was evaluated in PS+ and CC+., Results: PS+ showed significantly worse visuospatial performances ( P = 0.025) and SVV perception ( P = 0.038) than their controls, whereas CC+ did not show significant differences compared with their control group. Reduced awareness of postural abnormality was observed in >60% of patients with PS or CC., Conclusions: Low visuospatial performances and vestibular tone imbalance are significantly associated with PS but not with CC. These findings suggest different pathophysiology for the two main postural abnormalities associated with PD and can foster adequate therapeutic and prevention strategies., (© 2022 International Parkinson and Movement Disorder Society.)

Background: Several neurological complications have been reported following SARS-Cov-2 vaccination, without a clear causal relationship ever being verified, including some cases of worsening of Parkinson's disease (PD) symptoms and new onset of movement disorders in non-parkinsonian patients., Methods: We describe two new cases of PD patients treated with device-aided therapy who developed worsening of parkinsonian symptoms after receiving the third vaccine dose (booster). We also conducted a short review of the cases reported in literature of PD symptoms worsening and new onset of movement disorders in non-parkinsonian patients after SARS-Cov-2 vaccination., Results: The first patient, a 46-year-old man implanted with bilateral Subthalamic Deep Brain Stimulation, experienced temporary motor and non-motor symptoms worsening after mRNA-1273 booster, improved after stimulation settings modification. The second patient, a 55-year-old man implanted with percutaneous endoscopic transgastric jejunostomy (PEG-J) for levodopa-carbidopa intestinal gel (LCIG) infusion experienced severe temporary worsening of dyskinesia and managed through temporary LCIG dose reduction. Other seven cases of vaccine-related movement disorder are currently reported in literature, four describing PD symptoms worsening and three the onset of new movement disorders in otherwise healthy people., Conclusion: Both our patients and the cases described so far completely recovered after few days with parkinsonian therapy modification, symptomatic treatment, or even spontaneously, underlining the transient and benign nature of side effects from vaccine. Patients should be reassured about these complications, manageable through a prompt evaluation by the reference neurologist., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Botulinum toxin (BoNT) is a valuable treatment in movement disorders; however, time to onset and duration of efficacy may widely differ among patients. We aimed to clarify the impact of main demographic and clinical features on time to onset and duration of BoNT efficacy., Methods: We analyzed time-to-onset and duration of BoNT efficacy in 186 consecutive patients treated with BoNT for blepharospasm, cervical dystonia, facial hemispasm, oromandibular dystonia, limb dystonia, and sialorrhea due to Parkinsonism. The following factors were considered as potential efficacy predictors: doses and types of toxin, sex, age, years of treatment, and clinical condition. Kruskall-Wallis, Spearman correlation, and multivariate linear regression were used for statistical analysis., Results: The average time to onset was 6.7 ± 5 days and duration of BONT efficacy 78.5 ± 28.4 days. Both time to onset and duration of efficacy were correlated with BoNT doses (p: 0.007 and p: 0.02). The multiple regression analysis showed that sex, age, years of BoNT treatment, doses, type of toxin, and clinical condition significantly predicted time to onset (F(11, 171) = 2.146, p: 0.020) with age being the strongest predictor (p: 0.004). The same model explained 20.1% of the variance of duration of BoNT efficacy, showing a significant prediction of the outcome (F(11, 164) = 3.754, p < 0.001), with doses (p < 0.001), type of toxin (p: 0.017), and clinical condition (p < 0.001) being the strongest predictors., Conclusion: Our findings suggest that age, type of toxin, clinical condition and especially doses may account for the variability of BoNT efficacy in terms of time to onset and duration., (© 2022. The Author(s).)

Background: There is no consensus with regard to the nosology and cut-off values for postural abnormalities in parkinsonism., Objective: To reach a consensus regarding the nosology and cut-off values., Methods: Using a modified Delphi panel method, multiple rounds of questionnaires were conducted by movement disorder experts to define nosology and cut-offs of postural abnormalities., Results: After separating axial from appendicular postural deformities, a full agreement was found for the following terms and cut-offs: camptocormia, with thoracic fulcrum (>45°) or lumbar fulcrum (>30°), Pisa syndrome (>10°), and antecollis (>45°). "Anterior trunk flexion," with thoracic (≥25° to ≤45°) or lumbar fulcrum (>15° to ≤30°), "lateral trunk flexion" (≥5° to ≤10°), and "anterior neck flexion" (>35° to ≤45°) were chosen for milder postural abnormalities., Conclusions: For axial postural abnormalities, we recommend the use of proposed cut-offs and six unique terms, namely camptocormia, Pisa syndrome, antecollis, anterior trunk flexion, lateral trunk flexion, anterior neck flexion, to harmonize clinical practice and future research., (© 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective surgical treatment for advanced Parkinson's disease (PD). However, some patients still experience motor fluctuations or dyskinesia after STN-DBS. Safinamide is approved as add-on treatment to levodopa in fluctuating PD patients. In this study, we evaluated the effect of safinamide as adjunctive therapy in PD patients still experiencing motor fluctuations and dyskinesias after STN-DBS., Methods: PD patients treated for at least 2 years with bilateral STN-DBST and with troublesome motor fluctuation and/or dyskinesias were examined by means of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the quality of life questionnaire Parkinson's Disease Questionnaire-8 (PDQ-8) and the Non-Motor Symptoms Scale (NMSS) at baseline (T0), after 1 month of treatment with safinamide 50 mg daily (T1) and after another month of treatment with safinamide 100 mg daily (T2)., Results: Twenty-nine PD patients were examined. An improvement of the MDS-UPDRS IV score (motor complications) was observed between T0 and T1, T0 and T2, and T1 and T2. The time spent in the OFF state, the functional impact and the complexity of motor fluctuations significantly improved between T0 and T1 and T0 and T2. The mean levodopa equivalent daily dose significantly decreased from T0 to T1 and from T0 to T2. Regarding non-motor symptoms, an improvement on mood and pain was observed., Conclusions: Safinamide seems to be an effective adjunctive treatment in PD patients treated with bilateral STN-DBS, leading to an improvement of motor complications, mood and pain., (© 2022. Fondazione Società Italiana di Neurologia.)

Introduction: Postural abnormalities (PA) are disabling features of Parkinson's disease (PD). Indirect analyses suggested a higher prevalence of PA among Asian patients compared to Caucasian ones, but no direct comparisons have been performed so far., Methods: An international, multicenter, cross-sectional study was performed in 6 European and Asian movement disorders centers with the aim to clarify differences and similarities of prevalence and characteristics of PA in Asian vs. Caucasian PD patients. Axial PA, encompassing antecollis (AC), camptocormia (CC), and Pisa syndrome (PS), and appendicular PA (appPA) were systematically searched and analysed in consecutive patients., Results: 88 (27%) of 326 PD patients had PA (29.1% in Asians and 24.3% in Caucasians, p: 0.331). Prevalence of axial PA was 23.6% in Asians and 24.3% in Caucasians (p = 0.886), in spite of a longer disease duration among Caucasians, but a longer PA duration among Asians. No differences in prevalence between AC, CC, and PS were found between the two ethnicities. The prevalence of appPA was higher in Asians (p = 0.036), but the regression analysis did not confirm a significant difference related to ethnicity. Considering the whole population, male gender (OR, 4.036; 95% CI, 1.926-8.456; p < 0.005), a longer disease duration (OR, 2.61; 95% CI, 1.024-6.653; p = 0.044), and a higher axial score (OR, 1.242; 95% CI, 1.122-1.375; p < 0.0005) were the factors associated with axial PA., Conclusion: The prevalence of axial PA in PD patients is not influenced by ethnicity. However, Asian PD patients tend to develop PA earlier in the disease course, particularly AC., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Atypical Parkinsonisms (APs) -including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB)- are neurodegenerative diseases lacking satisfying symptomatic therapies. Deep Brain Stimulation (DBS) is an established neurosurgical option for advanced Parkinson disease (PD). Although DBS effectiveness in PD fed expectations for the treatment of APs, DBS is still not recommended for APs on the basis of expert consensus and lack of clinical trials., Objective: In this systematic review, we sought to analyze current evidence on the safety and efficacy of DBS in APs, discussing clinical indications, anatomical targets, and ethical issues., Methods: Following the PRISMA guidelines, we systematically searched PubMed for studies reporting the outcome of patients with APs treated with DBS., Results: We identified 25 eligible studies for a total of 66 patients with APs treated with DBS: 31 PSP, 22 MSA, 12 DLB, 1 unspecified parkinsonism with tongue tremor. Targeted nuclei were subthalamic nucleus (STN), globus pallidus pars-interna (GPi), pedunculopontine nucleus (PPN), and nucleus basalis of Meynert (nbM). Only 3/25 studies were randomized controlled trials, and most studies showed a high risk of bias., Conclusion: Taking into account study biases and confounding factors, current evidence does not support the use of DBS in APs. However, some interesting insights arise from the literature, such as the high frequency of cognitive/neurobehavioral issues in MSA patients treated with STN-DBS, the low frequency of complications in trials of nbM-DBS for DLB, and the possible good response of dystonic symptoms in PSP with GPi DBS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) is increasingly recognized as a multidimensional disorder, characterized by several non-motor symptoms, including disturbances of sleep and cognition. Current studies on the relationship between sleep problems and neuropsychological functions, mainly conducted in early to moderate PD patients, outline mixed results. In this study, we analysed the relationship between subjectively reported sleep alterations and cognitive functions in a large cohort of 181 advanced PD patients., Methods: All consecutive, non-demented, advanced PD patients candidates for device-aided therapy completed two self-administered sleep questionnaires-the Parkinson's Disease Sleep Scale (PDSS-2) and the Epworth Sleepiness Scale (ESS)-and underwent a comprehensive battery of neuropsychological tests encompassing five cognitive domains (reasoning, memory, attention, frontal executive functions, and language)., Results: Patients showed mild to moderate sleep problems (PDSS-2 score: 23.4 ± 1.2) and mild daytime sleepiness (ESS 8.6 ± 5.1). A significant correlation was found between PDSS-2 total score and non-verbal reasoning, as well as attentive skills, executive functions, and language abilities. No correlations were found between sleep measures and memory tests scores. Patients with clinically relevant sleep disturbances performed worse on attention, executive functions, and language. No significant correlations were found between daytime sleepiness and any neuropsychological test., Conclusions: In advanced PD patients, sleep disturbances selectively correlate with specific neuropsychological functions and not with short-term memory and consolidation. Even if confirmations by means of longitudinal studies are needed, our observations suggest the importance of considering treatment of sleep disturbances to minimize their potential impact on cognition., (© 2021. The Author(s).)

Background: The psychological impact of the COVID-19 outbreak and lockdown on frail populations with advanced Parkinson disease (APD) and their caregivers may present with peculiar features and require specific interventions., Methods: We enrolled here 100 APD patients and 60 caregivers. Seventy-four patients were treated with device-aided therapies (DAT) and 26 with standard medical treatment (SMT). Through a telephonic interview, subjects underwent the Hospital Anxiety and Depression Scale (HADS-A; HADS-D), and an ad hoc questionnaire to explore thoughts and emotions related to the pandemic., Results: Depression was observed in 35% of APD patients and anxiety in 39%, with a significant reduction of the latter after the lockdown (p= 0.023). We found a significant correlation between the type of therapy and the HADS-A score (p= 0.004). Patients' main worries were as follows: a possible higher risk of COVID-19 infection (25%), interruption of non-pharmacological treatments (35%), interruption of outpatient clinics (38%), PD complications related to COVID-19 (47%). Patients treated with DAT manifested worries about device-related issues and risk for caregivers' infection. The 40% of caregivers showed anxiety, while the 21.7% of them showed depression., Conclusion: Our study reveals a higher prevalence of anxiety and the presence of peculiar worries and needs in APD patients during the pandemic alongside psychological sequelae of their caregivers. These findings are important for neurologists and healthcare services to foster strategies for the management of psychological distress in both patients and caregivers., (© 2021. The Author(s).)

Objectives: To provide new insights into neurological manifestations of COVID-19. We describe a patient with mild COVID-19 associated with diplopia from right sixth cranial nerve palsy and early diffuse leukoencephalopathy, successfully treated with intravenous methylprednisolone., Methods: The patient was evaluated for diplopia that occurred 1 day after the onset of fever, myalgia, and headache. A complete neurological workup, including neurological examination, cerebrospinal fluid (CSF) analysis with viral polymerase chain reaction (PCR), serum autoimmune encephalitis, and anti-nerve antibodies and brain magnetic resonance imaging (MRI), was performed., Results: Clinical examination revealed incomplete right sixth cranial nerve palsy. Brain MRI showed diffuse confluent fluid-attenuated inversion recovery (FLAIR) hyperintense white matter abnormalities, while CSF analysis showed mild hyperproteinorrachia (61 mg/dL) without pleocytosis. The patients were treated with high-dose intravenous methylprednisolone with rapid improvement of neurological symptoms and resolution of CSF and MRI abnormalities., Discussion: Our report shows that COVID-19 may predominantly present with neurological symptoms; furthermore, it argues the notion of leukoencephalopathy as a typical feature of a severe case of the disease. Mechanisms underpinning neurological symptoms in COVID-19 still need to be elucidated; nonetheless, early recognition and prompt management may ensure their improvement or even complete recovery and are therefore recommended., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: Neurological involvement in Coronavirus disease-2019 (COVID-19) is widely recognized. However, the role of pre-existing neurological comorbidities in modulating COVID-19-related mortality still remains unclear. This cohort study evaluates the COVID-19-related case fatality rate (CFR) of patients with pre-existing neurological diseases., Methods: We retrospectively evaluated all patients consecutively admitted to our hospital with a diagnosis of COVID-19 between March and April 2020. We used a multivariate regression analysis to estimate the association between pre-existing neurological diseases and COVID-19-related mortality. Then, we compared the CFR and survival curves of two cohorts (patients suffering vs. those not suffering from pre-existing neurological disease), matched trough the propensity score (PS). Age and other comorbidities were considered for PS calculation. We applied a 1:1 matching for the entire neurological cohort and, separately, for cerebrovascular, neurodegenerative, and other neurological diseases., Results: Among 332 patients, 75 (22.6%) were affected by pre-existing neurological disease (n = 29 cerebrovascular, n = 26 neurodegenerative, n = 20 others). From the multivariate regression analysis, they resulted with a significant increase of COVID-19-related mortality (OR:2.559; 95%CI 1.181-5.545; p < 0.017). From the cohort analysis, CFR resulted 2-fold higher in patients with neurological disease (48.0% vs. 24.0%; p = 0.002). CFR was significantly higher in patients with neurodegenerative diseases compared to matched individuals (73.9% vs. 39.1%; p = 0.017), while CFR increase in patients with cerebrovascular diseases did not reach statistical significance (48.3% vs. 41.4%; p = 0.597)., Conclusions: Pre-existing neurological comorbidities, in particular neurodegenerative diseases, increase significantly COVID-19-related case fatality, indicating a clear priority for viral screening, access to care facilities and vaccination in these populations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Digital health, including telemedicine, is increasingly recommended for the management of chronic neurological disorders, and it has changed the roles of patients and clinicians., Methods: In this cross-sectional study we aimed to investigate the digital work engagement of Italian neurologists through a survey collected between September 2020 and January 2021. Questionnaires were anonymous and collected demographic characteristics, attitudes towards digital devices and social media, and details about the clinician-patient relationship. We used logistic-regression models to identify characteristics associated with the propensity to communicate with patients using social media., Results: Among the 553 neurologists who participated to the study, smartphones and computers were widely preferred compared with tablets; wearable devices were not common, although some neurologists desired them. A total of 48% of participants reported communicating with patients using social media but only a few were in favor of social friendship with patients; WhatsApp was the social media most popular for professional (86%) and personal (98%) purposes. Propensity to communicate with social media was significantly higher among those who were older ( p  < 0.001) and lived in regions outside northern Italy (center: p  = 0.006; south and the islands: p  < 0.001). For 58% of responders, social media improved their relationship with patients, but 72% usually warned patients about unreliable websites., Conclusions: The preferred social media were those which were rapid and which safeguard privacy more effectively; neurologists made many efforts to disprove fake news circulating online, providing help to patients in various ways. This analysis can help direct future interventions for the management of chronic neurological disorders., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

We report here the first case of a young individual otherwise healthy, who presented with frequent focal seizures with impaired awareness as a possible long-term complication of severe acute respiratory syndrome coronavirus-2 infection. Seizures were documented by electroencephalography and responded clinically and neuro-physiologically to antiseizure therapy. The patient underwent an extensive investigation including cerebrospinal fluid examination, conventional and quantitative brain magnetic resonance imaging, and 18-FDG positron emission tomography. Beyond the clinical interest, this case contributes to clarify the possible pathways by which SARS-CoV-2 may enter the central nervous system and cause long-term neurological complications.

Purpose: Tolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson's disease (PD). However, safety issues hampered its use in clinical practice. We aimed to provide evidence of safety and efficacy of tolcapone by a systematic literature review to support clinicians' choices in the use of an enlarging PD therapeutic armamentarium., Methods: We searched PubMed for studies on PD patients treated with tolcapone, documenting the following outcomes: liver enzyme, adverse events (AEs), daily Off-time, levodopa daily dose, unified Parkinson's disease rating scale (UPDRS) part-III, quality of life (QoL), and non-motor symptoms. FAERS and EudraVigilance databases for suspected AEs were interrogated for potential additional cases of hepatotoxicity., Results: Thirty-two studies were included, for a total of 4780 patients treated with tolcapone. Pertaining safety, 0.9% of patients showed liver enzyme elevation > 2. Over 23 years, we found 7 cases of severe liver injury related to tolcapone, 3 of which were fatal. All fatal cases did not follow the guidelines for liver function monitoring. FAERS and EudraVigilance database search yielded 61 reports of suspected liver AEs possibly related to tolcapone. Pertaining efficacy, the median reduction of hours/day spent in Off was 2.1 (range 1-3.2), of levodopa was 108.9 mg (1-251.5), of "On" UPDRS-III was 3.6 points (1.1-6.5). Most studies reported a significant improvement of QoL and non-motor symptoms., Conclusion: Literature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium.

Background: subthalamic nucleus deep brain stimulation (STN-DBS) may have a detrimental effect on speech in Parkinson's disease (PD) patients and new stimulation technologies may help in addressing this issue., Objective: to evaluate the STN-DBS acute effect of 30 μs pulse width (30PW) versus conventional 60 μs PW (60PW) on speech and identify the core features of voice modified by 30PW., Methods: seven STN-DBS treated PD patients participated into a pilot cross-sectional study. Motor and speech performances were tested by means of both automatic analysis and blinded clinical evaluations in four stimulation conditions: 30PW and 60PW both at the usual amplitude and at an amplitude just below the threshold for stimulation-related side effects., Results: at the threshold amplitude, 30PW stimulation improved speech intelligibility for both words (p = 0.02) and sentences (p = 0.04), without worsening motor performance. A lower but not statistically significant voice variability and instability and percentage of stuttering disfluencies was also observed. The beneficial effect of 30PW detected by automatic analysis, was confirmed by patients' perception., Conclusions: STN-DBS treated patients experiencing low speech intelligibility may benefit from a 30PW stimulation trial at a higher amplitude. Deep characterization of PD speech profiles may help in a better application of recent DBS hardware advances., (Copyright © 2021 Elsevier Ltd. All rights reserved.)