Magnetic resonance-guided focused ultrasound unilateral thalamotomy for medically refractory essential tremor: 3-year follow-up data.

Introduction: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy of the ventralis intermediate (Vim) nucleus is an "incisionless" treatment for medically refractory essential tremor (ET). We present data on 49 consecutive cases of MRgFUS Vim thalamotomy followed-up for 3 years and review the literature on studies with longer follow-up data. Methods: A retrospective chart review of patients who underwent MRgFUS thalamotomy (January 2018-December 2020) at our institution was performed. Clinical Rating Scale for Tremor (CRST) and Quality of Life in Essential Tremor (QUEST) scores were obtained pre-operatively and at each follow-up with an assessment of side effects. Patients had post-operative magnetic resonance imaging within 24 h and at 1 month to figure out lesion location, size, and extent. The results of studies with follow-up ≥3 years were summarized through a literature review. Results: The CRST total (baseline: 58.6 ± 17.1, 3-year: 40.8 ± 18.0) and subscale scores (A + B, baseline: 23.5 ± 6.3, 3-year: 12.8 ± 7.9; C, baseline: 12.7 ± 4.3, 3-year: 5.8 ± 3.9) and the QUEST score (baseline: 38.0 ± 14.8, 3-year: 18.7 ± 13.3) showed significant improvement that was stable during the 3-year follow-up. Three patients reported tremor recurrence and two were satisfactorily retreated. Side effects were reported by 44% of patients (severe: 4%, mild and transient: 40%). The improvement in tremor and quality of life in our cohort was consistent with the literature. Conclusion: We confirmed the effectiveness and safety of MRgFUS Vim thalamotomy in medically refractory ET up to 3 years.

Autoimmune Movement Disorders Complicating Treatment with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) may trigger autoimmune neurological conditions, including movement disorders (MD). OBJECTIVES: The aim of this study was to characterize MDs occurring as immune-related adverse events (irAEs) of ICIs. METHODS: A systematic literature review of case reports/series of MDs as irAEs of ICIs was performed. RESULTS: Of 5682 eligible papers, 26 articles with 28 patients were included. MDs occur as a rare complication of cancer immunotherapy with heterogeneous clinical presentations and in most cases in association with other irAEs. Inflammatory basal ganglia T2/fluid attenuated inversion recovery abnormalities are rarely observed, but brain imaging is frequently unrevealing. Cerebrospinal fluid findings are frequently suggestive of inflammation. Half of cases are associated with a wide range of autoantibodies. Steroids and ICI withdrawal usually lead to improvement, even though some patients experienced relapses or a severe clinical course. CONCLUSION: MDs are a rare complication of ICIs that should be promptly recognized to offer patients a correct diagnosis and treatment.

The Association Between Neurocognitive Disorders and Gustatory Dysfunction: A Systematic Review and Meta-Analysis.

Olfactory and gustatory dysfunction have been reported in mild and major neurocognitive disorders (NCDs), with variable results. While olfactory dysfunction has been consistently explored, reports on gustatory alterations are limited. We systematically reviewed case-control studies evaluating gustatory function in NCDs with various etiologies and different neuropathology. Eighteen studies were included in the systematic review, and eight were included in the meta-analysis. Most studies were on Alzheimer's disease (AD) and Parkinson's disease (PD). Pooled analyses showed worse global taste threshold and identification (sour in particular) scores in AD than controls and worse global, sweet, and sour scores in AD compared to mild cognitive impairment (MCI). PD with MCI showed worse global, sweet, salty, and sour scores than controls and cognitively unimpaired PD. Taste dysfunction was differentially associated with the severity of cognitive deficits. Gustatory dysfunction may represent a potential cross-disease chemosensory biomarker of NCD. Whether gustatory alterations may be a pre-clinical biomarker of NCD requires further studies.

Treatment for cognitive and neuropsychiatric non-motor symptoms in Parkinson's disease: current evidence and future perspectives.

INTRODUCTION: Non-motor symptoms (NMS) affect patients with Parkinson's disease (PD) from the prodromal to the advanced stages. NMS phenotypes greatly vary and have a huge impact on patients' and caregivers' quality of life (QoL). The management of cognitive and neuropsychiatric NMS remains an unmet need. AREAS COVERED: The authors, herein, review the dopaminergic and non-dopaminergic pathogenesis, clinical features, assessment, and pharmacological and non-pharmacological treatments of cognitive and neuropsychiatric NMS in PD. They discuss the current evidence and report the findings of an overview of ongoing trials on pharmacological and selected non-pharmacological strategies. EXPERT OPINION: The treatment of cognitive and neuropsychiatric NMS in PD is poorly explored, and therapeutic options are unsatisfactory. Pharmacological treatment of cognitive NMS is based on symptomatic active principles used in Alzheimer's disease. Dopamine agonists, selective serotonin, and serotonin-norepinephrine reuptake inhibitors have some evidence on PD-related depression. Clozapine, quetiapine, and pimavanserin may be considered for psychosis in PD. Evidence on the treatment of other neuropsychiatric NMS is limited or lacking. Addressing pathophysiological and clinical issues, which hamper solid evidence on the treatment of cognitive and neuropsychiatric NMS, may reduce the impact on QoL for PD patients and their caregivers.

Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) targeting programmed death receptor 1 (PD-1), cytotoxic T-lymphocyte-associated-4 (CTLA-4) and programmed cell death ligand 1 can be associated with immune-related adverse events (iRAEs). Amongst neurological iRAEs, cerebellar involvement seems to be rare and currently lacks a proper characterization. The aim of this study was to phenotype cerebellar iRAEs. METHODS: A systematic review was performed according to PRISMA guidelines including reported patients with cerebellar involvement related to ICIs and with available individual data. RESULTS: After screening 2765 records, 32 studies with 46 patients were included. Median age was 63 years (20-82), and most patients were male (63.0%). Isolated cerebellitis was observed in 32.6% of cases, whilst the remaining cases had "cerebellitis plus", mostly associated with encephalitis/encephalopathy. Associated tumors included most frequently lung cancer, melanoma and Merkel cell carcinoma. PD-1 inhibitor was the most administered treatment (n = 29, 64.4%), whilst exposure to CTLA-4 inhibitor was rare (n = 2, 4.5%). Magnetic resonance imaging was abnormal in 43.2% of patients and inflammatory cerebrospinal fluid findings were frequently observed. Autoantibodies were detected in 61.9% of patients and included novel reactivities. Amongst treatment strategies, the most common were steroids (n = 36) and ICI discontinuation (n = 28, 90.3%). Relapses were reported in 10% of patients. Most patients showed improvement/remission (n = 31) but, at last follow-up, 12 had died. Isolated cerebellitis versus cerebellitis-plus differed in terms of outcomes, whilst seropositive versus seronegative patients had distinct tumor associations. DISCUSSION: Cerebellar iRAEs are usually multifocal, have heterogeneous tumor associations, are most associated with PD-1 inhibitor exposure and are related to autoantibodies, including novel reactivities.

Wearables, sensors, and smart devices for the detection and monitoring of chemotherapy-induced peripheral neurotoxicity: Systematic review and directions for future research.

Chemotherapy-induced peripheral neurotoxicity (CIPN) diagnosis is largely based on patient reported outcomes. Wearables, sensors, and smart devices may potentially provide early detection and monitoring of CIPN. We systematically reviewed data on wearables, sensors, and smart devices to detect and/or monitor signs and symptoms of CIPN. Moreover, we provide directions and recommendations for future studies. A literature search using PubMed/MEDLINE, Web of Science, IEEE Xplore, and CINHAL databases was conducted from database inception until March 2021. The search was further updated in July 2022 to ensure currency of results. A total of 1885 records were title-abstract screened, 33 full texts were assessed, and 16 were included. The retrieved papers were heterogeneous in terms of study design, sample size, CIPN severity, chemotherapy agents, type of wearable/sensor/device applied, parameters of interest, and purpose. Data are promising and provide preliminary evidence on wearables, sensors, and smart devices for CIPN detection and monitoring. There are several issues and knowledge gaps that should be addressed. We propose a framework for future studies.

Spasticity following brain and spinal cord injury: assessment and treatment.

PURPOSE OF REVIEW: Spasticity is a common sequela of brain and spinal cord injury and contributes to disability, reduces quality of life, and increases economic burden. Spasticity is still incompletely recognized and undertreated. We will provide an overview of recent published data on the definition, assessment, and prediction, therapeutic advances, with a focus on promising new approaches, and telemedicine applications for spasticity. RECENT FINDINGS: Two new definitions of spasticity have been recently proposed, but operational criteria should be developed, and test-retest and inter-rater reliability should be explored. Cannabinoids proved to be effective in spasticity in multiple sclerosis, but evidence in other types of spasticity is lacking. Botulinum neurotoxin injection is the first-line therapy for focal spasticity, and recent literature focused on optimizing its efficacy. Several pharmacological, interventional, and nonpharmacological therapeutic approaches for spasticity have been explored but low-quality evidence impedes solid conclusions on their efficacy. The recent COVID-19 pandemic yielded guidelines/recommendations for the use of telemedicine in spasticity. SUMMARY: Despite the frequency of spasticity, robust diagnostic criteria and reliable assessment scales are required. High-quality studies are needed to support the efficacy of current treatments for spasticity. Future studies should explore telemedicine tools for spasticity assessment and treatment.

D2/D3 Receptor Agonism: Paving the Way for a New Therapeutic Target for Taste Disorders in Parkinson's Disease and Other Conditions?

Chemosensory (i.e., olfaction and taste) dysfunction is common in neurodegenerative (e.g., Parkinson's disease, Alzheimer's disease, and dementia), psychiatric (e.g., depression, bipolar disorders, other conditions), and postinfectious (i.e., long COVID) diseases and in the elderly. Despite its impact on patients' quality of life, no established treatment for taste disorders exists so far. A recent report on the effect of pramipexole, a D2/D3 agonist, on taste performance in healthy participants provides support for a new potential therapeutic target for taste dysfunction to be tested in future randomized, placebo-controlled, clinical trials across several populations reporting gustatory symptoms.

A systematic review with expert opinion on the role of gepants for the preventive and abortive treatment of migraine.

INTRODUCTION: Gepants are small molecules targeting the calcitonin gene-related peptide (CGRP) that have been recently introduced and are under additional clinical development as preventive and abortive treatment options for migraine. AREAS COVERED: After providing a narrative overview of current preventive and acute treatment options for migraine and summarizing the pathophysiology of migraine attack and the role of CGRP, we performed a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on trials on gepants in preventive and acute treatment of migraine. Studies and results were reviewed and discussed, and expert opinion was presented. We also collected data on relevant ongoing trials. EXPERT OPINION: Whether direct targeting CGRP pathways within the central nervous system or indirectly modulating them from the peripheral nervous system is more effective and safer in migraine remains still unclear. The available data on the efficacy and safety of gepants suggest they may represent an abortive, and to some extent, preventive treatment option for migraine, in patients who do not respond or have adverse effects to first/second line treatments or at high risk for medication overuse headache; thus opening new therapeutic horizons.

Optimal outcome measures for assessing exercise and rehabilitation approaches in chemotherapy-induced peripheral-neurotoxicity: Systematic review and consensus expert opinion.

INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: We systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the gap in the identification of effective rehabilitation and treatment options for CIPN.

Rehabilitation, exercise, and related non-pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: Systematic review and evidence-based recommendations.

Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as "brain fog". These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient. In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.

The Effectiveness of Cognitive Behavioral Therapy Techniques for the Treatment of Substance Use Disorders: A Narrative Review of Evidence.

ABSTRACT: Substance use disorders (SUDs) are characterized by a recurrent and maladaptive use of drugs and/or alcohol. Cognitive behavioral therapies (CBTs) comprise different types of interventions: traditional CBT and the more recent "third wave" behavior therapies, such as acceptance and commitment therapy (ACT), dialectical behavior therapy (DBT), mindfulness-based cognitive therapy (MBCT), and schema therapy (ST). We searched English-language articles published between 2014 and present. This review includes randomized controlled trials (RCTs), quasi-RCTs, pilot studies, and reviews of CBTs for SUDs available on PubMed. Results seem to indicate that CBT and MBCT are effective interventions for SUDs; however, the studies showed a high degree of heterogeneity, so no exhaustive conclusions could be outlined at this time. ACT and DBT in SUD management are limited to few studies and results are therefore inconclusive.

Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors?

SARS-CoV-2 survivors may report persistent symptoms that resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We explored (a) ME/CFS-like symptom prevalence and (b) whether axonal, inflammatory, and/or lung changes may contribute to ME/CFS-like symptoms in SARS-CoV-2 survivors through clinical, neuropsychiatric, neuropsychological, lung function assessment, and serum neurofilament light chain, an axonal damage biomarker. ME/CFS-like features were found in 27% of our sample. ME/CFS-like group showed worse sleep quality, fatigue, pain, depressive symptoms, subjective cognitive complaints, Borg baseline dyspnea of the 6-min walking test vs. those without ME/CFS-like symptoms. These preliminary findings raise concern on a possible future ME/CFS-like pandemic in SARS-CoV-2 survivors.

Beyond chronic migraine: a systematic review and expert opinion on the off-label use of botulinum neurotoxin type-A in other primary headache disorders.

Introduction: Botulinum neurotoxin type-A (BoNTA) is licensed for the treatment of chronic migraine (CM), but it has been tested off-label as a therapeutic choice in other primary headaches (PHs). We aimed to provide a systematic review and expert opinion on BoNTA use in PHs, beyond CM.Areas covered: After providing an overview on PHs and mechanism of BoNTA action, we report the results of a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, of BoNTA therapeutic trials in PHs beyond CM. Studies and results were reviewed and discussed, and levels of evidence were graded. We also collected data on relevant ongoing trials.Expert opinion: Although there are contradictory findings on PHs other than CM, BoNTA may represent a therapeutic option for patients who do not respond to conventional prophylactic treatments. Based on limited available evidence, BoNTA may be considered in refractory tension-type headache, trigeminal autonomic cephalalgias, primary stabbing headache, nummular headache, hypnic headache, and new daily persistent headache, after the primary nature of cephalalgia has been documented and other drugs have failed. Experienced physicians in BoNTA treatment are required to guide the therapeutic protocol for each patient to optimize good and safe outcomes.

Olfaction in patients with Parkinson's disease: a new threshold test analysis through turning points trajectories.

Olfactory deficit is a widely documented non-motor symptom in Parkinson's disease (PD). Abnormal turning points trajectories through olfactory threshold testing have been recently reported in patients with olfactory dysfunction, who seem to adapt faster to olfactory stimuli, but data on PD patients are lacking. The aim of this study is to perform olfactory threshold test and explore the turning points trajectories in PD patients in comparison to normal controls. We recruited 59 PD patients without dementia, and no conditions that could influence evaluation of olfaction and cognition. Sixty healthy subjects served as controls. Patients and controls underwent a comprehensive olfactory evaluation with the Sniffin' Sticks extended test assessing threshold, discrimination and identification and a full neuropsychological evaluation. Besides, threshold test data were analyzed examining all the turning points trajectories. PD patients showed a different olfactory threshold test pattern, i.e., faster olfactory adaptation, than controls with no effect of age. Normosmic PD patients showed different olfactory threshold test pattern, i.e., better threshold score, than normosmic controls. Visuospatial dysfunction was the only factor that significantly influenced this pattern. Olfactory threshold trajectories suggested a possible adaptation phenomenon in PD patients. Our data offered some new insights on normosmic PD patients, which appear to be a subset with a specific psychophysical profile. The analysis of the turning points trajectories, through an olfactory threshold test, could offer additional information on olfactory function in PD patients. Future larger studies should confirm these preliminary findings.

Neuromuscular complications of cancer therapy.

PURPOSE OF REVIEW: The neuromuscular complications of cancer therapy include chemotherapy-induced peripheral neurotoxicity (CIPN), immune-related neuromuscular complications to immune checkpoint inhibitors and radiation-induced neuropathy/plexopathy. With a wider focus on CIPN, we will discuss new pathogenetic insights, recent predictive biomarkers and emerging therapies for neuromuscular complications of cancer therapy. RECENT FINDINGS: Findings from recent preclinical studies have improved our knowledge on new CIPN pathogenetic pathways, including the activation of senescence-like processes in neurons, axonal degeneration and neuroinflammation. Metabolomics and serum neurofilament light chain levels appear the most promising biomarkers to predict CIPN development and severity. There is some recent evidence of promising pharmacological compounds to prevent or treat CIPN, and new drugs are in early development and testing. SUMMARY: A multimodal assessment, with neurophysiological, imaging and patient-reported outcome measures, coupled with the use of reliable blood or genetic biomarkers, may offer pathogenetic grounds for future preventive and symptomatic strategies for the multidisciplinary treatment of neuromuscular complications of cancer therapy.

Remote clinical trials: A timely opportunity for a virtual reality approach and its potential application in neurology.

The COVID-19 pandemic boosted the expansion and development of new remote models of care and clinical research modalities. Health systems are going to implement telemedical innovations in the near future. Virtual clinical trials (VCT), also known as remote or decentralized ones, may profoundly change the way how clinical studies are conducted, for the benefit of patients with chronic and neurological diseases who are often fragile and may have limited access to traditional healthcare facilities. Despite significant progress, several limitations still need to be addressed to implement telemedicine technologies for VCT. The information and communication technology (ICT) devices (e.g., mobile apps and wearables) may be applied to VCTs but show some practical issues that may hamper the compliance with rigorous research criteria and protocols. We herewith discuss the advantages and disadvantages of virtual reality (VR) in combination with other ICT devices and solutions to improve the conduction of VCT in patients with neurological disorders. The so-called "digital divide," that is, the gap between people who can and those who cannot access high-speed and broadband internet connections, and issues related to VR, such as VR sickness, should be addressed to improve larger VCT participation to neurological patients.

An updated brief overview on post-traumatic headache and a systematic review of the non-pharmacological interventions for its management.

INTRODUCTION: Post-traumatic headache (PTH), a common type of headache secondary to traumatic brain injury (TBI) or whiplash, carries a relevant burden on patients. PTH is still an undertreated condition because of limited pharmacological treatment options. Therefore, multimodal non-pharmacologic approaches, which account for comorbidities and biopsychosocial factors, are often used in PTH patients. AREAS COVERED: After providing a brief overview of PTH, a systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations on recently published (2015-2020) papers on non-pharmacological interventions for PTH. We also collected data on ongoing trials on this topic. Studies and results are reviewed and discussed. EXPERT OPINION: PTH is one of the most common complications of TBI and accounts for almost 4% of symptomatic headache disorders. The most common clinical presentations of PTH are migraine-like or tension type (TTH)-like headache, neck pain, cognitive complaints, and psychological/psychiatric symptoms. Growing evidence suggests that combined pharmacological and non-pharmacological interventions, encompassing noninvasive neuromodulation, physical therapy, cognitive-behavioral treatment, and education, may be the best approaches for PTH and related comorbidities. Acute/preemptive pharmacological treatments for PTH include drugs used for migraine and TTH. When PTH management is multidisciplinary, the patient benefits most.

Comment on "The association between pain and impulse control behaviours in Parkinson's disease".

The recent paper by Kobylecki et al. explored the association between impulse control behaviours and pain in Parkinson's disease, under the hypothesis of shared mesolimbic dysfunction. We discuss cognitive and motivational disturbances as potential covariates and suggest the dorsolateral prefrontal cortex as a therapeutic target for this "pain-predominant" symptom subtype.