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

Objective: The purpose of this study was to determine whether patients with functional movement disorders (FMDs) differ in their internal versus external locus of control (LOC) and whether LOC in these patients affected disease severity, quality of life, and functional impairment compared with control subjects with degenerative (Parkinson's disease) and nondegenerative (focal dystonia) neurological conditions., Methods: A total of 156 patients with FMD (N=45), Parkinson's disease (N=64), and focal dystonia (N=47) were recruited between June 2015 and August 2017. The authors administered the general Levenson Multidimensional LOC (LOC-G) and health-specific Multidimensional Health LOC (LOC-H) scales. An internal LOC was represented similarly in both scales: the external LOC included "chance" and "powerful others" in the LOC-G measure and chance, "other people," and "doctors" in the LOC-H measure. Quality of life, functional impairment, and FMD severity were assessed. One-way analysis of variance and adjusted logistic regressions were used, as well as ordinary least-squares between and within groups, respectively., Results: Patients with FMD had lower external chance LOC-G scores compared with patients in the Parkinson's disease group (odds ratio=0.90, p=0.03) and higher internal (odds ratio=1.22, p=0.01) and lower external (odds ratio=0.77, p=0.02) doctors LOC-H scores compared with patients in the focal dystonia group. External powerful others LOC-G score was associated with functional impairment (regression coefficient=-0.04, p=0.02). There were no effects of LOC on quality of life or disease severity., Conclusions: Patients with FMD exhibited high "within our control" internal general and health-specific frame of reference. LOC had no influence on quality of life or disease severity in this patient population.

Paraneoplastic syndromes include, by definition, any symptomatic and non-metastatic condition associated with a neoplasm. Paraneoplastic movement disorders are a heterogeneous group of syndromes encompassing both hyperkinetic and hypokinetic conditions, characterized by acute/sub-acute onset, rapidly progressive evolution, and multifocal localizations with several overlapping features. These movement disorders are immune-mediated, as shown by the rapid onset and by the presence of antineuronal antibodies in biological samples of patients, fundamental for the diagnosis. Antineuronal antibodies could be targeted against intracellular or neuronal surface antigens. Paraneoplastic movement disorders associated with anti-neuronal surface antigens antibodies respond more frequently to immunotherapy. The underlying tumors may be different, according to the clinical presentation, age, and gender of patients. Our search considered articles involving human subjects indexed in PubMed. Abstracts were independently reviewed for eligibility criteria by one author and validated by at least one additional author. In this review, we sought to critically reappraise the clinical features and the pathophysiological mechanisms of paraneoplastic movement disorders, focusing on diagnostic and therapeutic strategies. Our main aim is to make clinicians aware of paraneoplastic movement disorders, and to provide assistance in the early diagnosis and management of these rare but life-threatening conditions., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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

The article discusses the shift in the approach to initiating medication, particularly levodopa, in early Parkinson's disease (PD) patients. It emphasizes the importance of early dopaminergic treatment based on individual needs and preferences. The study explores a shorter combination of patient-reported items from the Movement Disorder Society-UPDRS scale to predict the initiation of dopaminergic therapy accurately. The findings suggest that patient-reported information at baseline can help predict relevant clinical outcomes, such as the timing of medication initiation, and may improve patient care and management in PD. [Extracted from the article]

The article "The Whistle-Smile Reflex in Parkinson's Disease: A Cross-Sectional Study" published in Movement Disorders Clinical Practice explores the absence of the whistle-smile reflex (WSR) in Parkinson's disease (PD) patients compared to healthy controls (HCs). The study involved video recordings of participants performing a whistle and assessing their immediate smile response. Results showed that 76.47% of PD patients did not exhibit a smile after whistling, indicating a potential diagnostic marker for PD. Further research is needed to validate these findings and explore the clinical implications of the WSR in PD diagnosis. [Extracted from the article]

This document is an editorial from the journal Biomedicines, discussing the role of the immune system in neurological disorders. It highlights the increasing recognition of the immune system's involvement in various neurological conditions, including autoimmune movement disorders, autoimmune encephalitis, paraneoplastic neurological syndromes, and neurodegeneration. The editorial presents summaries of several research articles that explore these topics, including the pathophysiology, clinical presentation, and treatment perspectives of these immune-mediated neurological disorders. It emphasizes the importance of understanding immune mechanisms in order to improve the diagnosis, treatment, and management of these conditions. [Extracted from the article]

Paraneoplastic neurological syndromes (PNS) include any symptomatic and non-metastatic neurological manifestations associated with a neoplasm. PNS associated with antibodies against intracellular antigens, known as "high-risk" antibodies, show frequent association with underlying cancer. PNS associated with antibodies against neural surface antigens, known as "intermediate- or low-risk" antibodies, are less frequently associated with cancer. In this narrative review, we will focus on PNS of the central nervous system (CNS). Clinicians should have a high index of suspicion with acute/subacute encephalopathies to achieve a prompt diagnosis and treatment. PNS of the CNS exhibit a range of overlapping "high-risk" clinical syndromes, including but not limited to latent and overt rapidly progressive cerebellar syndrome, opsoclonus-myoclonus-ataxia syndrome, paraneoplastic (and limbic) encephalitis/encephalomyelitis, and stiff-person spectrum disorders. Some of these phenotypes may also arise from recent anti-cancer treatments, namely immune-checkpoint inhibitors and CAR T-cell therapies, as a consequence of boosting of the immune system against cancer cells. Here, we highlight the clinical features of PNS of the CNS, their associated tumors and antibodies, and the diagnostic and therapeutic strategies. The potential and the advance of this review consists on a broad description on how the field of PNS of the CNS is constantly expanding with newly discovered antibodies and syndromes. Standardized diagnostic criteria and disease biomarkers are fundamental to quickly recognize PNS to allow prompt treatment initiation, thus improving the long-term outcome of these conditions. [ABSTRACT FROM AUTHOR]

The aim of the present study was to obtain data from a large community sample of patients with Ménière's disease (MD) in Italy through a web-based nationwide survey. Demographic, clinical, and epidemiological features of MD among members of the Italian Association of Ménière's Disease (AMMI) were collected through a web-based survey. The questionnaire was posted on the AMMI website between 01/SEP/2021 and 31/OCT/2021. A total of 520 patients (374 F, 146 M) with MD were included. The age at interview (average ± standard deviation, SD) was 51.4 ± 10.9 years, with a disease duration of 9.9 ± 9.8 years. Eighty percent of cases were unilateral. No patients reported neurocognitive disorders or Parkinson's disease. A positive family history of MD was reported in 13% of participants, while a history of allergic diseases was reported in 33%. Comorbid thyroid disorders were present in 25% of participants, and 28% used betahistine as the main treatment. To our knowledge, this is the first study that has investigated the epidemiology and current patterns of care of MD in Italy, using an anonymous survey directly sent to patients, thus implying their active participation. We hope that future studies will support the utilization of web-based surveys to address the unmet needs in the management of patients with MD. [ABSTRACT FROM AUTHOR]

Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts. [ABSTRACT FROM AUTHOR]

Background: Functional movement disorders (FMD) are a commonly under-recognized diagnosis in patients with underlying neurodegenerative diseases. FMD have been observed in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) and other movement disorders. The prevalence of coexisting FMD among movement disorder-related DBS patients is unknown, and it may occur more often than previously recognized. Methods: We retrospectively assessed the relative prevalence and clinical characteristics of FMD occurring post-DBS, in PD and dystonia patients (FMD+, n = 29). We compared this cohort with age at surgery-, sex-, and diagnosis-matched subjects without FMD post-DBS (FMD-, n = 29). Results: Both the FMD prevalence (0.2%-2.1%) and the number of cases/DBS procedures/year varied across centers (0.15-3.65). A total of nine of 29 FMD+ cases reported worse outcomes following DBS. Although FMD+ and FMD- manifested similar features, FMD+ showed higher psychiatric comorbidity. Conclusions: DBS may be complicated by the development of FMD in a subset of patients, particularly those with pre-morbid psychiatric conditions. [ABSTRACT FROM AUTHOR]

Long-read sequencing (LRS) technologies have been recently introduced to overcome intrinsic limitations of widely-used next-generation sequencing (NGS) technologies, namely the sequencing limited to short-read fragments (150–300 base pairs). Since its introduction, LRS has permitted many successes in unraveling hidden mutational mechanisms. One area in clinical neurology in need of rethinking as it applies to genetic mechanisms is essential tremor (ET). This disorder, among the most common in neurology, is a syndrome often exhibiting an autosomal dominant pattern of inheritance whose large phenotypic spectrum suggest a multitude of genetic etiologies. Exome sequencing has revealed the genetic etiology only in rare ET families (FUS, SORT1, SCN4A, NOS3, KCNS2, HAPLN4/BRAL2 , and USP46). We hypothesize that a reason for this shortcoming may be non-classical genetic mechanism(s) underpinning ET, among them trinucleotide, tetranucleotide, or pentanucleotide repeat disorders. In support of this hypothesis, trinucleotide (e.g., GGC repeats in NOTCH2NLC) and pentanucleotide repeat disorders (e.g., ATTTC repeats in STARD7) have been revealed as pathogenic in patients with a past history of what has come to be referred to as "ET plus," bilateral hand tremor associated with epilepsy and/or leukoencephalopathy. A systematic review of LRS in neurodegenerative disorders showed that 10 of the 22 (45%) genetic etiologies ascertained by LRS include tremor in their phenotypic spectrum, suggesting that future clinical applications of LRS for tremor disorders may uncover genetic subtypes of familial ET that have eluded NGS, particularly those with associated leukoencephalopathy or family history of epilepsy. LRS provides a pathway for potentially uncovering novel genes and genetic mechanisms, helping narrow the large proportion of "idiopathic" ET. [ABSTRACT FROM AUTHOR]

Smartphone applications (apps) are instruments that assist with objective measurements during the clinical assessment of patients with movement disorders. We aim to test the hypothesis that Parkinson's disease (PD) patients will exhibit an increase in tapping variability and a decrease in tapping speed over a one-year period, compared to healthy controls (HC). Data was prospectively collected from participants enrolled in our Cincinnati Cohort Biomarker Program, in 2021–2023. Participants diagnosed with PD and age-matched HC were examined over a one-year-interval with a tapping test performed with customized smartphone app. Tapping speed (taps/s), inter-tap intervals and variability (movement regularity), and sequence effect were measured. We included 295 PD patients and 62 HC. At baseline, PD subjects showed higher inter-tap variability than HC (coefficient-of-variation-CV, 37 ms [22–64] vs 26 ms [8–51]) (p = 0.007). Conversely, there was no difference in inter-tap intervals (411 ms [199–593] in PD versus 478 ms [243–618] in HC) and tapping speed (3.42[2.70–4.76] taps/s in PD versus 3.21 taps/s [2.57–4.54] in HC) (p > 0.05). Only PD subjects (n = 135), at the one-year follow-up, showed a decreased tapping speed vs baseline (3.44 taps/s [2.86–4.81] versus 3.39 taps/s [2.58,4.30]) (p = 0.036), without significant changes in inter-tap variability (CV, 32 ms [18,55] baseline versus 34 ms [22,59] follow-up) (p = 0.142). No changes were found in HC at the one-year follow up (all p values>0.05). Inter-tap variability (dysrhythmia) but no inter-tap intervals or tapping speed are reliably distinctive feature of an app-based bradykinesia assessment in PD. • We evaluated a finger tapping test via a smartphone app in Parkinson's disease (PD). • We found higher tapping variability at baseline in PD patients versus controls. • Tapping speed decreased after one year only in PD patients. • Inter-tap variability but not inter-tap intervals or tapping speed is a distinctive feature of PD-associated bradykinesia. [ABSTRACT FROM AUTHOR]

Purpose: In the advanced stage of Parkinson disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). Recent evidence has underlined the general lack of randomized, blinded, head-to-head studies on device-aided therapies for advanced PD. Methods: To better clarify the real-world attitude of clinicians on this matter, we conducted an international survey of forty-four experienced movement disorder specialists regarding the management of device-aided therapies in advanced PD. Results: Our international survey showed a general agreement that nowadays, motor complications are less common compared to the past (59% agreement), that guidelines to identify candidates for device-aided therapies are currently lacking (57% agreement), and that device-aided therapies will have increased demand in the future (75% agreement). Conclusions: We conclude that guidelines to assist clinicians and patients to choose device-aided therapies are required. [ABSTRACT FROM AUTHOR]

Objective: We sought to test the hypothesis that technology could predict the risk of falls in Parkinson's disease (PD) patients with orthostatic hypotension (OH) with greater accuracy than in-clinic assessment. Methods: Twenty-six consecutive PD patients with OH underwent clinical (including home-like assessments of activities of daily living) and kinematic evaluations of balance and gait as well as beat-to-beat blood pressure (BP) monitoring to estimate their association with the risk of falls. Fall frequency was captured by a diary collected prospectively over 6 months. When applicable, the sensitivity, specificity, and diagnostic accuracy were measured using the area under the receiver operating characteristics curve (AUC). Additional in-clinic assessments included the OH Symptom Assessment (OHSA), the OH Daily Activity Score (OHDAS), and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Results: The prevalence of falls was 53.8% over six months. There was no association between the risk of falls and test of gait and postural stability (p ≥ 0.22) or home-like activities of daily living (p > 0.08). Conversely, kinematic data (waist sway during time-up-and-go, jerkiness, and centroidal frequency during postural sway with eyes-opened) predicted the risk of falls with high sensitivity and specificity (> 80%; AUC ≥ 0.81). There was a trend for higher risk of falls in patients with orthostatic mean arterial pressure ≤ 75 mmHg. Conclusions: Kinematic but not clinical measures predicted falls in PD patients with OH. Orthostatic mean arterial pressure ≤ 75 mmHg may represent a hemodynamic threshold below which falls become more prevalent, supporting the aggressive deployment of corrective measures. [ABSTRACT FROM AUTHOR]

While the "physiological" aging process is associated with declines in motor and cognitive features, these changes do not significantly impair functions and activities of daily living. Differently, motor and cognitive impairment constitute the most common phenotypic expressions of neurodegeneration. Both manifestations frequently coexist in the same disease, thus making difficult to detect "pure" motor or cognitive conditions. Movement disorders are often characterized by cognitive disturbances, and neurodegenerative dementias often exhibit the occurrence of movement disorders. Such a phenotypic overlap suggests approaching these conditions by highlighting the commonalities of entities traditionally considered distinct. In the present review, we critically reappraised the common clinical and pathophysiological aspects of neurodegeneration in both animal models and patients, looking at motricity as a trait d'union over the spectrum of neurodegeneration and focusing on synaptopathy and oscillopathy as the common pathogenic background. Finally, we discussed the possible role of movement as neuroprotective intervention in neurodegenerative conditions, regardless of the etiology. The identification of commonalities is critical to drive future research and develop novel possible disease-modifying interventions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the extent to which cancer, a biological opposite to neurodegenerative disorders, may affect the onset and progression of Parkinson's disease (PD). Methods: A nested case-control design in consecutive PD patients with (cases) vs. without (controls) cancer was used to compare time to clinical diagnosis and time to Hoehn & Yahr (H&Y) staging score ≥ 3 as a measure of progression. Further, we compared PD onset and progression between cases with cancer diagnosis before (cancer before PD group) and after (cancer after PD group) PD onset. Independent variables were age at PD onset, motor subscale of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, sex, cognitive impairment, falls, depression, anxiety, dementia, and autonomic symptoms. Time to H&Y ≥ 3 was determined using Cox proportional hazards, with adjusted results summarized as hazards ratio (HR). Group differences were evaluated using unpaired t -test or Fisher's exact test. Results: The clinical PD onset was later in cases vs. controls (median 67.2 vs. 59.8 years; p < 0.001), but the adjusted time to H&Y ≥ 3 was similar between groups (HR = 0.67; p = 0.13). Skin cancers constituted 75% of all cancers in cases. Amongst skin cancers, compared to controls, cases had an older age at PD onset (67.8 vs. 59.8 years; p < 0.001). There was no difference in risk of progression in PD patients with skin cancer compared to controls (HR = 0.54, p = 0.09). Conclusions: Cancer, in particular of the skin, may delay the onset but not the progression of PD. Future prospective observational studies are warranted to elucidate the complex interactions between these biologically divergent disorders. [ABSTRACT FROM AUTHOR]

Objective: Genetic subtypes of dystonia may respond differentially to deep brain stimulation of the globus pallidus pars interna (GPi DBS). We sought to compare GPi DBS outcomes among the most common monogenic dystonias.Methods: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. We searched PubMed for studies on genetically confirmed monogenic dystonia treated with GPi DBS documenting pre-surgical and post-surgical assessments using the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and Burke-Fahn-Marsden Disability Score (BFMDS). We performed (i) meta-analysis for each gene mutation; (ii) weighted ordinary linear regression analyses to compare BFMMS and BFMDS outcomes between DYT-TOR1A and other monogenic dystonias, adjusting for age and disease duration and (iii) weighted linear regression analysis to estimate the effect of age, sex and disease duration on GPi DBS outcomes. Results were summarised with mean change and 95% CI.Results: DYT-TOR1A (68%, 38.4 points; p<0.001), DYT-THAP1 (37% 14.5 points; p<0.001) and NBIA/DYT-PANK2 (27%, 21.4 points; p<0.001) improved in BFMMS; only DYT-TOR1A improved in BFMDS (69%, 9.7 points; p<0.001). Improvement in DYT-TOR1A was significantly greater than in DYT-THAP1 (BFMMS -31%), NBIA/DYT-PANK2 (BFMMS -35%; BFMDS -53%) and CHOR/DYT-ADCY5 (BFMMS -36%; BFMDS -42%). Worse motor outcomes were associated with longer dystonia duration and older age at dystonia onset in DYT-TOR1A, longer dystonia duration in DYT/PARK-TAF1 and younger age at dystonia onset in DYT-SGCE.Conclusions: GPi DBS outcomes vary across monogenic dystonias. These data serve to inform patient selection and prognostic counselling. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Impaired facial expression, including spontaneous and emotional movements such as smiling, has been often reported in Parkinson's disease (PD). There is a general consensus that spontaneous smiling is abnormal in PD. Investigations on posed smiling yield contrasting results. Moreover, no study has yet addressed the relationship between posed smiling and abnormalities of voluntary movements of the lower face, global motor impairment and the effects of dopaminergic medication. Methods: We investigated the kinematics of posed smiling (mimicking a smile shown in a picture) and those of voluntary movements of the lower face (showing the teeth as fast as possible – voluntary grinning) in 15 patients with PD (ON and OFF therapy) and in 16 healthy controls. Facial movements were recorded using a 3D optoelectronic system and analyzed using dedicated software. Results: Some kinematic parameters of both posed smiling and voluntary grinning were abnormally lower in PD patients in comparison to healthy subjects. The kinematics of posed smiling correlated with those of voluntary grinning in PD patients but not in healthy controls. Posed smiling and voluntary grinning abnormalities were related to global motor severity but did not significantly improve upon L-dopa administration. Conclusions: These results suggest that posed smiling and voluntary grinning are both abnormal in PD patients and that they are likely mediated by a common pathophysiological mechanism. [Copyright &y& Elsevier]

Secondary parkinsonism, namely parkinsonism due to causes other than idiopathic neurodegeneration, may have multiple etiologies. Common secondary etiologies of parkinsonism such as drug-induced or vascular etiologies are well documented. Other secondary causes of parkinsonism such as infectious (mainly viral and prion-like diseases), autoimmune (systemic/drug-induced) and paraneoplastic etiologies are rare but are a topic of increasing interest. Older examples from the existing literature demonstrate the intricacies of viral infection from the last pandemic of the 20th century on the development of hypokinetic symptoms experienced in post-encephalitic patients. Viral and prion-like infections are only part of a complex interplay between the body's immune response and aberrant cell cycle perturbations leading to malignancy. In addition to the classic systemic autoimmune diseases (mainly systemic lupus erythematosus – SLE, and Sjögren syndrome), there have been new developments in the context of the current COVID-19 pandemic as well as more prominent use of immunotherapies such as immune checkpoint inhibitors in the treatment of solid tumors. Both of these developments have deepened our understanding of the underlying pathophysiologic process. Increased awareness and understanding of these rarer etiologies of parkinsonism is crucial to the modern diagnostic evaluation of a patient with parkinsonian symptoms as the potential treatment options may differ from the conventional levodopa-based therapeutic regimen of idiopathic Parkinson's disease. This review article aims to give an up-to-date review of the current literature on parkinsonian symptoms, their pathogenesis, diagnostic methods, and available treatment options. Many potential future directions in the field of parkinsonian conditions remain to be explored. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna. • Secondary parkinsonism has multiple etiologies. • Infectious, autoimmune, and paraneoplastic etiologies are rare but of increasing interest. • Awareness of rare parkinsonian syndromes is crucial for diagnosis and treatment. • Research efforts are needed to clarify the molecular underpinnings of parkinsonism. [ABSTRACT FROM AUTHOR]

Background: the study of movement disorders associated with oncological diseases and anticancer treatments highlights the wide range of differential diagnoses that need to be considered. In this context, the role of immune-mediated conditions is increasingly recognized and relevant, as they represent treatable disorders. Methods: we reappraise the phenomenology, pathophysiology, diagnostic testing, and treatment of movement disorders observed in the context of brain tumors, paraneoplastic conditions, and cancer immunotherapy, such as immune-checkpoint inhibitors (ICIs). Results: movement disorders secondary to brain tumors are rare and may manifest with both hyper-/hypokinetic conditions. Paraneoplastic movement disorders are caused by antineuronal antibodies targeting intracellular or neuronal surface antigens, with variable prognosis and response to treatment. ICIs promote antitumor response by the inhibition of the immune checkpoints. They are effective treatments for several malignancies, but they may cause movement disorders through an unchecked immune response. Conclusions: movement disorders due to focal neoplastic brain lesions are rare but should not be missed. Paraneoplastic movement disorders are even rarer, and their clinical-laboratory findings require focused expertise. In addition to their desired effects in cancer treatment, ICIs can induce specific neurological adverse events, sometimes manifesting with movement disorders, which often require a case-by-case, multidisciplinary, approach. [ABSTRACT FROM AUTHOR]

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