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Background/Objectives: Although COVID-19 has been linked to worse outcomes in patients with neurological disorders, its impact on those with essential tremor (ET) remains unclear. To investigate clinical outcomes of ET patients with and without COVID-19 three and a half years post-pandemic. Methods: 1074 ET patients were evaluated in this retrospective study in the Montefiore Health System from January 2016 to July 2023. Comparisons between ET patients with and without a positive SARS-CoV-2 polymerase chain reaction test were made. Outcomes included post-index date major adverse cardiovascular events (MACEs), new-onset sleep disturbances, fatigue, dyspnea, first-time fall, new-onset anxiety, new-onset depression, headache, new-onset imbalance, new-onset mild cognitive impairment, and all-cause mortality, adjusted hazard ratios (aHR) adjusting for covariates were calculated. Results: ET patients with COVID-19 had higher prevalence of pre-existing type-2 diabetes, depression, and anxiety compared to ET patients without COVID-19. COVID-19 was significantly associated with higher risk of MACEs, (aHR = 2.39 [1.49, 3.82]), new-onset sleep disturbance, (aHR = 2.12 [1.44, 3.13]), fatigue, (aHR = 1.83 [1.27, 2.65]), dyspnea, (aHR = 1.98 [1.40, 2.80]), first-time fall, (aHR = 4.76 [2.24, 10.14]), new-onset anxiety, (aHR = 3.66 [2.02, 6.64]), and new-onset depression, (aHR = 2.38 [1.20, 4.70]). COVID-19 was not associated with all-cause mortality. Conclusions: In patients with ET, COVID-19 significantly increases the risk of several long-term adverse health outcomes, but not mortality.

BackgroundFunctional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD.MethodsSixty-nine patients with a ‘clinically defined’ diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala–frontal connectivity was analysed using a whole-brain seed-based approach.ResultsAmong the SNPs analysed, a tryptophan hydroxylase 2 (TPH2) gene polymorphism—G703T—significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity.ConclusionsThis is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.

Functional neurological disorder (FND) is a complex and heterogenous condition characterised by abnormal neurological symptoms that are linked to structural and functional alterations in widely distributed brain networks. For many patients with FND, the emergency department (ED) is the first point of contact with the healthcare system. This review seeks to provide up-to-date FND diagnostic criteria to ED providers, with a focus on common FND subtypes. Furthermore, we summarise the appropriate management course for these patients. Proper recognition and management of FND at the time of initial presentation in the acute care setting has the potential to improve patient prognosis and reduce overall costs to the healthcare system.

ObjectivesWe aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes.MethodsA systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group.ResultsFive FND-specific measures were identified—three clinician-rated and two patient-rated—but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost–utility (eg, healthcare resource use and quality-adjusted life years).ConclusionsThere are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.

Objectives Patients with pre‐existing Parkinson's disease (PD) face higher risks of severe acute COVID‐19 outcomes than matched controls, but long‐term post‐COVID‐19 outcomes remain largely unknown. This study investigated clinical outcomes up to 3.5 years post‐infection in a Bronx inner‐city PD population. Methods This retrospective study evaluated 3512 patients with PD in the Montefiore Health System (January 2016–July 2023), which serves a large diverse population and was an epicenter of the early COVID‐19 pandemic and subsequent infection surges. Comparisons were made with PD patients without a positive SARS‐CoV‐2 test (defined by polymerase chain reaction test). Outcomes were post‐index date all‐cause mortality, major adverse cardiovascular events (MACE), altered mental status, fatigue, dyspnea, headache, psychosis, dementia, depression, anxiety, dysphagia, falls, and orthostatic hypotension. Changes in Levodopa prescriptions were also tabulated. Adjusted hazard ratios (aHR) were computed accounting for competing risks. Results PD patients with COVID‐19 had similar demographics but a higher prevalence of pre‐existing comorbidities compared to PD patients without COVID‐19. PD patients with COVID‐19 had greater risk of mortality (aHR = 1.58 [95% CI: 1.03, 2.41]), MACE (aHR = 1.57 [1.19, 2.07]), dyspnea, fatigue, and fall compared to PD patients without COVID‐19. Levodopa dose adjustment was higher post‐infection in the COVID‐19 cohort. Conclusions Among PD patients, COVID‐19 was associated with a higher risk of adverse long‐term outcomes. PD patients who survive COVID‐19 may benefit from heightened clinical awareness and close follow‐up. Findings highlight the need to improve post‐COVID care for PD patients to mitigate disease progression and maintain quality of life.

Ceramide engagement in apoptotic pathways has been a topic of controversy. To address this controversy, we tested loss-of-function (lf) mutants of conserved genes of sphingolipid metabolism in Caenorhabditis elegans. Although somatic (developmental) apoptosis was unaffected, ionizing radiation-induced apoptosis of germ cells was obliterated upon inactivation of ceramide synthase and restored upon microinjection of long-chain natural ceramide. Radiation-induced increase in the concentration of ceramide localized to mitochondria and was required for BH3-domain protein EGL-1-mediated displacement of CED-4 (an APAF-1-like protein) from the CED-9 (a Bcl-2 family member)/CED-4 complex, an obligate step in activation of the CED-3 caspase. These studies define CEP-1 (the worm homolog of the tumor suppressor p53)-mediated accumulation of EGL-1 and ceramide synthase-mediated generation of ceramide through parallel pathways that integrate at mitochondrial membranes to regulate stress-induced apoptosis.

BackgroundTo determine gender differences in rates of sexual and physical abuse in functional movement disorders compared to controls and evaluate if the gender disparity of functional movement disorders is associated with abuse history.MethodsWe performed a retrospective case-control study of self-reported trauma data from 696 patients (512 women) with functional movement disorders from six clinical sites compared to 141 controls (98 women) and population data. Chi-square was used to assess gender and disorder associations; logistic regression was used to model additive effects of abuse and calculate the attributable fraction of abuse to disorder prevalence.ResultsHigher rates of sexual abuse were reported by women (35.3%) and men (11.5%) with functional movement disorders compared to controls (10.6% of women; 5.6% of men). History of sexual abuse increased the likelihood of functional movement disorders among women by an odds ratio of 4.57 (95% confidence interval 2.31–9.07; p < 0.0001) and physical abuse by an odds ratio of 2.80 (95% confidence interval 1.53–5.12; p = 0.0007). Population attributable fraction of childhood sexual abuse to functional movement disorders in women was 0.12 (0.05–0.19). No statistically significant associations were found in men, but our cohort of men was underpowered despite including multiple sites.ConclusionsOur study suggests that violence against women may account for some of the gender disparity in rates of functional movement disorders. Most people with functional movement disorders do not report a history of abuse, so it remains just one among many relevant risk factors to consider.

Cell death is a common metazoan cell fate, and its inactivation is central to human malignancy. In Caenorhabditis elegans, apoptotic cell death occurs via the activation of the caspase CED-3 following binding of the EGL-1/BH3-only protein to the antiapoptotic CED-9/BCL2 protein. Here we report a major alternative mechanism for caspase activation in vivo involving the F-box protein DRE-1. DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death. Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis.

Functional movement disorder (FMD) is a common manifestation of functional neurological disorder presenting with diverse phenotypes such as tremor, weakness and gait disorder. Our current understanding of the basic epidemiological features of this condition is unclear. We aimed to describe and examine the relationship between age at onset, phenotype and gender in FMD in a large meta-analysis of published and unpublished individual patient cases. An electronic search of PubMed was conducted for studies from 1968 to 2019 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Individual patient data were collected through a research network. We described the distribution of age of onset and how this varied by gender and motor phenotype. A one-stage meta-analysis was performed using multilevel mixed-effects linear regression, including random intercepts for country and data source. A total of 4905 individual cases were analysed (72.6% woman). The mean age at onset was 39.6 years (SD 16.1). Women had a significantly earlier age of onset than men (39.1 years vs 41.0 years). Mixed FMD (23.1%), tremor (21.6%) and weakness (18.1%) were the most common phenotypes. Compared with tremor (40.7 years), the mean ages at onset of dystonia (34.5 years) and weakness (36.4 years) were significantly younger, while gait disorders (43.2 years) had a significantly later age at onset. The interaction between gender and phenotype was not significant. FMD peaks in midlife with varying effects of gender on age at onset and phenotype. The data gives some support to ‘lumping’ FMD as a unitary disorder but also highlights the value in ‘splitting’ into individual phenotypes where relevant.