Journal of Neurology

The end-stage of amyotrophic lateral sclerosis [ALS] is presumed to be a complete Locked-In Syndrome [cLIS], assuming an internally preserved consciousness that would not be accessible anymore from the outside. However, whether consciousness persists at this stage of ALS remains to be demonstrated. Shifting the perspective from cLIS (presupposed consciousness) to Cognitive Motor Dissociation (to-be-demonstrated consciousness), we attempted to demonstrate consciousness and communication with two cLIS-ALS patients using a multimodal awareness assessment battery. It involved complete neurophysiological assessments, passive and active auditory oddball paradigm (Subject-Own-Name/P300), an auditory-based Brain-Computer-Interface [BCI] and activation-task imaging using functional MRI or [15O]H2O PET. Wakefulness (long-term EEG), brain morphology (CT or MRI scans) and resting brain metabolism ([18F]fluoro-deoxy-glucose PET) were used to describe the underlying cLIS brain function. While Patient 1 could initially follow simple commands, he failed twice to control the BCI. At follow-up, he showed no more evidence of command following and his oddball (Own Name - P300) cognitive responses has disappeared. At his unique evaluation, Patient 2 was neither able to follow simple commands nor to control the BCI. Both patients had altered wakefulness, brain atrophy, and a global cortico-sub-cortical hypometabolism pattern compatible with a disorder of consciousness, regarded as an extreme form of an ALS-associated fronto-temporal dementia. While it is not possible to firmly demonstrate the absence of awareness, each independent measure concurred with suggesting that a "degenerative disorder of consciousness" rather than a cLIS might be the final stage of ALS. In future cases, this dramatic cognitive decline should be anticipated before communication disappears to enable precise advance directives regarding end-of-life issues in case complete - and neurophysiologically confirmed - unresponsiveness occurs. Altogether, the neuroimaging features distinguishing the mechanisms in this rare condition is a significant milestone to understand end-stage ALS. The present clinical study calls for further exploration of this terminal stage to determine the prevalence of this profile in whom communication seems hopeless.

Neurological manifestations of COVID-19 are increasingly described in the literature. There is uncertainty whether these occur due to direct neuroinvasion of the virus, para-infectious immunopathology, as result of systemic complications of disease such as hypercoagulability or due to a combination of these mechanisms. Here we describe clinical and radiological manifestations in a sequential cohort of patients presenting to a district hospital in South Africa with neurological symptoms with and without confirmed COVID-19 during the first peak of the epidemic. In these patients, where symptoms suggestive of meningitis and encephalitis were most common, thorough assessment of presence in CSF via PCR for SARS-CoV2 did not explain neurological presentations, notwithstanding very high rates of COVID-19 admissions. Although an understanding of potential neurotropic mechanisms remains an important area of research, these results provide rationale for greater focus towards the understanding of para-immune pathogenic processes and the contribution of systemic coagulopathy and their interaction with pre-existing risk factors in order to better manage neurological disease in the context of COVID-19. These results also inform the clinician that consideration of an alternative diagnosis and treatment for neurological presentations in this context is crucial, even in the patient with a confirmed diagnosis COVID-19.

IntroductionThe novel corona virus (COVID19) can result in several neurological complications. Guillain-Barre Syndrome (GBS) is one of them and has been reported from different parts of the world in this pandemic. It is an acute post infectious polyneuropathy. The review aims to summarize the demographic features, clinical presentation, diagnostics workup, and management strategies of COVID-19 associated GBS reported in literature. Material and methodWe searched Medline, PubMed Central, SCOPUS and Google Scholar using pre-defined keywords, with no time limits and in English language only. We aimed to include all kind of manuscripts. Last search was done on 18th May 2020. Demographics, clinical features, diagnostic workup, management, and outcomes were documented in the data sheet. ResultsWe identified 24 cases of COVID-19 associated GBS. Most of the cases were reported from Italy followed by USA. Majority were males (18 /24) The age ranged from 23 -84 years. The clinical presentation was typical sensory-motor GBS in most. Nine patients had facial palsy of which five had bilateral involvement. Two patients had bilateral abducent nerve palsy while two presented as paraparetic GBS variant with autonomic dysfunction. Electrodiagnostics was performed in 17 patients only and 12 had typical features of acute inflammatory demyelinating polyneuropathy.. Intravenous immunoglobulins were the preferred mode of treatment in most of the patient. There was one death, and most were discharged to rehabilitation or home. ConclusionGBS is a frequent neurological complication associated with COVID-19. There is no clear causative relationship between GBS, and COVID-19 at present and more data are needed to establish the casualty. However, most cases have a post-infectious onset with male preponderance. Most of the cases have a typical presentation but some may present in an atypical way. Prognosis is generally good.

BackgroundPost-critical illness cognitive dysfunction (PCICD) is a common and debilitating condition affecting survivors of critical illness. While sepsis has been implicated in poor cognitive outcomes, its independent contribution remains unclear due to multiple associated confounders in critical illness. This study aimed to characterize cognitive recovery trajectories over 12 months post-intensive care unit (ICU) and to evaluate the influence of sepsis and benzodiazepine exposure on cognitive outcomes. MethodsIn this single-center, prospective cohort study, adult ICU survivors were assessed at 30 days, 3 months, 6 months, and 12 months post-discharge using the telephone-administered Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA). Scores were standardized into z-scores for comparability. Mixed-effects models assessed changes over time and the effects of clinical covariates, including sepsis status and benzodiazepine exposure. Additionally, we investigated whether any one specific cognitive domain was disproportionally impaired by critical illness over time. ResultsOf 197 eligible patients during the enrollment period, 77 (39%) completed at least one cognitive assessment. Standardized cognitive scores significantly improved over time, with the greatest gains observed within 6 months: +0.40 SD at 3 months (p = 0.041), +0.54 SD at 6 months (p = 0.016), and +0.49 SD at 12 months (p = 0.033) compared to scores at the time of acute illness. Sepsis status had no significant effect on recovery trajectory. No single cognitive domain was disproportionately affected by critical illness; instead, changes were observed in the overall score over time. Benzodiazepine exposure showed complex associations: longer duration (-0.24 SD/day, p = 0.008) and higher daily dose (-0.02 SD/unit, p = 0.006) were linked to worse cognition, while total cumulative dose was paradoxically associated with better scores (+0.03 SD/unit, p < 0.001), possibly reflecting confounding by indication or survival bias. ConclusionsICU survivors experience gradual cognitive recovery over the first year, primarily within 6 months. Sepsis does not independently affect this trajectory. Benzodiazepine exposure, especially prolonged or high daily dosing, emerges as a modifiable risk factor for cognitive impairment, consistent with prior investigations of PCICD. These findings highlight the importance of sedation strategies and structured cognitive follow-up.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to significant morbidity and mortality, but with substantial variability in the rate of progression [1,2]. A common primary outcome measure used in ALS clinical studies is the ALSFRS-R. Change in this measure may also be used to stratify fast and slow progressors, typically with the assumption of linear decline. Reported limitations of the ALSFRS-R and the assumption of linear slope may hinder novel therapy development. Here we use two distinct populations from a clinical trial database (PRO-ACT) and a natural history registry (ALS TDI) to show that ALSFRS-R fine and gross motor subdomains are more sensitive to disease progression than total score and bulbar and respiratory subdomain scores. We also present a novel non-linear method for defining fast and slow progressors. Together these results may improve demonstration of outcomes in ALS interventional studies using the ALSFRS-R.

Transient loss of consciousness (TLoC) is a leading cause of referrals to acute neurological services. A witness account is often lacking and ancillary investigations are a critical diagnostic adjunct. Hypophosphataemia was recently identified as a potential maker of epileptic seizures in ward and emergency department presentations. We evaluated the real-world utility of checking phosphate in an unselected cohort of people presenting with TLoC. We retrospectively reviewed 182 episodes (91 referrals to first seizure clinic and 91 consults) from 173 patients. We assessed nine pre-specified serological markers frequently measured in people presenting with TLoC. Raw P-values comparing mean levels showed significant difference between epileptic seizures and non-epileptic episodes only for phosphate (0.98 vs. 1.19 mmol/L, P=0.006) and lactate (2.82 vs. 1.82 mmol/L, P=0.007). No blood biomarkers were significant after multiple comparison correction, although a phosphate below 0.8mmol/L was significantly more likely to associate with epileptic seizures than non-epileptic episodes (17/64, 26.5% vs. 7.4%, 2/27, P=0.049). Logistic regression showed that a model including lactate and phosphate was most accurate to predict epileptic seizures with an area-under-the ROC curve of 0.728 (96% CI 0.607-0.848). Checking serum phosphate may be valuable in helping to determine the aetiology of an episode of TLoC. Plain language summaryWe studied blood test results of 173 people suspected of having had an epileptic seizure who presented to a UK hospital neurology service. Although blood phosphate tests were infrequently requested, our results suggest a low phosphate level could be useful to help distinguish between epileptic and non-epileptic attacks.

BackgroundAlterations in tryptophan (TRP)-serotonin metabolism have been implicated in multiple system atrophy (MSA). However, the involvement of the TRP-kynurenine (KYN) pathway, which is associated with neuroinflammatory and neuroprotective processes, is elusive. ObjectivesTo investigate tryptophan metabolism in cerebrospinal fluid (CSF), we examined the relationships between metabolites and their associations with clinical biomarkers reflecting microglial activation and axonal injury in MSA patients. MethodsCSF and clinical data from 51 patients with clinically established MSA and 56 control subjects were analyzed. CSF concentrations of TRP, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KA) were quantified. Additionally, 5-hydroxyindoleacetic acid (5-HIAA), glycoprotein nonmetastatic melanoma protein B (GPNMB), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light chain (NfL) were measured. Group differences and inter-biomarker correlations were assessed, with hierarchical cluster analysis performed on the resulting correlation matrix. Principal component analysis (PCA) was performed to explore the latent relationships among biomarkers. ResultsPatients with MSA showed higher CSF levels of QA, a neuroinflammatory marker (adjusted median difference controlling for age and sex, 2.56CnM; 95% CI, 0.99-3.60) and lower levels of KA, which is considered neuroprotection (-6.46CnM; 95% CI, -9.08 to -3.12), yielding an elevated QA/KA ratio (+0.52; 95% CI, 0.27-0.88). In contrast, CSF levels of TRP, KYN, and 3-HK did not differ significantly between the two groups. TRP was correlated only with KYN (Spearmans {rho} = 0.56, adjusted for age and sex), while KYN was correlated with 3-HK ({rho} = 0.47) and QA ({rho} = 0.64), forming a shared cluster. KA did not show significant correlations with any of the measured kynurenine metabolites. Although GPNMB, sTREM2, and NfL were also increased, these inflammatory and neurodegenerative markers showed no correlation with kynurenic metabolites and formed distinct clusters. PCA indicated that these markers are independent of KYN pathway metabolites. ConclusionsThis study revealed a marked imbalance in KYN metabolism in MSA, which suggests a metabolic shift that may promote excitotoxicity and proinflammatory processes that are distinct from classic neuroinflammatory markers. These findings may highlight future therapeutic strategies targeting the kynurenine pathway.

The two predominating subtypes of late-onset GM2 gangliosidosis are late-onset Tay-Sachs (LOTS) and late-onset Sandhoff disease (LOSD). Due to shared deficiencies of {beta}-hexosamindase A and significant clinical overlap, the two diseases have been considered indistinguishable. However, a growing body of evidence supports the notion of several distinctions between the two diseases. In this study, we highlight these distinctions through the cross-sectional evaluation of 27 late-onset GM2 gangliosidosis participants. Twenty-one participants with LOTS and 6 with LOSD were included in this study. We performed physical examinations alongside assessments for gait, balance, muscle strength, ataxia, nerve conduction velocities, and analyzed brain magnetic resonance imaging. Lower limb weakness (95% in LOTS, 100% in LOSD) and later development of upper limb weakness (90% in LOTS, 83% in LOSD) was highly prevalent in both cohorts. Accompanying gait disturbances, balance issues, and dysmetria (as assessed by the brief ataxia rating scale [BARS]) were also prevalent in both cohorts. Strength testing for the quadriceps and hamstrings demonstrated weakness in both cohorts, primarily impacting extensor muscles. Supratentorial gray and white matter volumes in both cohorts were similar to normative data. In contrast, BARS scores for dysarthria and oculomotor dysfunction were present and heterogenous in LOTS participants and absent in LOSD participants. 24% of LOTS participants and none of the LOSD participants had a history of neuropsychiatric symptoms. Cerebellar volume including lobules V and VI were lower in LOTS compared to LOSD and normative data. However, length dependent sensory neuropathy was present in all LOSD participants but absent in LOTS participants. Dysfunction of the posterior cerebellum (lobules VI, VII, and IX) has been shown to cause cerebellar cognitive affective syndrome (CCAS), that includes cognitive and behavioral disturbances. Furthermore, cerebellar dysfunction of lobules V and VI has been linked to dysarthric speech, and dysfunction of the posterior cerebellum has been linked to oculomotor symptoms. The finding of low cerebellar lobule volumes in LOTS, suggests the distinctive features of the LOTS phenotype are related to cerebellar dysfunction. However, the sensory symptoms unique to LOSD remains a mystery. The molecular and biochemical basis for the dichotomy between the LOTS and LOSD phenotypes requires further investigation.

BackgroundProgressive supranuclear palsy (PSP) is a tauopathy marked by early degeneration of brainstem nuclei such as the locus coeruleus (LC), a central player of the ascending reticular activating system (ARAS). ARAS dysfunction contributes to cognitive and arousal disturbances and is increasingly recognized as a therapeutic target. Methods14 PSP patients (eight females, age 70.81 {+/-} 6.32 years, disease duration 4.69 {+/-} 3.24 years) were assessed before and after [&ge;]4 weeks of SNRI (serotonin-norepinephrine reuptake inhibitor) treatment. Participants were assessed by non-invasive neurophysiological measures as pupillometry, performed at rest and during an auditory oddball paradigm, and clinically, using PSP-specific clinical scales and quantitative gait analysis. Pupil, cognitive, and gait parameters were compared with age-matched healthy controls. ResultsAt baseline, pupil size, pupil dilation responses and surprise pupil responses were reduced in PSP patients compared to controls, accompanied by impaired executive functions, reduced phonemic verbal fluency and depressive symptoms in PSP patients. SNRI treatment selectively rescued certain impaired pupil metrics in PSP, leading to a significant improvement of the surprise pupil response and partial normalization of pupil fluctuations at rest. Pupil metric changes were associated with notable improvement in executive functions and quality of life at follow-up. ConclusionIn summary, our findings reveal altered pupil-linked arousal regulation in PSP and its modulation by SNRI therapy, suggesting pupillometric indices as promising biomarkers of therapeutic response.

Introductionseveral cases of Guillain-Barre Syndrome (GBS) associated with SARS-CoV-2 infection have been described. This study illustrated the demographic, clinical, and neurophysiological characteristics of patients with GBS and COVID-19, as well as associated factors with disability at discharge. MethodsA retrospective analytical observational study was conducted. It included patients diagnosed with GBS admitted in a national reference center in Peru between 2019 and 2021. Epidemiological, clinical, neurophysiological and cerebrospinal fluid data were analyzed. A multivariate analysis, using the generalized linear model, was performed, considering the presence of disability at discharge as the dependent variable. Results81 subjects diagnosed with GBS were included. The mean age was 46.8 years (SD: 15.2), with a predominance of males (61.73%). The most frequent clinical presentation was the classic sensory-motor form in 74 cases (91.36%) with AIDP (82.35%) as the most frequent neurophysiological pattern in the group with COVID-19, while AMAN pattern predominated (59.26%) in those without COVID-19 (p=<0.000). The disability prevalence ratio at discharge between subjects with COVID-19 and those without COVID-19 was 1.89 (CI 1.06-3.34), p=0.030, adjusted for age, sex, and neurophysiological subtype. ConclusionsThe neurophysiologic subtype AIDP, and a higher disability were associated with the presence of COVID-19.

BackgroundParkinsons disease (PD) is frequently accompanied by mood and chronic fatigue syndrome (CFS) symptoms. It is unknown whether immune activation and insulin resistance (IR) or brain injuries impacts the severity of affective and CFS symptoms due to PD. AimsTo examine whether immune, IR, and/or brain injury biomarkers determine affective and CFS symptoms due to PD. MethodsUsing a case (70 PD patients) control (60 healthy controls) study design, we assessed affective and CFS symptoms, measured the peripheral immune-inflammatory response system (IRS) using interleukin-6 (IL-6), IL-10, zinc, and calcium levels, the Homeostasis Model Assessment 2 insulin resistance (HOMA2IR) index, and serum brain injury markers including S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), phosphorylated tau217 (pTau217), and glial fibrillary acidic protein (GFAP). ResultsPD patients showed increased affective and CFS scores, IRS activation, HOMA2IR, NSE, GFAP, pTau217, and S100B levels as compared to controls. A large part (52.5%) of the variance in the mood+CFS score was explained by the regression on NSE, S100B, HOMA2IR index, interleukin-10 (IL-10) (all positively) and calcium (inversely). The HOMA2IR and IRS indices were significantly associated with all 4 brain injury biomarkers. A large part of the variance in the latter markers (37.0%) was explained by the cumulative effects of the IRS and HOMA2IR indices. DiscussionRS activation and IR in patients with PD contribute to damage to glial cell projections and type III intermediate filament, which in turn contribute to affective and CFS symptoms.

Even though various neurological presentations of COVID-19 have surfaced up, ataxia as a presenting feature has rarely been reported so far. We hereby describe a confirmed case of SARS-CoV-2 infection which not only presented with ataxia but also had delayed onset of typical respiratory features. This case represents an atypical manifestation of COVID-19.

BackgroundProgressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given Indias large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. ObjectiveTo characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. MethodsSubjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021-2025). Standardized demographic and clinical data were collected. ResultsA total of 1,035 subjects were enrolled (M:F = 709:326), with a median age of 65 years and a mean onset age of 62.2{+/-}7.9 years. Regional distribution reflected pan-Indian recruitment (South 35%, North 26%, West 21%, East 18%). PSP-Richardsons syndrome was most common (41%), followed by PSP-Parkinsonism (18%) and PSP-CBS (11%); rarer phenotypes included PSP-PI (7%), PSP-F (7%), PSP-PGF (5%), PSP-OM (2%), PSP-SL (1%), and PSP-C (1%). Falls occurred earliest in PSP-PGF (13.7 months) and PSP-SL (16.3 months), while PSP-P showed delayed disability (falls at 31 months). Cognitive onset was prominent in PSP-F (21%) and PSP-SL (57%). Levodopa was prescribed to 893 patients; 186 (21%) reported >25% subjective benefit, and 358 (40%) reported [&le;]25% benefit. Amantadine was used in 351 (34%) patients, with improvement in 177. ConclusionThis largest systematically profiled PSP cohort highlights both shared and distinctive features: high frequency of non-RS variants, aggressive course in PSP-RS/SL, better survival in PSP-P, and limited pharmacological benefit. These findings establish a foundation for longitudinal and genetic studies in diverse populations.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a highly variable clinical presentation and multifaceted genetic and biological bases that translate into great patient heterogeneity. The identification of homogeneous subgroups of patients in terms of both clinical presentation and biological causes, could favour the development of effective treatments, healthcare, and clinical trials. We aimed to identify and characterise homogenous clinical subgroups of ALS, examining whether they represent underlying biological trends. MethodsLatent class clustering analysis, an unsupervised machine-learning method, was used to identify homogenous subpopulations in 6,523 people with ALS from Project MinE, using widely collected ALS-related clinical variables. The clusters were validated using 7,829 independent patients from STRENGTH. We tested whether the identified subgroups were associated with biological trends in genetic variation across genes previously linked to ALS, polygenic risk scores of ALS and related neuropsychiatric traits, and in gene expression data from post-mortem motor cortex samples. ResultsWe identified five ALS subgroups based on patterns in clinical data which were general across international datasets. Distinct genetic trends were observed for rare variants in the SOD1 and C9orf72 genes, and across genes implicated in biological processes relevant to ALS. Polygenic risk scores of ALS, schizophrenia and Parkinsons disease were also higher in distinct clusters with respect to controls. Gene expression analysis identified different altered biological processes across clusters reflecting the genetic differences. We developed a machine learning classifier based on our model to assign subgroup membership using clinical data available at first visit, and made it available on a public webserver at http://latentclusterals.er.kcl.ac.uk. ConclusionALS subgroups characterised by highly distinct clinical presentations were discovered and validated in two large independent international datasets. Such groups were also characterised by different underlying genetic architectures and biology. Our results showed that data-driven patient stratification into more clinically and biologically homogeneous subtypes of ALS is possible and could help develop more effective and targeted approaches to the biomedical and clinical study of ALS.

ImportanceSeveral preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet. Objectiveto describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment. DesignThe ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. ResultsOut of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions and relevanceWe found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations. Questionwhat are the phenotypes of encephalitis associated to SARS-CoV-2 infection? Findings25 cases of encephalitis in SARS-CoV-2 infection were included in a prospective observational multi-centre study. Encephalitis cases in COVID-19 exhibited a wide heterogeneity in terms of clinical features, CSF, MRI findings, response to treatment and outcomes with 13 cases with normal MRI, 7 with heterogeneous MRI alterations and rarer ADEM/limbic encephalitis cases. Meaningheterogeneity of presentation, response to treatment and outcomes of encephalitis of COVID-19 underlines different pathophysiological mechanisms

ObjectivesReport a case series of new onset small fiber neuropathy (SFN) after COVID-19 treated with intravenous immunoglobulin (IVIG). SFN is a critical objective finding in long COVID and amenable to treatment. MethodsA retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We documented demographics, symptoms, treatments, diagnostics, and clinical response to treatment. ResultsSixteen patients were diagnosed with length dependent or independent SFN on skin biopsy (median age 47, 75% female, 75% Caucasian). Among the nine patients tested for autoantibodies, six were positive for either trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor 3 (FGFR3). Eight patients underwent treatment with IVIG and experience significant clinical improvement in their neuropathic symptoms. 92% of patients reported post-exertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and six patients underwent invasive cardiopulmonary exercise testing (iCPET), which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. DiscussionHere we present preliminary evidence that SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating post-infectious small fiber neuropathy.

BackgroundSeed amplification assay (SAA) testing has become an important biomarker in the diagnosis of alpha-synuclein related neurodegenerative disorders. ObjectivesTo assess the rate of alpha-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and analyse the clinical and pathological features of SAA positive and negative cases. Methods106 CSF samples from clinically diagnosed PSP (n=59), CBS (n=37) and indeterminate parkinsonism cases (n=10) were analysed using alpha-synuclein SAA. ResultsThree cases (1 PSP, 2 CBS) were Multiple System Atrophy (MSA)-type SAA positive. 5/59 (8.5%) PSP cases were Parkinsons disease (PD)-type SAA positive, and these cases were older and had a shorter disease duration compared with SAA negative cases. In contrast, 9/35 (25.7%) CBS cases were PD-type SAA positive. ConclusionsOur results suggest that PD-type seeds can be detected in PSP and CBS using a CSF alpha-synuclein SAA, and in PSP this may impact on clinical course.

Dystonia is one of the most prevalent movement disorders, but its neural substrates have remained enigmatic despite decades of research. Brain lesions leading to dystonia offer unique causal inference that could lend insight into the neural networks driving the disorder. Here, we studied the published cases of lesions causing dystonia to a variety of different body parts (n=179) and used lesion network mapping to test whether lesion locations mapped to a common brain network. Specificity was investigated by comparing the findings to 216 lesions causing other movement disorders, and 499 lesions causing non-specific neurological symptoms. While lesions causing dystonia occurred in heterogeneous locations, they localised to a common and specific cortico-basal ganglia-cerebellar network. Stronger connectivity to this dystonia network from a causal brain lesion was associated with a greater extent of dystonia throughout the body. Further, there were significant differences in the brain networks depending on the body parts affected by dystonia, which also demonstrated different somatotopic representations in the cerebellum. Our results suggest that dystonia stems from a cortico-basal ganglia-cerebellar network, with the manifestation in the body depending on the preferential involvement of the hubs of the network, and its somatotopy.

BackgroundProgressive supranuclear palsy (PSP) is typically characterized by vertical supranuclear gaze palsy and early falls, referred to as Richardsons syndrome (PSP-RS). Other presentations include postural instability (PSP-PI), parkinsonism (PSP-P), speech/language disorder (PSP-SL), frontal presentation (PSP-F), ocular motor dysfunction (PSP-OM), and corticobasal syndrome (PSP-CBS). Differences across the early presentations and in their subsequent progression have yet to be elucidated. ObjectiveThis study aimed to characterize early PSP subtypes and their subsequent progressions using a large postmortem dataset. MethodsAn automated pipeline incorporating fine-tuned Chat Generative Pre-trained Transformer (ChatGPT) was developed. The pipeline collected 195 clinical features with onset information from autopsy-confirmed PSP cases without significant neurodegenerative co-pathologies. ResultsA structured clinicopathologic dataset from 588 patients was analyzed. After distilling results with unsupervised clustering, a decision tree model was developed. With five clinical manifestations: frontal presentation, postural instability, ocular motor dysfunction, speech/language disorder, and parkinsonism, this mutually exclusive algorithm identified seven subtypes: PSP-PF (postural and frontal dysfunction), PSP-RS, PSP-PI, PSP-P, PSP-SL, PSP-F, and PSP-OM. PSP-PF showed rapid progression, the shortest median disease duration (six years), and high tau burden in cortical and subcortical regions. In PSP-F, frontal presentation preceded other symptoms by four years, with a nine-year disease duration--second longest after PSP-P (10 years). PSP-CBS was not identified as an independent subtype. ConclusionsThis data-driven study identified a novel, aggressive PSP phenotype characterized by early postural and frontal dysfunction. Early subtyping utilizing the decision tree model would help clinicians estimate progression and facilitate early patient recruitment for clinical trials.

BackgroundThere is a lack of studies on large-sample, medium-, or long-term follow-up data of peripheral neuropathy (PNP) in the COVID-19 survivors. This study evaluated the characteristics and related risk factors of PNP in the medium- and long-term rehabilitation, which provided real-world study data for the complete recovery of COVID-19 patients. MethodsThis study was a prospective cohort study of the COVID-19 survivors. We collected data on baseline characteristics, symptoms at onset and after discharge during the 6-month and 12-month follow-up. Peripheral nerves were measured by electromyography and inducible potentiometer. We used multivariable logistic regression to analyze the influencing factors of PNP. Additionally, we compared the difference between the two measurements among the population who completed both measurements. Results313 patients were included in the study and all of them underwent nerve conduction study. 67 patients completed two measurements at 6-month and 12-month follow-up. Commonly reported symptoms contained memory loss (86%), hair loss (28%), anxiety (24%), and sleep difficulties (24%). 232 patients (74%) were found with PNP, including 51 (16%) with mononeuropathy and 181 (58%) with generalized PNP. Patients with measurement at 12-month follow-up had a higher prevalence of generalized PNP (p=0.006). For pathological types, 64 (20%) patients had only axonal loss, 67 (21%) had only demyelination, and 101 (32%) had a mixed type. There was no significant difference in the prevalence of accompanying symptoms after discharge between the two groups with or without PNP. After adjustment, age was positively associated with PNP (OR=1.22 per 10-year increase of age, 95% CI, 1.05-1.41). Compared with less than the median amount of IgG at discharge, higher amount of IgG was associated with decreased risk of F-wave abnormality (OR=0.32, 95%CI, 0.11-0.82), but no significant difference in other types of PNP. Conclusions and RelevanceSARS-CoV-2 could cause PNP in hospital survivors with COVID-19, which persisted and was associated with age, education, and IgG antibody at discharge, but had no significant correlation with symptoms after discharge.