Basket to Purkinje Cell Inhibitory Ephaptic Coupling Is Abolished in Episodic Ataxia Type 1.

Dominantly inherited missense mutations of the KCNA1 gene, which encodes the KV1.1 potassium channel subunit, cause Episodic Ataxia type 1 (EA1). Although the cerebellar incoordination is thought to arise from abnormal Purkinje cell output, the underlying functional deficit remains unclear. Here we examine synaptic and non-synaptic inhibition of Purkinje cells by cerebellar basket cells in an adult mouse model of EA1. The synaptic function of basket cell terminals was unaffected, despite their intense enrichment for KV1.1-containing channels. In turn, the phase response curve quantifying the influence of basket cell input on Purkine cell output was maintained. However, ultra-fast non-synaptic ephaptic coupling, which occurs in the cerebellar 'pinceau' formation surrounding the axon initial segment of Purkinje cells, was profoundly reduced in EA1 mice in comparison with their wild type littermates. The altered temporal profile of basket cell inhibition of Purkinje cells underlines the importance of Kv1.1 channels for this form of signalling, and may contribute to the clinical phenotype of EA1.

Neuronal activity reorganization in motor cortex for successful locomotion after a lesion in the ventrolateral thalamus.

Thalamic stroke leads to ataxia if the cerebellum-receiving ventrolateral thalamus (VL) is affected. The compensation mechanisms for this deficit are not well understood, particularly the roles that single neurons and specific neuronal subpopulations outside the thalamus play in recovery. The goal of this study was to clarify neuronal mechanisms of the motor cortex involved in mitigation of ataxia during locomotion when part of the VL is inactivated or lesioned. In freely ambulating cats, we recorded the activity of neurons in layer V of the motor cortex as the cats walked on a flat surface and horizontally placed ladder. We first reversibly inactivated ∼10% of the VL unilaterally using glutamatergic transmission antagonist CNQX and analyzed how the activity of motor cortex reorganized to support successful locomotion. We next lesioned 50%-75% of the VL bilaterally using kainic acid and analyzed how the activity of motor cortex reorganized when locomotion recovered. When a small part of the VL was inactivated, the discharge rates of motor cortex neurons decreased, but otherwise the activity was near normal, and the cats walked fairly well. Individual neurons retained their ability to respond to the demand for accuracy during ladder locomotion; however, most changed their response. When the VL was lesioned, the cat walked normally on the flat surface but was ataxic on the ladder for several days after lesion. When ladder locomotion normalized, neuronal discharge rates on the ladder were normal, and the shoulder-related group was preferentially active during the stride's swing phase.NEW & NOTEWORTHY This is the first analysis of reorganization of the activity of single neurons and subpopulations of neurons related to the shoulder, elbow, or wrist, as well as fast- and slow-conducting pyramidal tract neurons in the motor cortex of animals walking before and after inactivation or lesion in the thalamus. The results offer unique insights into the mechanisms of spontaneous recovery after thalamic stroke, potentially providing guidance for new strategies to alleviate locomotor deficits after stroke.

Heritability and Genomic Architecture of Episodic Exercise-Induced Collapse in Border Collies.

An episodic nervous system disorder triggered by strenuous exercise, termed border collie collapse (BCC), exists in border collies and related breeds. The genetic basis of BCC is unknown but is believed to be a complex genetic disorder. Our goal was to estimate the heritability (h2SNP) of BCC, define its underlying genetic architecture, and identify associated genomic loci using dense whole-genome single-nucleotide polymorphism (SNP) genotyping data. Genotype data were obtained for ~440,000 SNPs from 343 border collies (168 BCC cases and 175 controls). h2SNP was calculated to be 49-61% depending on the estimated BCC prevalence. A total of 2407 SNPs across the genome accounted for nearly all the h2SNP of BCC, with an estimated 2003 SNPs of small effect, 349 SNPs of moderate effect, and 56 SNPs of large effect. Genome-wide association analyses identified significantly associated loci on chromosomes 1, 6, 11, 20, and 28, which accounted for ~5% of the total BCC h2SNP. We conclude that BCC is a moderately- to highly-heritable complex polygenetic disease resulting from contributions from hundreds to thousands of genetic variants with variable effect sizes. Understanding how much the BCC phenotype is determined by genetics and whether major gene mutations are likely to exist inform veterinarians and working/stock dog communities of the true nature of this condition.

Instability of speech in Parkinson disease patients with subthalamic nucleus deep brain stimulation.

INTRODUCTION: The impact of deep brain stimulation (DBS) on speech rhythm and its mechanism remains unclear. We investigated speech rhythm characteristics of patients with Parkinson's disease (PD) treated with subthalamic nucleus (STN) DBS to understand the underlying pathophysiology better. METHODS: We enrolled a total of 105 participants and evaluated speech rhythm performances among patients with PD who had undergone STN-DBS (the PD-DBS group), patients with PD treated only with medication (the PD-Med group), patients with cerebellar ataxia (the CA group), and healthy controls (the HC group). Each participant was asked to repeat the syllable/pa/at a comfortable self-chosen steady pace. A widely-used software (the Motor Speech Profile) program performed an acoustic analysis. RESULTS: Compared to the PD-Med and HC groups, speech rate instability (DDKjit) was significantly higher in the PD-DBS and CA groups (p < 0.01). However, after DBS was turned off, the DDKjit of the PD-DBS group improved to a level comparable to that of the PD-Med and HC groups. In contrast to the significantly higher variability of speech volume (DDKcvi) in the CA group, the PD-DBS group showed similar DDKcvi to the PD-Med and HC groups. CONCLUSIONS: STN-DBS affects the speech rate stability of patients with PD. Speech rhythm disorders caused by STN-DBS were phenotypically similar to that in CA in terms of interval variability but different regarding amplitude variability. Further studies are warranted to elucidate the underlying pathophysiology of speech rhythm disorders in PD patients treated with DBS.

Mechanisms of Genome Instability in the Fragile X-Related Disorders.

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5' UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54-200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.

The Phenotypic Spectrum of Patients with PHARC Syndrome Due to Variants in ABHD12: An Ophthalmic Perspective.

This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0; range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9; range from 0.1 to 2.8; equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity.

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes.

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult "gain-of-function" syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

Improving the objectivity of the current World Para Swimming motor coordination test for swimmers with hypertonia, ataxia and athetosis using measures of movement smoothness, rhythm and accuracy.

The current protocol for classifying Para swimmers with hypertonia, ataxia and athetosis involves a physical assessment where the individual's ability to coordinate their limbs is scored by subjective clinical judgment. The lack of objective measurement renders the current test unsuitable for evidence-based classification. This study evaluated a revised version of the Para swimming assessment for motor coordination, incorporating practical, objective measures of movement smoothness, rhythm error and accuracy. Nineteen Para athletes with hypertonia and 19 non-disabled participants performed 30 s trials of bilateral alternating shoulder flexion-extension at 30 bpm and 120 bpm. Accelerometry was used to quantify movement smoothness; rhythm error and accuracy were obtained from video. Para athletes presented significantly less smooth movement and higher rhythm error than the non-disabled participants (p < 0.05). Random forest algorithm successfully classified 89% of participants with hypertonia during out-of-bag predictions. The most important predictors in classifying participants were movement smoothness at both movement speeds, and rhythm error at 120 bpm. Our results suggest objective measures of movement smoothness and rhythm error included in the current motor coordination test protocols can be used to infer impairment in Para swimmers with hypertonia. Further research is merited to establish the relationship of these measures with swimming performance.

Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected. FXTAS is caused by a CGG-repeat expansion (CGGexp) in the fragile X mental retardation 1 (FMR1) gene. CGGexp RNA is translated into the FMRpolyG protein by a mechanism called RAN translation. Although both gene and pathogenic trigger are known, no therapeutic interventions are available at this moment. Here, we present, for the first time, primary hippocampal neurons derived from the ubiquitous inducible mouse model which is used as a screening tool for targeted interventions. A promising candidate is the repeat binding, RAN translation blocking, small molecule 1a. Small molecule 1a shields the disease-causing CGGexp from being translated into the toxic FMRpolyG protein. Primary hippocampal neurons formed FMRpolyG-positive inclusions, and upon treatment with 1a, the numbers of FMRpolyG-positive inclusions are reduced. We also describe for the first time the formation of FMRpolyG-positive inclusions in the liver of this mouse model. Treatment with 1a reduced the insoluble FMRpolyG protein fraction in the liver but not the number of inclusions. Moreover, 1a treatment had a reducing effect on the number of Rad23b-positive inclusions and insoluble Rad23b protein levels. These data suggest that targeted small molecule therapy is effective in an FXTAS mouse model and has the potential to treat CGGexp-mediated diseases, including FXTAS.

The impairment of motor coordination following chronic carbamazepine-levetiracetam combination treatment with evidence of corticocerebellar toxicity in male Wistar rats.

This study examined the effects of carbamazepine (CBZ) or levetiracetam (LEV) and sub-therapeutic doses of the combination of the two conventional antiepileptics on some of the markers of motor coordination. Twenty-four male Wistar rats (140 ± 5 g) were randomized into 4 groups (n = 6). Group I rats received physiological saline (0.2 ml), group II were administered CBZ (25.0 mg/kg), group III received LEV (50 mg/kg), while group IV rats were given sub-therapeutic doses of CBZ (12.5 mg/kg) and LEV (25 mg/kg) intraperitoneally for 28 days. Thereafter the animals were subjected to behavioral and biochemical investigations, while the frontal lobe and cerebellar tissue were preserved for histological investigation. Data were subjected to descriptive and inferential statistics, and the results presented as mean ± SEM, analyzed using one-way Analysis of variance (ANOVA) and Student- Newman Keuls post hoc analysis where appropriate. p < 0.05 was considered statistically significant. There was significant alteration in fine and skilled movement after the CBZ, and CBZ + LEV chronic treatment compared with the control. The CBZ, and CBZ + LEV combination treatment increased the frontal lobe and cerebellar activities of acetylcholinesterase, malondialdehyde concentration, tissue necrotic factor alpha and decreased the activities of super oxide dismutase relative to the control. Disorganization of the histoarchitecture of the frontal lobe and cerebellum was characterized by cellular atrophy, chromatolysis and hyalinization. Chronic CBZ, and CBZ + LEV combination treatment produced psychomotor dysfunction and neurotoxicity in this order CBZ + LEV > CBZ > LEV in the rats.

Paraneoplastic Progressive Downbeat Nystagmus, Ataxia and Sensorineural Hearing Loss due to the ANTI-Kelch-11 Protein Antibody.

ABSTRACT: A 45-year-old man with a history of testicular seminoma treated 8 years earlier presented with chronic progressive truncal and limb ataxia, progressive sensorineural hearing loss, and episodic vertigo. Eye movement and neuro-otology examinations showed localizing abnormalities to the bilateral cerebellar flocculus, vermis, and bilateral cerebellar hemispheres. Audiometric testing showed bilateral symmetric sensorineural hearing loss. There was a normal MRI of the brain. Cerebrospinal fluid (CSF) showed modest lymphocytic pleocytosis, and there was an elevated serum choriogonadotrophic hormone. An abdominal CT scan showed a solitary, large retroperitoneal lymph node, and histopathologic examination of the node biopsy showed granulomatous inflammation without microorganisms; eventually, immunohistochemical markers confirmed the diagnosis of metastatic seminoma. Although normal neuroimaging and inflammatory CSF reaction suggested a paraneoplastic etiology, the initial paraneoplastic antibody testing was negative. Subsequent investigation identified a positive kelch-11 protein antibody, thus confirming the paraneoplastic connection between the metastatic seminoma and the subacute neurologic-cochleovestibular syndrome.

Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.

BACKGROUND: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. CASE PRESENTATION: Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. CONCLUSION: This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.

Validation of new measures of arm coordination impairment in Wheelchair Rugby.

This study aims were twofold: (1) to evaluate the construct validity of the Repetitive Movement Test (RMT) a novel test developed for Wheelchair Rugby classification which evaluates arm coordination impairment at five joints - shoulder, elbow, forearm, wrist and fingers - and (2), pending sufficiently positive results, propose objective minimum impairment criteria (MIC). Forty-two WR athletes with an eligible coordination impairment, and 20 volunteers without impairment completed the RMT and two clinically established coordination tests: the finger-nose test (FNT) and the spiral test (ST). Coordination deduction (CD), an ordinal observational coordination scale, currently used in WR classification, was obtained. Spearman-rank correlation coefficients (SCC) between RMT and ST (0.40 to 0.67) and between RMT and CD (0.31 to 0.53) generally supported RMT construct validity, SCC between RMT and FNT were lower (0.12-0.31). When the scores on ST, FNT and RMT from the sample of WR players were compared with the scores from volunteers without impairment, 93.5% to 100% of WR players had scores > 2SD below the mean of volunteers without impairment on the same test. In conclusion, RMT at the elbow, forearm, wrist and fingers have sufficient construct validity for use in WR. MIC were recommended with ST and RMT.

Optimising classification of proximal arm strength impairment in wheelchair rugby: A proof of concept study.

This study examined the relationship between proximal arm strength and mobility performance in wheelchair rugby (WR) athletes and examined whether a valid structure for classifying proximal arm strength impairment could be determined. Fifty-seven trained WR athletes with strength impaired arms and no trunk function performed six upper body isometric strength tests and three 10 m sprints in their rugby wheelchair. All strength measures correlated with 2 m and 10 m sprint times (r ≥ -0.43; p ≤ 0.0005) and were entered into k-means cluster analyses with 4-clusters (to mirror the current International Wheelchair Rugby Federation [IWRF] system) and 3-clusters. The 3-cluster structure provided a more valid structure than both the 4-cluster and existing IWRF system, as evidenced by clearer differences in strength (Effect sizes [ES] ≥ 1.0) and performance (ES ≥ 1.1) between adjacent clusters and stronger mean silhouette coefficient (0.64). Subsequently, the 3-cluster structure for classifying proximal arm strength impairment would result in less overlap between athletes from adjacent classes and reduce the likelihood of athletes being disadvantaged due to their impairment. This study demonstrated that the current battery of isometric strength tests and cluster analyses could facilitate the evidence-based development of classifying proximal arm strength impairment in WR.

Is impaired coordination related to match physical load in footballers with cerebral palsy of different sport classes?

Impaired coordination is a characteristic feature in cerebral palsy (CP) football players. This study aimed to determine the relationships of three coordination tests with match physical load during competition of para-footballers from different sport classes. Records from 259 para-footballers from 25 national teams were obtained in four international competitions held in 2018 and 2019. The three coordination tests were conducted prior to competition (i.e., rapid heel-toe, side-stepping, and split jumps), and physical match load was recorded by GPS devices during the real game: i.e., maximum/mean, total distance, distance covered at different speed zones, number of accelerations/decelerations at different intensities, and player load. FT1 and FT3 players have the lowest and highest performance in all the coordination tests, respectively, but inconclusive between-groups differences were obtained (p=0.022‒0.238). Split jumps and side-stepping tests are associated with the performance of moderate and high accelerations during competition (r = -0.20‒0.71; p<0.01). Significant correlations (r = 0.36‒0.71; p<0.01) were obtained between all the coordination measures. Coordination tests better discriminate those with more severe impairments and some evidence for the validity of the new CP football sport classes is provided. Further research is necessary to identify the portion of the variance in sports performance that coordination explains.

Progressive midbrain clefts after head trauma and decompressive surgery: a report of two patients.

This report describes two patients with acute-onset ptosis, oculomotor dysfunction, ataxia and drowsiness, referable to the midbrain tegmentum. Both patients had previously suffered severe closed head injuries requiring craniotomy for cerebral decompression. Serial brain scans in both cases revealed a newly developing cleft in the midbrain, with features suggestive of abnormal cerebrospinal fluid (CSF) flow across the aqueduct. A trial of acetazolamide was initiated to reduce CSF production, followed by a third ventriculostomy for CSF diversion in one patient, which resulted in arrested disease progression and partial recovery. There are only two previous reports in the literature of midbrain clefts that developed as remote sequelae of head trauma. We postulate that altered CSF flow dynamics in the aqueduct, possibly related to changes in brain compliance, may be contributory. Early recognition and treatment may prevent irreversible structural injury and possible death.

Metronidazole-induced reversible cerebellar dysfunction.

A 73-year-old man who presented with fever and abdominal discomfort was diagnosed to have a liver abscess. He was treated with antimicrobials which included metronidazole. One month into treatment, he developed neurological symptoms and signs that were suggestive of cerebellar pathology. MRI of the brain showed T2/fluid attenuated inversion recovery hyperintensities involving bilateral dentate, fastigial and interpositus nuclei. After excluding common aetiologies, the possibility of metronidazole-induced neurotoxicity was considered. After stopping metronidazole, his symptoms and signs resolved. A subsequent MRI scan of the brain showed reversal of changes. Neurotoxicity caused by metronidazole is an uncommon adverse effect of a commonly used antimicrobial drug and should be considered in the appropriate clinical scenario.

Predictive Validity of the Scale for the Assessment and Rating of Ataxia for Medium-Term Functional Status in Acute Ataxic Stroke.

OBJECTIVES: This study examines the prognostic validity of the Scale for the Assessment and Rating of Ataxia for patients with acute stroke. MATERIALS AND METHODS: We enrolled 120 patients with posterior circulation stroke having ischemic or hemorrhagic lesions with ataxia who had physical therapy. We recorded the clinical stroke features and obtained the scale for the assessment and rating of ataxia and National Institutes of Health Stroke Scale scores 7 days after admission and at discharge. Predictive factors for a 3-month modified Rankin Scale score of <3 were investigated. RESULTS: During hospitalization, the Scale for the Assessment and Rating of Ataxia score decreased from 7.5 (interquartile range, 4.5-12.5) to 4.0 (interquartile range, 1.5-8.0) points, whereas the National Institutes of Health Stroke Scale score changed from 1 (interquartile range, 0-3) to 1 (interquartile range, 0-2) point. A significant correlation between functional outcome and the Scale for the Assessment and Rating of Ataxia scores 7 days after onset was observed. The cutoff value for the assessment and rating of ataxia for predicting favorable outcome (modified Rankin scale, 0-2) at 3 months post-onset was 14 points (0-40) at 7 days after onset. CONCLUSIONS: The Scale for the Assessment and Rating of Ataxia scores showed good responsiveness to neurological changes in patients with acute ataxic stroke, could predict functional outcomes 3 months after onset on day 7, and could be a useful and reliable marker for patients with ataxic stroke.

A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice.

Rationale: Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. Methods: We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. Results: The new-KD, that markedly increased plasma Beta-hydroxybutyrate (ß-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. Conclusion: The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.

Neurologic Syndromes Predict Higher In-Hospital Mortality in COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is protean in its manifestations, affecting nearly every organ system. However, nervous system involvement and its effect on disease outcome are poorly characterized. The objective of this study was to determine whether neurologic syndromes are associated with increased risk of inpatient mortality. METHODS: A total of 581 hospitalized patients with confirmed SARS-CoV-2 infection, neurologic involvement, and brain imaging were compared to hospitalized non-neurologic patients with coronavirus disease 2019 (COVID-19). Four patterns of neurologic manifestations were identified: acute stroke, new or recrudescent seizures, altered mentation with normal imaging, and neuro-COVID-19 complex. Factors present on admission were analyzed as potential predictors of in-hospital mortality, including sociodemographic variables, preexisting comorbidities, vital signs, laboratory values, and pattern of neurologic manifestations. Significant predictors were incorporated into a disease severity score. Patients with neurologic manifestations were matched with patients of the same age and disease severity to assess the risk of death. RESULTS: A total of 4,711 patients with confirmed SARS-CoV-2 infection were admitted to one medical system in New York City during a 6-week period. Of these, 581 (12%) had neurologic issues of sufficient concern to warrant neuroimaging. These patients were compared to 1,743 non-neurologic patients with COVID-19 matched for age and disease severity admitted during the same period. Patients with altered mentation (n = 258, p = 0.04, odds ratio [OR] 1.39, confidence interval [CI] 1.04-1.86) or radiologically confirmed stroke (n = 55, p = 0.001, OR 3.1, CI 1.65-5.92) had a higher risk of mortality than age- and severity-matched controls. CONCLUSIONS: The incidence of altered mentation or stroke on admission predicts a modest but significantly higher risk of in-hospital mortality independent of disease severity. While other biomarker factors also predict mortality, measures to identify and treat such patients may be important in reducing overall mortality of COVID-19.