Limb Ataxia Research Articles

N4-Hydroxycytidine/molnupiravir inhibits RNA virus-induced encephalitis by producing less fit mutated viruses.

A diverse group of RNA viruses have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease. Current treatment for people with this type of infection is generally limited to supportive care. To address the need for reliable antivirals, we utilized a strategy of lethal mutagenesis to limit virus replication. We evaluated ribavirin (RBV), favipiravir (FAV) and N4-hydroxycytidine (NHC) against La Crosse virus (LACV), which is one of the most common causes of pediatric arboviral encephalitis cases in North America and serves as a model for viral CNS invasion during acute infection. NHC was approximately 3 to 170 times more potent than RBV or FAV in neuronal cells. Oral administration of molnupiravir (MOV), the prodrug of NHC, decreased neurological disease development (assessed as limb paralysis, ataxia and weakness, repeated seizures, or death) by 31% (4 mice survived out of 13) when treatment was started on the day of infection. MOV also reduced disease by 23% when virus was administered intranasally (IN). NHC and MOV produced less fit viruses by incorporating predominantly G to A or C to U mutations. Furthermore, NHC also inhibited virus production of two other orthobunyaviruses, Jamestown Canyon virus and Cache Valley virus. Collectively, these studies indicate that NHC/MOV has therapeutic potential to inhibit viral replication and subsequent neurological disease caused by orthobunyaviruses and potentially as a generalizable strategy for treating acute viral encephalitis.

AntiSox-1 Limbic Encephalitis: When A Movement Disorder Evolves Oddly And Delirium Just Does Not Feel Right

Abstract Background A 74year old male presented to a Movement Disorder service with a 15year history of a parkinsonian syndrome with asymmetric, akinetic rigidity and prominent axial features. Motor features were stable for almost 13years. Neuropsychiatric features rapidly emerged over several months including: multimodality perceptual hallucinosis, upside down and tilt illusion, akinetopsia, intractable insomnia, emotional incontinence and Othello syndrome. A marked motor, mysaesthenic pattern, deterioration occurred in conjunction with hypoactive delirium, dysphagia, pyrexias, raised inflammatory markers and weight loss, necessitating hospitalisation. Computed tomography (CT) of chest, abdomen and pelvis did not demonstrate infective or neoplastic aetiology. CT brain did not demonstrate cerebellar atrophy. Positron emission tomography did not demonstrate a vasculitis. Drg regimen alterations brought about minor improvements, but he remained very severely frail and discharged to hospice care. Unexpectedly, cognition then markedly improved and neuropsychiatric symptoms resolved over months, and he returned home, albeit now severely frail. There was persistence of hemiparkinsonian symptoms, contralateral to which, dystonia had emerged with new bilateral upper limb ataxia and nystagmus. No mysaesthenic features persisted. Methods Cerebrospinal fluid analysis and electroencephalography were not undertaken. MRI brain was not undertaken. Results Anti Sox-1 positive. Anti Zic-4 and Recoverin were equivocal. Neuronal antibodies were negative. Conclusion Limbic encephalitis as a result of AntiSox-1 onconeural antibodies is most commonly associated with small cell cancer of the lung (prevalence of 36.5% of cases). Lambert-Eaton Mysaesthenic Syndrome is a more common presentation than paraneoplastic cerebellar degeneration. Hindsight raises the possibility of non-convulsive status epilepticus as an explanation for abrupt hypoactive delirium presentation on the background of deteriorating neuropsychiatric features. Oncological or immunotherapeutic intervention was not considered appropriate by respiratory or neurology teams respectively; nor did the patient wish for these to be pursued. Case reports indicate that an underlying neoplasm is not always identified. Non-paraneoplastic autoimmune encephalitis can have a better prognosis.

Localization and Network Connectivity of Lesions Causing Limb Ataxia in Patients With Stroke.

Ataxia is primarily considered to originate from the cerebellum. However, it can manifest without obvious cerebellar damage, such as in anterior circulation stroke, leaving the mechanisms of ataxia unclear. The aim of this study was to investigate whether stroke lesions causing limb ataxia localize to a common brain network. In this prospective cohort study, adult patients with new-onset stroke with visible lesions on CT or MRI from Turku University Hospital, Finland, were clinically examined (1) after their stroke while still admitted to the hospital (baseline) and (2) 4 months later (follow-up) to assess limb ataxia. Lesion locations and their functional connectivity, computed using openly available data from 1,000 healthy volunteers from the Brain Genome Superstruct Project, were compared voxel-by-voxel across the whole brain between patients with and without ataxia, using voxel-based lesion-symptom mapping and lesion network mapping. The findings were confirmed in an independent stroke patient cohort with identical clinical assessments. One hundred ninety-seven patients (mean age 67.2 years, 39%female) were included in this study. At baseline, 35 patients (68.3 years, 34%female) had and 162 (67.0 years, 40%female) did not have new-onset acute limb ataxia. At follow-up, additional 4 patients had developed late-onset limb ataxia, totalling to 39 patients (68.6 years, 36%female) with limb ataxia at any point. One hundred eighteen patients (66.2 years, 40%female) did not have ataxia at any point (n = 40 with missing follow-up data). Lesions in 54% of the patients with acute limb ataxia were located outside the cerebellum and cerebellar peduncles, and we did not find an association between specific lesion locations and ataxia. Lesions causing acute limb ataxia, however, were connected to a common network centered on the intermediate zone cerebellum and cerebellar peduncles (lesion connectivity in patients with vs without acute limb ataxia, pFWE < 0.05). The results were similar when comparing patients with and without ataxia at any point, and when excluding lesions in the cerebellum and cerebellar peduncles (pFWE < 0.05). The findings were confirmed in the independent stroke dataset (n = 96), demonstrating an OR of 2.27 (95% CI 1.32-3.91) for limb ataxia per standard deviation increase in limb ataxia network damage score. Lesions causing limb ataxia occur in heterogeneous locations but localize to a common brain network.

Adult‐onset neuronal ceroid lipofuscinosis in a smooth‐haired dachshund

AbstractA 5‐year‐old, smooth‐haired miniature dachshund exhibited a progressive history of frequent episodes of aggression towards objects, head pressing, circling and intermittent pelvic limb ataxia over a period of 2 weeks. Visual impairment was also noticed several months prior. Neurolocalisation was consistent with forebrain disease. Blood and urine analysis, magnetic resonance imaging of the brain and cerebrospinal fluid analysis were all unremarkable. The patient was euthanased due to disease progression, and postmortem histopathological analysis and electronic microscopy identified the accumulation of intracellular granular material in a number of neurons, mainly located in the thalamus and hypothalamus. This supported a diagnosis of neuronal ceroid lipofuscinosis. Genetic testing showed no mutations in the causative genes reported for this breed. This case reports the occurrence of a potentially novel subtype of neuronal ceroid lipofuscinosis, due to a currently unidentified genetic mutation, leading to an adult onset of clinical signs in the dachshund.

Computed tomographic findings of a medically managed canine renal cortical abscess

AbstractA 10‐year‐old, neutered, male labrador retriever was referred for acute history of abdominal pain and distention, pyrexia and pelvic limb ataxia. Peritoneal free fluid with intracellular bacteria was confirmed, and subsequent abdominal computed tomography revealed a hypoattenuating and rim‐enhancing focal lesion in the cortex of the left kidney, with associated regional inflammation. The dog underwent fine‐needle aspiration of the lesion with ultrasound guidance confirming the presence of a renal abscess with growth of Escherichia coli on culture of the acquired purulent intralesional fluid. Medical management was commenced, and on repeat clinical examination and computed tomography imaging, the clinical signs and renal lesion had resolved. To the authors’ best knowledge, this is the first report of confirmation of complete resolution of a cortical renal abscess, treated with only medical management, using computed tomography examination.

NANO-LM: An updated scorecard for the clinical assessment of patients with leptomeningeal metastases.

There are no validated tools for the clinical neurological assessment of patients with leptomeningeal metastases (LM). However, clinical examination during the course of the disease guides medical management and is part of response assessment in clinical trials. Because neuroimaging may not always be obtained owing to rapid clinical deterioration, clinical neurological assessment of LM is essential, and standardization Is important to minimize rater disagreement. The RANO-LM group launched a 2-steps process, aiming at improving and standardizing the clinical assessment of patients with LM. We report here on the first step: the establishment of a consensus scorecard. The task force had 9 virtual meetings to define general recommendations on neurological assessment and selected domains of interest that should be tested. Fourteen domains of neurological symptoms and signs were selected: level of consciousness, cognition, nausea and vomiting, vision, eye movement, facial strength, hearing, swallowing, speech, limb strength, limb ataxia, walking, bladder bowel functions. For each item, a clear instruction on how to perform the assessment is provided with scoring criteria between 0 and 2. The general clinical status of the patient and use of steroids, pain medications, and anti-emetics should be documented. Neurological sequelae from previous brain metastases or cancer treatment should be rated at the baseline evaluation; it should be specified when symptoms or signs may be related to a condition other than LM. A revised NANO-LM consensus scorecard for clinical assessment has been established. An international prospective validation study of the proposal is currently ongoing (NCT06417710).

Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy.

Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology. To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause. Clinical and postmortem evaluations, together with a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing. Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed. RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pediatric brainstem glioma: a rare childhood cancer - clinical profile, treatment, and challenges of management - a single-center experience from a developing country

Introduction: Brainstem gliomas (BSGs) occur in the brainstem, located at the base of the brain. BSGs account for 10-20% of all primary CNS tumors. In a hospital-based study conducted at NICRH, BSGs constituted 7.69% of all childhood brain tumors. Objective: To determine the clinical profiles of childhood BSGs and assess the outcomes of pediatric BSGs while addressing the challenges of management. Methodology: It was a cross-sectional prospective study with a sample size of 44. We included all children during the study period and analyzed their data.The children were under 18 years of age. The study period was January 2020 and October 2022 at the Department of Pediatric Hematology and Oncology at the National Institute of Cancer Research and Hospital (NICRH), Bangladesh. Results: There were 44 patients, comprising 29 males and 15 females. The mean age of onset was 7 years. The majority (43.2%) of children fell within the 5-9 years age group. The most common symptoms were limb weakness, ataxia, and vision defects. The duration of symptoms varied from 10 days to 2 years. Sixteen of the patients experienced intracranial hypertension, which led to the development of hydrocephalus. The lesions were pontine in 18 cases, involving the entire brainstem in 13 cases, both pons and medulla in 7 cases, and medulla in 3 cases. Six patients underwent surgical intervention with histological evaluation, revealing astrocytoma (9.1%), oligodendroglioma (2.3%), and ependymoma (2.3%). Twenty-four (54.5%) patients received treatment, while others were unable to do so. The follow-up period extended to 12 months from the last enrollment. Only 8 patients completed both chemotherapy and radiotherapy treatments; other children discontinued or abandoned treatment due to financial constraints or the unavailability of 3D radiotherapy. Out of 44 children, a total of 41 patients passed away, with a mean survival period of 3.9 months. This is due to the high treatment cost in the private sector and disorganized government medical services for children with cancer. Conclusion: Most of the tumors in this series were located in the pons and demonstrated aggressive characteristics. The majority of our patients did not have access to radiotherapy due to their poor economic condition and the inadequate management of our government health system.

Equine Granulocytic Anaplasmosis: A Systematic Review and Meta-Analysis on Clinico-Pathological Findings, Diagnosis, and Therapeutic Management.

Equine granulocytic anaplasmosis (EGA) is a tick-borne disease affecting horses worldwide, caused by Anaplasma phagocytophilum. The disease ranges from non-specific clinical signs to fatal outcomes. This paper aimed to analyze EGA cases reported in peer-reviewed journals, particularly on clinico-pathological findings, diagnosis, and therapeutic management. Overall, 189 clinical cases from 31 publications were included in the study. Extensive symptomatology for the EGA cases was reported, of which mostly was fever (90.30%), followed by limb edema (48.51%), anorexia (41.79%), depression (32.84%), icterus (22.39%), ataxia (17.91), tachycardia (16.42%), and lethargy (15.67%). Laboratory tests revealed thrombocytopenia (90.32%), anemia (75%), decreased hematocrit (70.59%), leukopenia (55.88%), lymphopenia (58.14%), and neutropenia (41.67%) as the most common hematological abnormalities. For a subset of tested animals, hyperbilirubinemia (20/29), hyperfibrinogenemia (13/15), and hyponatremia (10/10) were also reported. The diagnosis was established by microscopic identification of morulae (in 153 cases), and/or PCR (120 cases), isolation (1 case), or serology (56 cases). For treatment, oxytetracycline was used in the majority (52.24%) of EGA cases, but recovery without antibiotherapy (10.34%) was also noted. In conclusion, the variety of clinical and pathological findings and the challenging therapeutic approaches reported suggest that EGA should be included in the differential diagnosis when fever occurs.

Immunization with Sez6L2 protein mimics the human condition of late-onset cerebellar ataxia with associated Sez6L2 autoantibodies in mice

Abstract Sez6L2 autoantibodies have been identified in a subset of human patients with progressive cerebellar ataxia. Sez6L2 is a transmembrane protein expressed by most neurons, including Purkinje cells and granular cells of the cerebellum. Patients with Sez6L2 autoantibodies present with gait ataxia, slurred speech, and ocular motor symptoms. Some patients also develop limb ataxia and cognitive deficits. These case studies have led to the hypothesis that autoimmunity against Sez6L2 can directly cause cerebellar damage leading to ataxia. We tested whether C57BL/6J mice immunized against Sez6L2 protein develop ataxia symptoms. We also investigated the systemic immune response against Sez6L2 and whether there was increased immune cell infiltration into the brain. We found that mice immunized with Sez6L2 generated significant levels of anti-Sez6L2 antibodies, in addition to a significant population of Sez6L2-specific CD4 and CD8 T cells. Furthermore, these mice had increased CD4+ T cell infiltration into the brain. The Sez6L2 immunized mice also exhibited mild mobility impairments in open field and wire grid walk assays. Overall, our results demonstrate that an autoimmune response to Sez6L2 in mice can lead to mobility impairments and pathology consistent with human patients who develop cerebellar ataxia associated with Sez6L2 autoantibodies. This new mouse model should be useful for mechanistic studies on a poorly understood autoimmune disease.

Multifeature quantitative motor assessment of upper limb ataxia including drawing and reaching.

Voluntary upper limb movements are an ecologically important yet insufficiently explored digital-motor outcome domain for trials in degenerative ataxia. We extended and validated the trial-ready quantitative motor assessment battery "Q-Motor" for upper limb movements with clinician-reported, patient-focused, and performance outcomes of ataxia. Exploratory single-center cross-sectional assessment in 94 subjects (46 cross-genotype ataxia patients; 48 matched controls), comprising five tasks measured by force transducer and/or position field: Finger Tapping, diadochokinesia, grip-lift, and-as novel implementations-Spiral Drawing, and Target Reaching. Digital-motor measures were selected if they discriminated from controls (AUC >0.7) and correlated-with at least one strong correlation (rho ≥0.6)-to the Scale for the Assessment and Rating of Ataxia (SARA), activities of daily living (FARS-ADL), and the Nine-Hole Peg Test (9HPT). Six movement features with 69 measures met selection criteria, including speed and variability in all tasks, stability in grip-lift, and efficiency in Target Reaching. The novel drawing/reaching tasks best captured impairment in dexterity (|rho9HPT| ≤0.81) and FARS-ADL upper limb items (|rhoADLul| ≤0.64), particularly by kinematic analysis of smoothness (SPARC). Target hit rate, a composite of speed and endpoint precision, almost perfectly discriminated ataxia and controls (AUC: 0.97). Selected measures in all tasks discriminated between mild, moderate, and severe impairment (SARA upper limb composite: 0-2/>2-4/>4-6) and correlated with severity in the trial-relevant mild ataxia stage (SARA ≤10, n = 20). Q-Motor assessment captures multiple features of impaired upper limb movements in degenerative ataxia. Validation with key clinical outcome domains provides the basis for evaluation in longitudinal studies and clinical trial settings.

(220) Sexual Dysfunction in Krabbe Disease Patients - A Scoping Review

Abstract Introduction Krabbe Disease (KD) or globoid cell leukodystrophy is a rare autosomal recessive lysosomal storage disorder affecting approximately 1 in 100,000 people worldwide. GALC gene mutations associated with KD involve a galactosylceramidase deficiency, which damages the oligodendrocytes and Schwann cells. Therefore, nervous system demyelination is a hallmark of KD. While only a few infants survive beyond two years in early-onset Krabbe disease, patients with late-onset Krabbe Disease exhibit a milder phenotype and longer life expectancy. Late-onset KD symptoms include progressive muscle weakness and stiffness, developmental regression, behavioral changes, dementia, hearing loss, vision problems, and seizures. Only a few cases of sexual dysfunction associated with KD have been reported in literature but they highlight the wide-ranging impact of this condition on young adults and adults. Objective This review aims to examine sexual dysfunction in KD, as reported in literature. We employ a broad definition of sexual dysfunction (erectile dysfunction, dyspareunia, orgasmic disorder, muscle weakness, etc.) and its incidence in both sexes with KD. A comprehensive review of this topic has not yet been conducted, and we offer here preliminary information for healthcare providers when addressing sexual concerns in patients with lysosomal storage disorders. Methods A literature search was conducted by two separate investigators who independently screened studies and abstracted data. Data sources included peer reviewed publications from the following databases: PubMed, Scopus, Web of Science, EMBASE, Cochrane, Google Scholar and Clinical trials.gov. There were no restrictions on language nor date of publication. The search algorithm utilized to generate the review list was: (Globoid cell leukodystrophy OR Galactosylcerebrosidase deficiency OR Galactosylceramidase deficiency OR Krabbe disease OR Late-onset Krabbe disease OR GALC mutation). Results were further filtered by article type, restricting articles to Case Reports, Clinical Trials, Reviews, and Systematic Reviews. Results were then screened for reports containing data on sexual dysfunction in patients with KD. Results A total of four case reports and one review paper contained reports of sexual dysfunction in KD patients. All cases involved late-onset Krabbe disease, characterized by a milder and more insidious presentation. Genitourinary symptoms reported included urinary incontinence (N=3) and erectile dysfunction (N=2), however, there were no reports (N=0) of symptoms related to female sexual dysfunction. Other symptoms commonly reported in late-onset KD that might be linked to sexual function were ataxia, spasticity and weakness of lower limbs (N=3), and sensory dysfunction due to peripheral neuropathy (N=4). Conclusions This pioneering review reveals that patients with KD experience symptoms of sexual dysfunction. While the rarity of KD makes it challenging to study it clinically, sexual dysfunction may be consistent with the known pathophysiology of late-onset KD. This review also highlights that sexual dysfunction in female patients with KD is an under-investigated component of the disease presentation. Future clinical research into this important comorbidity, especially in female patients where the literature is lacking, may improve the care of patients with KD. Disclosure No.

Homozygous CNP Mutation and Neurodegeneration in Weimaraners: Myelin Abnormalities and Accumulation of Lipofuscin-like Inclusions.

A progressive neurological disorder was observed in a male neutered Weimaraner. Clinical signs included fecal incontinence, lethargy, moderate paraparesis, proprioceptive pelvic limb ataxia, falling, cognitive decline, incoordination, decreased interest in food, changes in posture, and episodes of trance-like behavior. Neurologic signs were first observed at approximately 4 years, 10 months of age and progressed slowly. Magnetic resonance imaging showed generalized brain atrophy with areas of white matter pathology. Humane euthanasia was elected at 6 years, 7 months of age due to increasing severity of the neurological signs. Autofluorescent intracellular granules were observed in the cerebral and cerebellar cortexes, optic nerve, and cardiac muscle of the affected dog. These abnormal inclusions in the cerebral cortex and cardiac muscle immunolabeled with antibodies to mitochondrial ATP synthase subunit c protein, like that observed in the neuronal ceroid lipofuscinosis group of lysosomal storage diseases. Immunolabeling also demonstrated pronounced neuroinflammation in brain tissues. The ultrastructural appearances of the disease-related inclusion bodies in the brain and optic nerve were quite variable. The ultrastructure and locations of many of the inclusions in the nervous tissues suggested that they were derived, at least in part, from the myelin surrounding axons. The storage bodies in the cardiac muscle were located in mitochondria-rich regions and consisted of parallel arrays of membrane-like components interspersed with electron-dense flocculent material. The disease was characterized by pronounced abnormalities in the myelin of the brain and optic nerve consisting of distinctive areas of ballooning between the layers of myelin. The whole genome sequence generated from the affected dog contained a homozygous G-to-A missense mutation in CNP, which encodes proteins with CNPase enzyme activity and a structural role in myelin. The mutation predicts a Thr42Met amino acid sequence substitution. Genotyping of archived Weimaraner DNA samples identified an additional G > A variant homozygote with a clinical history and brain lesions similar to those of the proband. Of 304 Weimaraners and over 4000 other dogs of various breeds, the proband and the other Weimaraner that exhibited similar signs were the only two that were homozygous for the CNP missense variant. CNPase immunolabeling was widespread in brain tissues from normal dogs but was undetectable in the same tissues from the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the late-onset Weimaraner disorder likely results from the missense mutation that results in CNPase deficiency, leading to myelin abnormalities, accumulation of lysosomal storage bodies, and brain atrophy. Similar disorders have been associated with different CNP variants in Dalmatians and in human subjects.

A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats.

Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.

Initial stroke severity and discharge outcome in patients with muscle mass deficit.

This study aimed to investigate the association between muscle mass deficit and the initial severity of ischemic stroke. The impact of muscle mass deficit on the discharge outcome was also evaluated. This retrospective study included 660 patients with acute ischemic stroke who underwent bioelectrical impedance analyses. We compared the National Institute of Health Stroke Scale (NIHSS) score, occurrence of moderate stroke (NIHSSS ≥ 5) at admission, and unfavorable functional outcome (modified Rankin Scale score ≥ 2) at discharge between patients with and without muscle mass deficit using Poisson and logistic regression analyses. The mean age of the study patients was 65.6 ± 13.0, and 63.3% were males. Muscle mass deficit was present in 24.4% of patients. Muscle mass deficit was significantly and independently associated with NIHSS score or moderate stroke (all p < 0.05). This association was noted regardless of patient characteristics. Among the respective NIHSS items, muscle mass deficit was significantly associated with facial palsy, motor function of the arm or leg, limb ataxia, and dysarthria. Muscle mass deficit also led to unfavorable functional outcome, which was mediated by the initial NIHSS score. In conclusion, muscle mass deficit is associated with higher NIHSS score and unfavorable functional outcome in patients with acute ischemic stroke.

PCYT2 deficiency in Saarlooswolfdogs with progressive retinal, central, and peripheral neurodegeneration

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system. Pedigrees indicated autosomal recessive inheritance. We mapped the suspected genetic defect to a 15 Mb critical interval by combined linkage and autozygosity analysis. Whole genome sequencing revealed a private homozygous missense variant, PCYT2:c.4A>G, predicted to change the second amino acid of the encoded ethanolamine-phosphate cytidylyltransferase 2, XP_038402224.1:(p.Ile2Val). Genotyping of additional Saarlooswolfdogs confirmed the homozygous genotype in all eleven affected dogs and demonstrated an allele frequency of 9.9% in the population. This experiment also identified three additional homozygous mutant young dogs without overt clinical signs. Subsequent examination of one of these dogs revealed early-stage progressive retinal atrophy (PRA) and expansion of subarachnoid CSF spaces in MRI. Dogs homozygous for the pathogenic variant showed ether lipid accumulation, confirming a functional PCYT2 deficiency. The clinical and metabolic phenotype in affected dogs shows some parallels with human patients, in whom PCYT2 variants lead to a rare form of spastic paraplegia or axonal motor and sensory polyneuropathy. Our results demonstrate that PCYT2:c.4A>G in dogs cause PCYT2 deficiency. This canine model with histopathologically documented retinal, central, and peripheral neurodegeneration further deepens the knowledge of PCYT2 deficiency.

Atypical magnetic resonance imaging findings of a vertebral melanotic melanoma in a dog

AbstractAn 8‐year‐8‐month‐old whippet was investigated by magnetic resonance imaging for acute thoracolumbar discomfort and pelvic limb stiffness, which had progressed to severe ambulatory paraparesis and proprioceptive ataxia of the pelvic limbs in the 24 hours before presentation. An aggressive, extradural T10 vertebral mass‐like lesion was identified, with resultant marked compression of the spinal cord. The lesion was heterogeneously T2‐weighted hyperintense and moderately T1‐weighted hyperintense relative to the adjacent vertebrae and paravertebral musculature. Cytological analysis of the lesion was consistent with a melanotic melanoma, which was confirmed by histopathological analysis and immunohistochemistry. The vertebral column is an uncommon location for either primary or metastatic melanomas in both humans and veterinary species. This lesion was particularly unusual in that its imaging characteristics were not typical for melanotic melanoma. This case report illustrates the unusual anatomical and imaging features of this tumour and outlines the diagnostic considerations pertinent to this case.

Chapter 9 - Familial hemiplegic migraine

Hemiplegic migraine consists of attacks of migraine with aura that includes reversible motor weakness. It is classified as familial or sporadic depending on the involvement or not of a first or second degree relative. The most described subtypes of familial hemiplegic migraine include FHM1, FHM2, and FHM3. These have been demonstrated to have a mutation in either CACNA1A, ATP1A2 or SCN1A, which encode different subunits of channels, involving P/Q-type calcium channel, Na/K pump and Na channel, respectively, located in neurons and glial cells. Mutations localized in different genes are defined as "other loci." Patients with a known mutation can have different genetic penetrance, and may present a more complex and disabling phenotype that develops earlier in life. The clinical manifestations can be similar in the three mutations, including neurologic comorbidities other than muscular weakness, such as episodes of loss of consciousness, epilepsy, gait or limb ataxia or movement disorders, among others. Treatment includes antiepileptics such as lamotrigine, valproate or topiramate, calcium blockers such as flunarizine or verapamil and acetazolamide.

Anti-glutamic acid decarboxylase antibodies-associated cerebellar ataxia: A treatable ataxia

Abstract Background: Anti-glutamate decarboxylase 65 antibody-associated cerebellar ataxia (anti-GAD65Ab-associated CA) is the most widely studied immune-mediated CA. There are few case series evaluating the clinical, radiological, treatment profile, and outcome of anti-GAD65Ab-associated CA. Objective: To study the clinical, radiological profile, associated neoplasm, treatment outcome, and prognosis in patients diagnosed with anti-GAD65Ab-associated CA. Methods: A retrospective descriptive analysis of a cohort of patients diagnosed with anti-GAD65Ab-associated CA was performed and analyzed. Results: Thirteen patients were selected for the analysis with female predominance (70%). The mean age at presentation was 47.5 ± 11.1 years (range, 29–65 years), and the median duration of the symptoms was 4 months. All 13 patients (100%) had gait ataxia. Ten patients had limb ataxia along with gait ataxia (75%). Seven patients had cerebellar dysarthria (54%). Four patients (31%) had gaze-evoked jerky nystagmus. Five patients (39%) were diagnosed with type 2 diabetes mellitus, and one patient had hypothyroidism in addition to type 2 diabetes mellitus. Brain magnetic resonance imaging was normal in seven (54%) patients, and pure cerebellar atrophy was observed in six patients. One patient was detected with a colon neoplasm. All 13 patients received intravenous methylprednisolone, followed by oral steroids over 3 months. Six patients (50%) received plasma exchange along with intravenous methylprednisolone. Favorable outcomes (modified Rankin scale score ≤2) were observed in five patients and poor outcomes in two; six patients were lost to follow-up after the first admission. Conclusion: Anti-GAD65Ab-associated CA presents as subacute to chronic progressive CA with a favorable outcome with immunotherapy. Anti-GAD antibodies should be assessed in serum or cerebrospinal fluid in patients presenting subacute to chronic sporadic CA. The occurrence of a systemic neoplasm is rare in anti-GAD65Ab-associated CA.

Pembrolizumab-associated Neuronopathy with Improved Lower Limb Somatosensory Evoked Potential After Intravenous Methylprednisolone Treatment: A Case Report.

Cases of neuronopathy associated with immune checkpoint inhibitors (ICIs) have rarely been reported. We herein report a case of ICI-associated neuronopathy. A 54-year-old man underwent chemotherapy for right maxillary sinus cancer. Two months after pembrolizumab treatment, diarrhea, worsening of abnormal sensations, and severe ataxia of the lower limbs were observed. Somatosensory evoked potentials (SEPs) with tibial nerve stimulation showed disappearance of the N21 waveform. A colonic biopsy suggested ICI-associated colitis. Based on these findings, the patient was diagnosed with ICI-associated neuronopathy. Clinical symptoms and SEP findings improved markedly after two courses of intravenous methylprednisolone.