Cerebellar Symptoms Research Articles

Prediction of comorbid depression in patients with disseminated sclerosis of residents in the northern region

The mechanism of development of neuropsychological disorders and the assessment of predictors of their development in patients with multiple sclerosis (MS) are insufficiently studied. Prediction of comorbid depression in this category of patients is of great interest and is aimed at personalized medical care for patients with optimal personal and environmental adaptation of the patient with MS. Objective. To study the predictors of the development of depressive syndrome and to develop a mathematical model for predicting comorbid depression in patients with multiple sclerosis living in the northern region. Material and methods. A standard neurological examination was conducted in 149 patients with reliable MS who lived in the northern region, including an assessment of the severity of MS disability on the EDSS scale. All patients underwent neuroimaging (magnetic resonance imaging — MRI) of the brain and spinal cord. The Beck Depression Scale was used to identify depressive disorders. Results. The prevalence of depressive disorders in patients with MS in the studied population of patients in the northern region was 35%. In terms of severity, the identified comorbid depression ranged from subdepression to moderate depression. According to the results of the study, it can be stated that the predictors of the development of comorbid depressive disorders in MS are signs of brain atrophy; chronic intoxication (tobacco smoking and alcohol abuse); foci of demyelination (the semi-oval center, corpus callosum); neurological symptoms in the form of paresis, paralysis, cerebellar symptoms (nystagmus); presence of frontal dysfunction (phonetic associations, selection reactions simple and complicated). Conclusion. Comorbid depressive manifestations in MS patients living in the northern region occur in 35% of patients and are a multidisciplinary problem. In order to reduce the effect of depressive manifestations on the main symptoms of the disease, adherence to therapy and improve the quality of life indicators in patients with MS, it is necessary to influence neurological symptoms and psychological state, paying special attention to the prevention of depression in these patients.

Alcohol and IL-6 Alter Expression of Synaptic Proteins in Cerebellum of Transgenic Mice with Increased Astrocyte Expression of IL-6

Recent studies indicate that neuroimmune factors, including the cytokine interleukin-6 (IL-6), play a role in the CNS actions of alcohol. The cerebellum is a sensitive target of alcohol, but few studies have examined a potential role for neuroimmune factors in the actions of alcohol on this brain region. A number of studies have shown that synaptic transmission, and in particular inhibitory synaptic transmission, is an important cerebellar target of alcohol. IL-6 also alters synaptic transmission, although it is unknown if IL-6 targets are also targets of alcohol. This is an important issue because alcohol induces glial production of IL-6, which could then covertly influence the actions of alcohol. The persistent cerebellar effects of both IL-6 and alcohol typically involve chronic exposure and, presumably, altered gene and protein expression. Thus, in the current studies we tested the possibility that proteins involved in inhibitory and excitatory synaptic transmission in the cerebellum are common targets of alcohol and IL-6. We used transgenic mice that express elevated levels of astrocyte produced IL-6 to model persistently elevated expression of IL-6, as would occur in alcohol use disorders, and a chronic intermittent alcohol exposure/withdrawal paradigm (CIE/withdrawal) that is known to produce alcohol dependence. Multiple cerebellar synaptic proteins were assessed by Western blot. Results show that IL-6 and CIE/withdrawal have both unique and common actions that affect synaptic protein expression. These common targets could provide sites for IL-6/alcohol exposure/withdrawal interactions and play an important role in cerebellar symptoms of alcohol use such as ataxia.

Factors Associated with Prescribing Oral Disease Modifying Agents in Multiple Sclerosis: a Real-world Analysis of Electronic Medical Records

BackgroundLittle is known about the factors associated with the selection of Disease Modifying Agents (DMA) for the management of Multiple Sclerosis (MS) since the introduction of oral DMAs in 2010. ObjectivesTo examine the factors associated with initiation of oral DMAs in patients with MS using data from electronic medical records (EMR). MethodsA retrospective longitudinal study was conducted using TriNetX, a federated EMR network of over 38 million patients from the US, from 2009–2019. Adult (≥18 years) patients with MS from the United States were identified using a MS diagnosis (ICD-9-CM: 340 or ICD-10-CM: G35) and a newly prescribed DMA with a one-year baseline period. Patients with new DMA prescriptions were classified as oral or injectable users based on their index medication. A multivariable logistic regression model was used to determine the predisposing (age category, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, symptomatic medication, and healthcare utilization) associated with initiation of an oral versus injectable DMA. ResultsThe study cohort consisted of 7,511 MS patients with a newly prescribed DMA, of whom most were 18-44 years old (48.33%), female (75.18%), and white (80.92%). About 42.32% of MS patients were diagnosed with at least one comorbidity (mean±SD: 0.86±1.37). Two thirds (66.32%) of the patients with MS started injectable DMAs, and the remaining one third (33.68%) started oral DMAs. Multivariable regression revealed that middle-aged (45–64 years; Adjusted Odds Ratio [aOR]=0.88; 95% Confidence Interval [CI]: 0.79–0.98) and older adults (≥65 years; aOR=0.67, 95% CI: 0.53–0.84) were associated with a decreased likelihood of receiving oral DMAs. The presence of general symptoms (aOR=1.26, 95% CI: 1.10-1.45) and cerebellar symptoms (aOR=1.56, 95% CI: 1.26-1.93) was associated with an increased likelihood of an oral DMA. However, the presence of sensory symptoms (aOR: 0.72, 95% CI: 0.59-0.88) was associated with a decreased likelihood of an oral DMA. Comorbidities such as renal failure (aOR=0.16, 95%% 0.04-0.62), obesity (aOR=0.60, 95% CI: 0.45-0.80), drug abuse (aOR=0.61, 95% CI: 0.38-0.99), and other neurological disorders (aOR=0.82, 95% CI: 0.69-0.96) were associated with a decreased likelihood of receiving an oral DMA prescription. While the use of analgesics (aOR=0.78, 95% CI: 0.69-0.88) was associated with decreased likelihood, the use of antispasmodics (aOR=1.14, 95% CI: 1.01-1.28) was associated with an increased likelihood of receiving an oral DMA. Relative to the time-period when first oral DMAs entered into the market (2010-11), with time, the likelihood of prescribing oral DMA increased by multiple folds (2012-13, aOR=4.30, 95% CI: 3.08-6.00; 2014-15, aOR=19.34, 95% CI: 14.10-26.54; 2016-17, aOR=17.63, 95% CI: 12.76-24.35; and 2018-19, aOR=20.73, 95% CI: 14.64-29.37). ConclusionsOral DMA use steadily increased over the years, with one in three MS patients receiving oral agents. Both demographic and clinical factors were associated with the initiation of oral DMA over injectable DMA.

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear. Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms. Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores. Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p < 0.001) and EDSS (β = 0.16, p < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89, p = 0.01) and EDSS (β = −0.06, p < 0.001). Neither presentation was associated with changes in relapse risk. Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes, APP and PSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia

Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelic SPG7 mutations are known to cause recessively inherited HSP, heterozygous SPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare SPG7 variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targeted SPG7 sequencing was done in a cohort of 214 European ALS patients. The consequences of a splice site variant were analyzed on the mRNA level. The resulting protein alterations were visualized in a crystal structure model. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization. In 9 of 214 (4.2%) ALS cases, we identified five different rare heterozygous SPG7 variants, all of which were previously reported in patients with HSP or ALS. All detected SPG7 variants affect the AAA+ domain of the encoded mitochondrial metalloprotease paraplegin and impair its stability or function according to predictions from mRNA analysis or crystal structure modeling. ALS patients with SPG7 mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those without SPG7 mutations, and showed a partial clinical overlap with HSP. Brain MRI findings in SPG7 mutation carriers included cerebellar atrophy and patterns suggestive of frontotemporal dementia. Collectively, our findings suggest that SPG7 acts as a genetic risk factor for ALS. ALS patients carrying SPG7 mutations present with distinct features overlapping with HSP, particularly regarding cerebellar findings.

Is Asian type MS an MS phenotype, an NMO spectrum disorder, or a MOG-IgG related disease?

BackgroundA specific particularity of neurological diseases in Asia is the relative commonality of neuromyelitis optica (NMO) and Asian type MS (OSMS). Both conditions also occur in South American patients. The Brazilian population differs from the European and the Asian populations due to the mixture of ancestralities between European colonizers and African slaves. To better know the clinical characteristics of Brazilian patients with Asian type MS this study aimed to analyze the clinical, radiological and serological data that would help to distinguish between OSMS and NMO and clarify, in a Non-Asian population, if OSMS is an MS phenotype, an NMO spectrum disorder by 2015 classification, or a complement activating antibody to myelin oligodendrocyte glycoprotein (MOG-IgG) antibody-related disease. MethodsWe selected cases retrospectively with NMO and OSMS in the medical registry of patients with idiopathic inflammatory demyelinating diseases under follow-up since 1997 in Federal Hospital da Lagoa, the principal reference center for MS treatment in Rio de Janeiro, Brazil. OSMS has selective involvement of the optic nerve and spinal cord with no cerebral or cerebellar symptoms associated with small spinal cord lesions and negativity for the aquaporin-4 antibody (AQP4-IgG). NMO full-filled the revised criteria (2006) associated with longitudinally extensive transverse myelitis (LETM). We recorded the following data: ethnicity/skin color, neurologic impairment “at nadir” and “at recovery” of the index events (optic neuritis and transverse myelitis), long term disability, mortality, health quality of life scores by the SF-36 questionnaire, CSF IgG oligoclonal bands and serological AQP4-IgG and MOG-IgG antibodies tested by Cell-based assay. The last brain MRIs were classified as either satisfying or not satisfying MAGNIMS radiologic criteria for MS or typical or not typical for NMOSD. The new classification of NMO spectrum disorders (2015) was applied. ResultsForty-one OSMS and 122 NMO cases were analyzed. OSMS affected mainly young white women, causing unilateral optic neuritis and partial myelitis with excellent recovery. After a mean disease duration of 20 years, 90% of the patients had free ambulation, and 70% had a mild disability or no disability. Only 7.2% presented a secondary progressive course, and no deaths occurred. All cases had negativity to AQP4-IgG and MOG-IgG biomarkers. 95% had resonance criteria for MS. OSMS differed from NMO by ethnicity, morbidity, and mortality: most were African descendants, with severe motor and visual dysfunction, and one third died. Only NMO cases full-filled the new NMOSD classification (52 AQP4-IgG positive, 29 AQP4-IgG negative, and 41 AQP4-IgG unknown). ConclusionIn Brazilian patients, OSMS and NMO are different immune-mediated diseases. OSMS is a milder MS phenotype.

Cerebellar Cognitive Affective Syndrome in Children With Acute Postinfectious Cerebellar Ataxia

BackgroundAcute postinfectious cerebellar ataxia is the most common cause of acute ataxia in childhood. One previous case study has suggested that cerebellar cognitive affective syndrome may be comorbid with acute postinfectious cerebellar ataxia, but this was not confirmed by formal assessments. MethodsChildren aged three to 15 years with a confirmed diagnosis of acute postinfectious cerebellar ataxia were invited to participate. Three patients were included and assessed by a pediatrician, neuropsychologist, and logopedist at the subacute stage (less than 14 days post-onset) and after six months and one year of follow-up. ResultsAll three children complied with the diagnostic criteria of cerebellar cognitive affective syndrome. The cognitive and affective symptoms persisted longer than the motor symptoms. Child A (girl, aged three years and eight months) was most severely affected with slow progression of motor cerebellar symptom; the cerebellar cognitive affective symptoms had not entirely remitted at one-year follow-up. Child B (boy, aged four years and four months) had more subtle motor cerebellar symptoms that swiftly remitted within the first week; the cerebellar cognitive affective symptoms were also more subtle. Child C (boy, aged seven years and eleven months) was considerably affected by motor cerebellar symptoms but showed marked improvement within the first month; the cerebellar cognitive affective symptoms had not entirely remitted at one-year follow-up. ConclusionCognitive affective cerebellar syndrome may be an overlooked complication of acute postinfectious cerebellar ataxia. The severity of cerebellar cognitive affective symptoms seemed to correspond to the severity of the cerebellar motor symptoms, but the improvement was remarkably slower.

Clinical features of central nervous system demyelinating diseases with myelin-oligodendrocyte glycoprotein antibody positive in children

Objective To investigate the clinical features and treatment effect of children with central nervous system demyelinating diseases and seropositivity to myelin-oligodendrocyte glycoprotein (MOG) antibody. Methods The clinical characteristics of 28 had seropositivity to MOG among 115 children with central nervous system demyelinating diseases and who were hospitalized at Department of Neurology, Children′s Hospital of Zhejiang University School of Medicine from March 2017 to February 2019 were retrospectively analyzed. Results Twenty-eight patients were included in this study, including 10 males and 18 females, with the ratio of male/female of 1.00∶1.80, and the median age of 7 years and 9 months.The clinical manifestations were diverse, including encephalopathy symptoms such as hea-dache, vomiting, and drowsiness (13/28 cases), vision loss (7/28 cases), spinal symptoms (6/28 cases), cerebellar symptoms such as ataxia, slurred speech (4/28 cases), convulsions (2/28 cases), and cranial nerve symptoms (1/28 cases). Among 24 cases who underwent CSF detection, 10 patients (41.7%) had slightly increased white blood cells, 2 patients (8.3%) had elevated protein, 6 patients (25.0%) had positive MOG antibody, and CSF-restricted oligoclonal band was negative in all 24 patients.Twenty-five cases (89.3%) showed brain magnetic resonance imaging (MRI) abnormalities, including cerebral white matter (20/28 cases), cerebellum (10/28 cases), cerebral gray matter (9/28 cases), thalamus/basal ganglia (6/28 cases), brainstem (6/28 cases), optic nerve (5/28 cases), and corpus callosum (4/28 cases). Of the 28 cases, 13 patients had spinal cord involvement, involving cervical spinal cord in 10 cases, thoracic cord in 9 cases and lumbar spinal cord in 5 cases; besides, 8 cases of them had long segmental spinal cord lesions with ≥ 3 segments.Fourteen patients received the visual evoked potentials′ examination, and the subclinical visual impairment was found in 2 of them with unobstructed clinical performance.All patients underwent high-dose Methylprednisolone therapy.The clinical symptoms of 16 patients who were treated with Gamma globulin were relieved in the acute phase.Seven patients had recurrence during the follow-up period, with the recurrence rate of 25.0%.Relapsed patients re-treated with high-dose Methylprednisolone therapy combined with Gamma globulin, clinical symptoms could be alleviated. Conclusion The main clinical phenotype of children with central nervous system demyelinating diseases and seropositivity to MOG is acute disseminated encephalomyelitis.The spinal cord lesions are mainly involving cervical and thoracic segments.The current treatments of this disease include glucocorticoid and Gamma globulin, which have significant effect, but the disease is easy to relapse.The re-use of glucocorticoid and Gamma globulin after relapse is still effective. Key words: Myelin-oligodendrocyte glycoprotein antibody; Child; Central nervous system demyelinating disease

Global Knockdown of Retinoid-related Orphan Receptor α in Mature Purkinje Cells Reveals Aberrant Cerebellar Phenotypes of Spinocerebellar Ataxia

Retinoid-related orphan receptor α (RORα) is a transcription factor expressed in a variety of tissues throughout the body. Knockout of RORα leads to various impairments, including defects in cerebellar development, circadian rhythm, lipid metabolism, immune function, and bone development. Previous studies have shown significant reduction of RORα expression in Purkinje cells (PCs) of spinocerebellar ataxia (SCA) type 1 and type 3/MJD (Machado–Joseph disease) model mice. However, it remains unclear to what extent the RORα reduction in PCs is involved in the disease pathology. Here, RORα expression was downregulated specifically in mature mouse PCs by intravenous infusion of blood–brain barrier-permeable adeno-associated virus (AAV), expressing a microRNA against RORα (miR-RORα) under the control of the PC-specific L7-6 promoter. The systemic AAV infusion led to extensive transduction of PCs. The RORα knock-down caused degeneration of PCs including disruption of the PC monolayer alignment and dendrite atrophy. In behavioral experiments, mice expressing miR-RORα showed motor learning deficits, and later, overt cerebellar ataxia. Thus, RORα in mature PCs plays pivotal roles in maintenance of PC dendrites and the monolayer alignment, and consequently, motor learning and motor function. Decrease in RORα expression in PCs could be a primary etiology of the cerebellar symptoms in patients with SCA1 and SCA3/MJD.

Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature

The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.

Allan-Herndon-Dudley-Syndrome: Considerations about the Brain Phenotype with Implications for Treatment Strategies.

Despite its first description more than 75 years ago, effective treatment for "Allan-Herndon-Dudley-Syndrome (AHDS)", an X-linked thyroid hormone transporter defect, is unavailable. Mutations in the SLC16A2 gene have been discovered to be causative for AHDS in 2004, but a comprehensive understanding of the function of the encoded protein, monocarboxylate transporter 8 (MCT8), is incomplete. Patients with AHDS suffer from neurodevelopmental delay, as well as extrapyramidal (dystonia, chorea, athetosis), pyramidal (spasticity), and cerebellar symptoms (ataxia). This suggests an affection of the pyramidal tracts, basal ganglia, and cerebellum, most likely already during fetal brain development. The function of other brain areas relevant for mood, behavior, and vigilance seems to be intact. An optimal treatment strategy should thus aim to deliver T3 to these relevant structures at the correct time points during development. A potential therapeutic strategy meeting these needs might be the delivery of T3 via a "Trojan horse mechanism" by which T3 is delivered into target cells by a thyroid hormone transporter independent T3 internalization.

Severe Cerebellar Syndrome Linked With Durvalumab

Durvalumab is a monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with programmed cell death 1 (PD-1) molecules. It has shown significant survival benefits in various cancers as an immune checkpoint inhibitor. With increased usage of this therapy, there are several cases with a predilection for neurological immune-related adverse effects from checkpoint inhibitor neurotoxicity. We identified an index patient with lung cancer treated with durvalumab, who developed disabling ocular and bulbar symptoms and severe truncal ataxia, and found symptomatic benefit with plasmapheresis (PLEX). A 57-year-old African American woman presented with 3 months of oscillopsia, dizziness, scanning speech, and inability to stand and walk due to severe truncal ataxia. She was found to have stage IIIA lung adenocarcinoma. Brain magnetic resonance imaging (MRI) demonstrated abnormal T2-fluid-attenuated inversion recovery sequence (T2/FLAIR) signal in bilateral cerebellar hemispheres with lack of enhancement suggestive of paraneoplastic cerebellar involvement. No distinct paraneoplastic antibody was identified. She received combined pulse-dose steroids and intravenous immunoglobulin (IVIg) with no improvement of cerebellar syndrome. A month later, she started inpatient chemotherapy and concurrent radiation therapy with transient cancer regression. Because of subsequent metastatic spread, durvalumab was initiated. She completed four doses that were complicated by worsening cerebellar symptoms and autoimmune colitis. During durvalumab holiday, she received two courses of five PLEX treatments, 2 months apart, along with vigorous physical and speech therapy. Her neurologic symptoms and functional status improved considerably and continued to improve after treatment. At present time, the patient is largely independent for activities of daily living (ADLs) and uses a walker. Repeated brain MRI revealed resolution of previously seen abnormalities. Checkpoint inhibitors may worsen concomitant paraneoplastic neurologic syndromes that develop in association with malignancies potentially responsive to PD-L1 and PD-1 inhibitors. Meticulous coordination and timing of life-saving immune therapies for cancer with effective immune treatments for an underlying or associated neurological syndrome are essential for best outcomes. J Neurol Res. 2020;10(2):44-47 doi: https://doi.org/10.14740/jnr571

The Pathophysiology and Clinical Manifestations of Spinocerebellar Ataxia Type 6.

Spinocerebellar ataxias (SCA) constitute of a group of degenerative and progressive disorders that can be identified on a molecular and cellular basis. Along with histological changes, the clinical presentation of SCA differs between subtypes. In addition to basic cerebellar dysfunction symptoms, patients with SCA develop gait ataxia, dysphagia, dysarthria, oculomotor disturbances, pyramidal and extrapyramidal disease signs, rigidity, bradycardia, sensory deficits, and mild cognitive and executive function decline. MRI scans have confirmed reduction in mass of frontal, temporal, and parietal portions of the brain along with the cerebellar peduncles, brainstem, and cranial nerve III. Clinically, these damages manifest as decline in cognition and problems with speech, contemplation, and vision. This review article compares the most prevalent subtypes of SCA based on genetic background, pathogenesis, neurological manifestations, other presenting symptoms, and diagnostic workup. Further goals of research in this field should be directed towards a cure for SCA, which currently does not exist.

Natural History of Adult Patients with GM2 Gangliosidosis.

GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. We retrospectively described 12 patients from a French cohort and 45 patients from the literature. We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.

Abstract TP221: Cerebellar Infarction Presentations: A Population-Based Study From the Greater Cincinnati/Northern Kentucky Stroke Study

Background: Cerebellar lesions reportedly account for 2-7% of acute infarct visits, but this may be an underestimate since prior studies were not population-based or from the modern imaging era. Cerebellar symptoms are also often nonspecific such that increased MRI use might lead to a higher proportion of stroke due to cerebellar lesions. Details about presenting features of cerebellar infarcts and baseline medication use are also not well known. Methods: We used the 2010 Greater Cincinnati/Northern Kentucky Stroke Study. Strokes were identified by screening ICD9 codes 430-436 and physician verification. Infarct location was categorized as isolated cerebellar, mixed cerebellar (cerebellar plus ≥1 other location), or non-cerebellar. Isolated dizziness was defined as dizziness/vertigo without other focal symptoms. Atherosclerotic cardiovascular disease (ASCVD) 10-year risk scores were calculated. Descriptive statistics and multivariable logistic regression were used to compare infarct categories. Results: Isolated cerebellar lesions occurred in 4.6% (90/1940; 95% CI, 3.7%-5.7%) of infarct events. An additional 4% (77/1940; 95%CI, 3.1%-4.9%) were mixed cerebellar infarcts. Mixed cerebellar infarcts had clinical characteristics more similar to non-cerebellar events than to cerebellar events. The multivariable model found an association of isolated cerebellar infarct with low NIHSS (odds ratio [OR] 2.3, 95% CI 1.1-4.8) and any dizziness/vertigo (OR 5.1, 95% CI, 2.4-10.6), but not with isolated dizziness/vertigo, age, or sex. Median ASCVD scores were high in all infarct categories (21, interquartile range [IQR] 9-35 for isolated cerebellar; 32, IQR 15-42 for mixed cerebellar; 31, IQR 16-52 for all others). Both cerebellar and non-cerebellar strokes had a high frequency of baseline antiplatelet or anticoagulant use (52.1% vs 56.2%), whereas baseline statin therapy was less common in isolated cerebellar infarcts (34.1% vs 43.8%). Conclusions: This population-based study during the modern imaging era found that about 5% of stroke cases have isolated cerebellar infarcts and nearly 9% have any cerebellar infarct. Both cerebellar and non-cerebellar presentations have high baseline vascular risk and antiplatelet/anticoagulant use.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Clinical significance of Kelch-like protein 11 antibodies.

ObjectiveTo report the clinical and oncologic associations of antibodies against Kelch-like protein 11 (KLHL11-ab), recently suggested as biomarkers of a paraneoplastic brainstem cerebellar syndrome associated with testicular seminoma, and to determine the value of immunohistochemistry as a screening technique.MethodsStudies included 432 sera or CSF from 329 patients with paraneoplastic (157) or autoimmune neurologic syndromes (172); 63 with neurologic symptoms and benign teratomas; 28 with small-cell lung cancer, and 12 healthy subjects. KLHL11-abs were examined using a cell-based assay (CBA) with HEK293 cells transfected with a human KLHL11 clone. The CBA specificity was confirmed by immunoprecipitation. All positive samples were examined by immunohistochemistry on rat brain sections.ResultsKLHL11-abs were detected in 32 patients by CBA, and patients' antibodies immunoprecipitated KLHL11. Using rat brain immunohistochemistry, only 7 samples (22%) were positive. Patients' median age was 28 years (range 9–76 years), and 16 (50%) were women. Tumors were identified in 23/32 (72%) patients, including 14 teratomas and 7 seminomas or mixed germ cell tumors. Thirteen (41%) patients had cerebellar ataxia (7) or encephalitis with brainstem cerebellar symptoms (6), 7 (22%) anti-NMDA receptor (NMDAR) encephalitis (5 with ovarian teratoma), 5 (16%) opsoclonus-myoclonus, 3 (9%) limbic encephalitis, and 4 (12%) diverse neurologic symptoms (3 with benign teratomas). Concurrent autoantibodies occurred in 14 (44%) patients (7 anti-NMDAR, 6 Ma2, and 1 Hu).ConclusionsKLHL11-abs associate with a spectrum of syndromes and tumors wider than those previously reported; 44% of patients have concurrent neuronal antibodies, some of them (anti-NMDAR) pathogenically relevant. Brain immunostaining is not useful for routine screening of KLHL11-abs.

Hypomagnesaemia induced recurrent cerebellar ataxia: an interesting case with successful management

PurposeSevere Hypomagnesaemia is a rare biochemical findings utilized for identifying the etiology of cerebellar ataxia. It requires a high degree of suspicion to diagnose. MRI findings are often nonspecific.MethodsThe author presents a case of 38 yrs. old male patient presented with vomiting, gait imabalance and nystagmus. Biochemical investigations lead to severe hypomagnesaemia. Also MRI findings were matched suggesting of hyperintesity in left cerebellar hemisphere.ResultsPatient was treated with magnesium infusion which leads to recovery of patient. Again the same symptomology was repeated after 3 months and disappearance after same treatment. Offending cause was diagnosed and proton pump inhibitors stopped.ConclusionSevere Hypomagnesaemia is a rare but treatable cause if diagnosed at right time. It requires a high degree of suspicion to diagnose it. Measurement of serum magnesium levels should always be kept in back of mind if definite management of cerebellar symptoms has to be done.

Wernekink commissure syndrome secondary to a rare ‘V’-shaped pure midbrain infarction: a case report and review of the literature

Purpose: Wernekink commissure syndrome is a typical but extremely rare mesencephalic syndrome, and generally presents with bilateral cerebellar dysfunction, diverse oculomotor disorders and occasionally delayed-onset palatal myoclonus or tremor. However, it has been reported infrequently.Methods: We report a case of a 55-year-old man who suffered an acute paramedian midbrain infarction presenting with bilateral cerebellar ataxia, bilateral anterior internuclear ophthalmoplegia and unilateral pseudoabducens palsy, which is confirmed as Wernekink commissure syndrome by magnetic resonance imaging (MRI). We summarized the clinical data of this entity and performed a literature review of 20 previous reports of patients with this syndrome.Results: In combination with previous reports, we found that the most common symptom was bilateral cerebellar ataxia (100%) and other frequent symptoms were oculomotor disorders (81%), delayed palatal myoclonus or tremor (33%) and consciousness dysfunction (33%). Lesions on brain MRI of all patients affected the area of caudal paramedian midbrain (CPM).Conclusion: Bilateral cerebellar ataxia and lesions involved in the area of CPM on MRI are the major features of Wernekink commissure syndrome and should be the necessary conditions of diagnostic criteria. The simultaneous occurrence of bilateral cerebellar ataxia and oculomotor disorders is significant for localization diagnosis. Consciousness dysfunction is also a relatively frequent symptom of this syndrome. Moreover, pseudoabducens palsy might be attributed to a midbrain lesion. Clinicians should be familiar with and early to recognize this unique syndrome to avoid misdiagnosis.