Autoimmune Cerebellar Ataxia Associated with Anti-Glutamate Receptor δ2 Antibodies: a Rare but Treatable Entity.

We report two novel cases of autoimmune cerebellar ataxia (ACA) associated with anti-glutamate receptor δ2 antibodies (Gluδ2-Abs). The first case was confirmed by indirect immunofluorescence and cell-based assays: a 29-year-old woman presented after 5 days of headache and vomiting, a pancerebellar syndrome, downbeat nystagmus, decreased visual acuity linked to bilateral retrobulbar optic neuritis (RON), and lymphocytic pleocytosis in the cerebrospinal fluid (CSF) without any abnormality detected using cerebral magnetic resonance imaging (MRI). Second-line immunotherapy allowed progressive clinical improvement, with full recovery achieved after a 4-year follow-up. Thereafter, we retrospectively tested Gluδ2-Abs in 350 patients with a suspicion of autoimmune encephalitis without characterized autoantibody. We identified a second case, a 12-year-old boy who developed 10 days after a respiratory infection, a static cerebellar syndrome with lymphocytosis in the CSF, and right cerebellum hyperintensity in MRI. Five days of corticosteroid treatment allowed a quick clinical improvement. No tumor was identified in both cases, whereas laboratory analyses revealed autoimmune stigma. The present cases suggested that ACA associated with Gluδ2-Abs is an extremely rare but treatable disease. Therefore, testing for Gluδ2-Abs might be considered in the setting of suspected ACA and no initial antibody identification. The visual deficits and ocular motility abnormalities observed in the first reported case might be part of the clinical spectrum of Gluδ2-Abs ACA. Young age, infectious prodromes, lymphocytic pleocytosis, and autoimmune background usually appear together with this syndrome and should lead to discuss the initiation of immunotherapy (after ruling out differential diagnosis, especially infectious causes).

Comparison of tandospirone and escitalopram as a symptomatic treatment in Multiple System Atrophy-cerebellar ataxia: An open-label, non-controlled, 4 weeks observational study.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and motor dysfunction in parkinsonism and/or cerebellar ataxia. Patients with MSA usually present with depression and anxiety symptoms. This observational study of patients with MSA-cerebellar subtype (MSA-C) with subthreshold depression/anxiety symptoms aimed to compare the efficacy of escitalopram oxalate (an antidepressant drug) and tandospirone citrate (an anxiolytic drug). METHODS: Fifty-six MSA-C patients were included, with 28 patients in each treatment group. One group received escitalopram oxalate 10 mg/day and the other group received tandospirone citrate 30 mg/day. The patients were evaluated at baseline and after 4 weeks. Several psychiatric and neurological tests were performed, including the Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Scale for the Assessment and Rating of Ataxia (SARA), and the Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT). Furthermore, post-void residual urine volume (PVR) and blood pressure were measured. RESULTS: There was a more substantial reduction in the HAMA/HAMD, scores of stance, finger tracking, and finger nose test in the SARA, and PVR in the tandospirone group. There was a more substantial reduction in scores of dysuria, light-headed when standing up, syncope and hyperhidrosis in the SCOPA-AUT in the escitalopram group (p's < 0.05). CONCLUSIONS: Tandospirone citrate was more effective in improving depression/anxiety and some cerebellar ataxia symptoms, whereas escitalopram was more effective in improving some autonomic symptoms in MSA-C patients over a short-term period in an open-label observational study without a control group. Further research is needed to evaluate the long-term effects of tandospirone and escitalopram in MSA-C in long-term placebo controlled trials.

Advances in cerebellar disorders: pre-clinical models, therapeutic targets, and challenges.

INTRODUCTION: Cerebellar ataxias (CAs) represent neurological disorders with multiple etiologies and a high phenotypic variability. Despite progress in the understanding of pathogenesis, few therapies are available so far. Closing the loop between preclinical studies and therapeutic trials is important, given the impact of CAs upon patients' health and the roles of the cerebellum in multiple domains. Because of a rapid advance in research on CAs, it is necessary to summarize the main findings and discuss future directions. AREAS COVERED: We focus our discussion on preclinical models, cerebellar reserve, the therapeutic management of CAs, and suitable surrogate markers. We searched Web of Science and PubMed using keywords relevant to cerebellar diseases, therapy, and preclinical models. EXPERT OPINION: There are many symptomatic and/or disease-modifying therapeutic approaches under investigation. For therapy development, preclinical studies, standardization of disease evaluation, safety assessment, and demonstration of clinical improvements are essential. Stage of the disease and the level of the cerebellar reserve determine the goals of the therapy. Deficits in multiple categories and heterogeneity of CAs may require disease-, stage-, and symptom-specific therapies. More research is needed to clarify how therapies targeting the cerebellum influence both basal ganglia and the cerebral cortex, poorly explored domains in CAs.

Hericium erinaceus Promotes Anti-Inflammatory Effects and Regulation of Metabolites in an Animal Model of Cerebellar Ataxia.

Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although previous study demonstrated the neuroprotective effects of Hericium erinaceus (H.E.), the mechanisms of H.E. treatment on the neuroinflammatory response, neurotransmission, and related metabolites remain largely unknown. We demonstrated that 3-AP rats treated with 25 mg/kg H.E. extracts had improved motor coordination and balance in the accelerated rotarod and rod tests. We showed that the H.E. treatment upregulated the expression of Tgfb1, Tgfb2, and Smad3 genes to levels comparable to those in the non-3-AP control group. Interestingly, we also observed a significant correlation between Tgfb2 gene expression and rod test performance in the 3-AP saline group, but not in the non-3-AP control or H.E.+3-AP groups, indicating a relationship between Tgfb2 gene expression and motor balance in the 3-AP rat model. Additionally, we also found that the H.E. treatment increased mitochondrial COX-IV protein expression and normalized dopamine-serotonin neurotransmission and metabolite levels in the cerebellum of the H.E.+3-AP group compared to the 3-AP saline group. In conclusion, our findings suggest that the H.E. treatment improved motor function in the 3-AP rat model, which was potentially mediated through neuroprotective mechanisms involving TGFB2-Smad3 signaling via normalization of neurotransmission and metabolic pathways.

Cerebellar ataxia with anti-mGluR1 auto-antibody in a pediatric patient: A case report.

Cerebellar ataxia (CA) related to anti-metabolic glutamate receptor 1 (mGluR1) is a rare autoimmune encephalitis, which is manifested as acute or subacute CA in most cases.To the best of our knowledge, only three cases of pediatric patients have been reported in the literature so far. This article reports the 4th case of mGluR1 related CA in a pediatric patient.

Mitochondrial dysfunction and calcium dysregulation in COQ8A-ataxia Purkinje neurons are rescued by CoQ10 treatment.

COQ8A-ataxia is a rare form of neurodegenerative disorder due to mutations in the COQ8A gene. The encoded mitochondrial protein is involved in the regulation of coenzyme Q10 biosynthesis. Previous studies on the constitutive Coq8a-/- mice indicated specific alterations of cerebellar Purkinje neurons involving altered electrophysiological function and dark cell degeneration. In the present manuscript, we extend our understanding of the contribution of Purkinje neuron dysfunction to the pathology. By generating a Purkinje-specific conditional COQ8A knockout, we demonstrate that loss of COQ8A in Purkinje neurons is the main cause of cerebellar ataxia. Furthermore, through in vivo and in vitro approaches, we show that COQ8A-depleted Purkinje neurons have abnormal dendritic arborizations, altered mitochondria function and intracellular calcium dysregulation. Furthermore, we demonstrate that oxidative phosphorylation, in particular Complex IV, is primarily altered at presymptomatic stages of the disease. Finally, the morphology of primary Purkinje neurons as well as the mitochondrial dysfunction and calcium dysregulation could be rescued by CoQ10 treatment, suggesting that CoQ10 could be a beneficial treatment for COQ8A-ataxia.

Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.

BACKGROUND: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. METHODS: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. RESULTS: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. CONCLUSIONS: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.

CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options.

In the last decade, variants in the Ca2+ channel gene CACNA1A emerged as a frequent aetiology of rare neurological phenotypes sharing a common denominator of variable paroxysmal manifestations and chronic cerebellar dysfunction. The spectrum of paroxysmal manifestations encompasses migraine with hemiplegic aura, episodic ataxia, epilepsy and paroxysmal non-epileptic movement disorders. Additional chronic neurological symptoms range from severe developmental phenotypes in early-onset cases to neurobehavioural disorders and chronic cerebellar ataxia in older children and adults.In the present review we systematically approach the clinical manifestations of CACNA1A variants, delineate genotype-phenotype correlations and elaborate on the emerging concept of an age-dependent phenotypic spectrum in CACNA1A disease. We furthermore reflect on different therapy options available for paroxysmal symptoms in CACNA1A and address open issues to prioritize in the future clinical research.

Immunotherapies for the Effective Treatment of Primary Autoimmune Cerebellar Ataxia: a Case Series.

Primary autoimmune cerebellar ataxia (PACA) is an idiopathic sporadic cerebellar ataxia that is thought to be immune-mediated but lacks biomarkers or a known cause. Here, we report two cases of immune-mediated cerebellar ataxia that responded favorably to immunotherapy, in which tissue-based indirect immunofluorescence test for serum or cerebrospinal fluid (CSF) samples yielded positive results. Case 1 was a 78-year-old man who presented with subacute progressive gait ataxia with truncal instability and dysarthria in response to steroids. Case 2 was a 62-year-old man who presented with relapses and remissions of acute progressive cerebellar ataxia occurring 1-2 times per year. Despite a favorable response to steroid treatment, he relapsed repeatedly in the absence of long-term immunosuppression. In the case of "idiopathic" cerebellar ataxia, immune-mediated causes should be investigated, and immunotherapy may have therapeutic effects.

The Effects of N-Acetyl-L-Leucine on the Improvement of Symptoms in a Patient with Multiple Sulfatase Deficiency.

Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disease with specific clinical findings such as psychomotor retardation and neurological deterioration. No therapy is available for this genetic disorder. Previous studies have shown that N-acetyl-L-leucine (NALL) can improve the neurological inflammation in the cerebellum.In the current study, the effects of NALL on ataxia symptoms and quality of life were explored in a patient with MSD.This study was a crossover case study. The subject, a girl aged 12 years old, received NALL at a dose of 3 g/day (1 g in the morning, 1 g in the afternoon, and 1 g in the evening). A fasting blood sample was taken from the subject to evaluate side effects before the intervention and 4 weeks after taking supplement/placebo in every study stage. The ataxia moving symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) score in every study stage. Dietary intake was measured using 24-h dietary recall before and after the intervention. The diet compositions were assessed by Nutritionist IV software. Serum IL-6 level was measured using an ELISA kit.There was no significant change in complete blood count (CBC) and serum biochemical factors in the patient with MSD after receiving NALL (3 g/day) over 4 weeks. The SARA score was reduced by 25%. The gait whose maximum score accounts for approximately one-fifth of the maximum total SARA score (8/40) was decreased. The heel-to-shin slide, the only SARA item performed without visual control, was also improved after therapy. Furthermore, there was a downward trend in the 8MWT (8.71 to 7.93 s). Regarding quality of life assessments, the parent and child reported improved quality of life index, physical health, and emotional function after taking NALL. Moreover, total energy intake was increased with NALL treatment through the study period.Supplementation with NALL at a dose of 3 g/day over 4 weeks was well tolerated and improved ataxia symptoms, quality of life measure, and serum IL-6 levels in the patient with MSD. Further proof-of-concept trials are warranted to confirm the present findings.

The Effect of N-Acetyl-DL-Leucine on Neurological Symptoms in a Patient with Ataxia-Telangiectasia: a Case Study.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder with no available curative treatment. Although the positive effects of N-acetyl-DL-leucine on cerebellar ataxia have been reported previously, there is little evidence of N-acetyl-DL-leucine's effects in patients with AT. This study assessed the effect of 16 weeks N-acetyl-DL-leucine supplementation on ataxia symptoms in a 9-year-old female with AT. The subject consumed 4 g/day N-acetyl-DL-leucine (2 g in the morning and 2 g in the evening) for 16 weeks. Safety was assessed via clinical blood chemistry prior to the intervention and after 6 and 16 weeks. Additionally, The Scale for the Assessment and Rating of Ataxia (SARA) score was used to assess the drug's effects on ataxia symptoms at baseline, 6, 12, and 16 weeks. Quality of life has also been evaluated by a specialist using the PedsQL questionnaire.Despite some initial (first week only) nausea and constipation, supplementation with N-acetyl-DL-leucine was well tolerated and safe according to blood chemistry measures. The SARA score progressively improved, and by week 16 had improved by 11.0 points (48.88%). Parent and self-reported quality of life assessments indicated physical, emotional, social, and school functions all improved by 16 weeks. Supplementation with N-acetyl-DL-leucine at a dose of 4 g/day for 16 weeks was well tolerated and significantly improved ataxia symptoms and quality of life measures in a young child with AT.

Melittin ameliorates motor function and prevents autophagy-induced cell death and astrogliosis in rat models of cerebellar ataxia induced by 3-acetylpyridine.

BACKGROUND: Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. This study aims to investigate the therapeutic effects of melittin (MEL) on a 3-acetylpyridine-induced (3-AP) cerebellar ataxia (CA) rat model. METHODS: Initially, CA rat models were generated by 3-AP administration followed by the subcutaneous injection of MEL. The open-field test was used for the evaluation of locomotion and anxiety. Immunohistochemistry was also conducted for the autophagy markers of LC3 and Beclin1. In the next step, the morphology of the astrocyte, the cell responsible for maintaining homeostasis in the CNS, was evaluated by the Sholl analysis. RESULTS: The findings suggested that the administration of MEL in a 3-AP model of ataxia improved locomotion and anxiety (P < 0.001), decreased the expression of LC3 (P < 0.01) and Beclin1 (P < 0.05), increased astrocyte complexity (P < 0.05) and reduced astrocyte cell soma size (P < 0.001). CONCLUSIONS: Overall, the findings imply that the MEL attenuates the 3-AP-induced autophagy, causes cell death and improves motor function. As such, it could be used as a therapeutic procedure for CA due to its neuroprotective effects.

Modulation of the CB1 cannabinoid receptor has potential therapeutic utility in the 3-acetylpyridine cerebellar ataxia rat model.

Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently, it has been suggested that cannabinoids play a role in modulating ataxic symptoms. To understand the possible therapeutic effect of cannabinoids for the management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) rat model of ataxia. The role of the CB1R was examined using three different doses of the CB1R agonist, WIN-55,212-2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some groups, the CB1R antagonist AM251 (1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms; it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be considered in future studies.

The cerebellar bioenergetic state predicts treatment response in COQ8A-related ataxia.

INTRODUCTION: Primary coenzyme Q10 (CoQ10) deficiency, a recessive disorder associated with various defects of CoQ10 biosynthesis and widely varying clinical presentation, is customarily managed by oral Q10 supplementation but the benefit is debated. METHODS: To address this question, we mapped individual responses in two patients with COQ8A-related ataxia following coenzyme Q10 supplementation using noninvasive imaging. Metabolic 31phosphorus magnetic resonance spectroscopy imaging (31P-MRSI) and volumetric cerebellar neuroimaging were performed to quantify the individual treatment response in two patients with COQ8A-related ataxia, each compared with eight age- and gender-matched healthy control subjects. RESULTS: Post-treatment change in energy metabolite levels differed in the two patients, with higher energy levels and improved dysarthria and leg coordination in one, and decreased energy levels without clinical benefit in the other. CONCLUSIONS: Our results suggest that the cerebellar bioenergetic state may predict treatment response in COQ8A-related ataxia and highlight the potential of pathophysiology-orientated neuroimaging evidence to inform treatment decisions.

Anti-GAD65 Antibody-Associated Autoimmune Encephalitis With Predominant Cerebellar Involvement Following Toripalimab Treatment: A Case Report of a Novel irAE of Toripalimab.

Toripalimab (Junshi Bioscience Co., Ltd) is a new immune checkpoint inhibitor (ICI) that targets programmed cell death protein 1 (PD-1) in various cancers, including metastatic melanoma. No neurological immune-related adverse events (n-irAEs) of toripalimab have been reported, except for neuromuscular involvement. We report a case of a 63-year-old woman who presented with severe vertigo, vomiting, nystagmus, cerebellar ataxia, and cognitive impairment after toripalimab treatment for metastatic melanoma. Compared with the concomitant cognitive dysfunction and a pathological reflex involving the cerebral cortex, the signs and symptoms of cerebellar involvement were much more prominent. Anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody was positive in both serum and cerebrospinal fluid (CSF). After intravenous immunoglobulin (IVIG) and methylprednisolone (IVMP) administration, the symptoms of vertigo and vomiting resolved, with cognitive impairment and cerebellar ataxia remaining. This is the first report of autoimmune encephalitis (AIE) as an n-irAE of toripalimab.

Discovery of Novel Activators of Large-Conductance Calcium-Activated Potassium Channels for the Treatment of Cerebellar Ataxia.

Impaired cerebellar Purkinje neuron firing resulting from reduced expression of large-conductance calcium-activated potassium (BK) channels is a consistent feature in models of inherited neurodegenerative spinocerebellar ataxia (SCA). Restoring BK channel expression improves motor function and delays cerebellar degeneration, indicating that BK channels are an attractive therapeutic target. Current BK channel activators lack specificity and potency and are therefore poor templates for future drug development. We implemented an automated patch clamp platform for high-throughput drug discovery of BK channel activators using the Nanion SyncroPatch 384PE system. We screened over 15,000 compounds for their ability to increase BK channel current amplitude under conditions of lower intracellular calcium that is present in disease. We identified several novel BK channel activators that were then retested on the SyncroPatch 384PE to generate concentration-response curves (CRCs). Compounds with favorable CRCs were subsequently tested for their ability to improve irregular cerebellar Purkinje neuron spiking, characteristic of BK channel dysfunction in SCA1 mice. We identified a novel BK channel activator, 4-chloro-N-(5-chloro-2-cyanophenyl)-3-(trifluoromethyl)benzene-1-sulfonamide (herein renamed BK-20), that exhibited a more potent half-maximal activation of BK current (pAC50 = 4.64) than NS-1619 (pAC50 = 3.7) at a free internal calcium concentration of 270 nM in a heterologous expression system and improved spiking regularity in SCA1 Purkinje neurons. BK-20 had no activity on small-conductance calcium-activated potassium (SK)1-3 channels but interestingly was a potent blocker of the T-type calcium channel, Cav3.1 (IC50 = 1.05 µM). Our work describes both a novel compound for further drug development in disorders with irregular Purkinje spiking and a unique platform for drug discovery in degenerative ataxias. SIGNIFICANCE STATEMENT: Motor impairment associated with altered Purkinje cell spiking due to dysregulation of large-conductance calcium-activated potassium (BK) channel expression and function is a shared feature of disease in many degenerative ataxias. BK channel activators represent an outstanding therapeutic agent for ataxia. We have developed a high-throughput platform to screen for BK channel activators and identified a novel compound that can serve as a template for future drug development for the treatment of these disabling disorders.

Phenytoin and damage to the cerebellum - a systematic review of published cases.

INTRODUCTION: The antiseizure medication phenytoin has been associated with changes in the cerebellum, cerebellar signs, and permanent cerebellar damage. We have systematically reviewed the clinical and radiological features, and their correlation. AREAS COVERED: We identified sixty case reports and case series of the effects of phenytoin on the cerebellum by searching Medline and Embase and relevant reference lists. The reports described 92 [median 1, range 1-5] cases, documented median age 28 [2.7-78] years. Eighty-one cases described one or more clinical sign of ataxia (present in 96%), dysarthria (63%), and nystagmus (70%). The neurological outcome (in 76 cases): 10 (13%) recovered by 12 months; 55 (72%) suffered residual disability; and 11 (14%) died. Median serum phenytoin concentration (48 cases) was 50 (interquartile range 31-66) mg/L; only three values were below 20 mg/L. The radiological findings included cerebellar atrophy in 41 of 61 patients (67%) with at least one scan. EXPERT OPINION: Evidence mainly comes from case reports, and is inevitably biased. Most patients with cerebellar dysfunction have phenytoin concentrations above the reference range. Clinical signs of ataxia can persist without radiological evidence of cerebellar atrophy, and cerebellar atrophy is seen without any clinical evidence of cerebellar dysfunction.

SEZ6L2 Antibody-Associated Cerebellar Ataxia Responsive to Sequential Immunotherapy.

OBJECTIVES: Seizure-related 6 homolog like 2 (SEZ6L2) antibody-associated ataxia is an extremely rare disease. Six patients have been reported and none of them improved significantly with immunotherapy. Herein, we present the case of a patient with cerebellar ataxia and SEZ6L2 antibodies who benefited from immunotherapy, which dramatically altered the course of her disease. METHODS: We present a case report of a 73-year-old woman with progressive balance problems. Her condition had rapidly deteriorated in the 2 weeks before the admission to our hospital leading to repeated falls and eventually left her bed-ridden. RESULTS: She presented with severe trunk ataxia, bidirectional nystagmus, dysarthric speech, and persistent nausea. With the exception of cerebellar atrophy, extensive imaging studies revealed no pathology. SEZ6L2 antibodies were found in both CSF and serum. Over a period of 9 months, our patient received immunotherapy consisting of steroid pulse therapy, IV immunoglobulin infusions, rituximab, and cyclophosphamide. Consequently, her condition improved markedly, and she was discharged home from the neurologic rehabilitation unit. DISCUSSION: Our case report shows that intense sequential immunotherapy may considerably improve level of functioning in some patients with SEZ6L2 antibody-associated cerebellar ataxia. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.