Cerebellar Degeneration Research Articles

Disability in cerebellar ataxia syndromes is linked to cortical degeneration

ObjectiveWe aimed to relate clinical measures of disability in chronic cerebellar degeneration to structural whole-brain changes using voxel-based and surface-based morphometry (vbm and sbm). We were particularly interested in remote effects of cerebellar degeneration in the cerebral cortex.MethodsWe recruited 30 patients with cerebellar degeneration of different aetiologies (downbeat nystagmus syndrome, DBN n = 14, spinocerebellar ataxia, SCA n = 9, sporadic adult late-onset ataxia, SAOA n = 7). All patients were thoroughly characterised in the motor, cognitive, vestibular and ocular–motor domains. Vbm and sbm were used to evaluate structural differences between cerebellar degeneration patients and a group of healthy age- and gender-matched volunteers. Linear regression models were used to correlate functional measures of disease progression and postural stability with whole brain volumetry.ResultsPatients with SCA and SAOA showed widespread volume loss in the cerebellar hemispheres and less prominently in the vermis. Patients with DBN showed a distinct pattern of grey matter volume (GMV) loss that was restricted to the vestibular and ocular–motor representations in lobules IX, X and V–VII. Falls were associated with brainstem white matter volume. VBM and SBM linear regression models revealed associations between severity of ataxic symptoms, cognitive performance and preferred gait velocity. This included extra-cerebellar (sub-)cortical hubs of the motor and locomotion network (putamen, caudate, thalamus, primary motor cortex, prefrontal cortex) and multisensory areas involved in spatial navigation and cognition.ConclusionFunctional disability in multiple domains was associated with structural changes in the cerebral cortex.

Neuroprotective effect of quercetin nanoparticles: A possible prophylactic effect in cerebellar neurodegenerative disorders

Memory deficit, anxiety, coordination deficit and depression are common neurological disorders attributed to aluminum (Al) buildup in the nervous system. Quercetin nanoparticles (QNPs) are a newly developed effective neuroprotectant. We aimed to investigate the potential protective and therapeutic effects of QNPs in Al induced toxicity in rat cerebellum. A rat model of Al-induced cerebellar damage was created by AlCl3 (100 mg/kg) administration orally for 42 days. QNPs (30 mg/kg) was administered for 42-days as a prophylactic (along with AlCl3 administration) or therapeutic for 42-days (following AlCl3 induced cerebellar damage). Cerebellar tissues were assessed for structural and molecular changes. The results showed that Al induced profound cerebellar structural and molecular changes, including neuronal damage, astrogliosis and tyrosine hydroxylase downregulation. Prophylactic QNPs significantly reduced Al induced cerebellar neuronal degeneration. QNPs is a promising neuroprotectant that can be used in elderly and vulnerable subjects to protect against neurological deterioration. It could be a promising new line for therapeutic intervention in neurodegenerative diseases.

Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse.

By means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model (Harlequin, Hq) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male Hq and wild-type (WT) mice 8 weeks after the onset of clear symptoms of ataxia in the Hq mice (aged 5.2 ± 0.2 and 5.3 ± 0.1 months for WT and Hq, respectively), followed by a biochemical validation of the most relevant changes. Additional groups of 2-, 3- and 6-month-old WT and Hq mice were analyzed to assess the disease progression on the proteins altered in the proteomic study. The proteomic analysis showed that beyond the expected deregulation of oxidative phosphorylation, the cerebellum of Hq mice showed a marked astroglial activation together with alterations in Ca2+ homeostasis and neurotransmission, with an up- and downregulation of GABAergic and glutamatergic neurotransmission, respectively, and the downregulation of cerebellar "long-term depression", a synaptic plasticity phenomenon that is a major player in the error-driven learning that occurs in the cerebellar cortex. Our study provides novel insights into the mechanisms associated with cerebellar degeneration in the Hq mouse model, including a complex deregulation of neuroinflammation, oxidative phosphorylation and glutamate, GABA and amino acids' metabolism.

Quantitative Analysis of Cerebellar Cortical Degeneration Using MRI in Dogs

Quantitative Analysis of Cerebellar Cortical Degeneration Using MRI in Dogs

Phenotypic and genetic aspects of hereditary ataxia in dogs.

Hereditary ataxias are a large group of neurodegenerative diseases that have cerebellar or spinocerebellar dysfunction as core feature, occurring as an isolated sign or as part of a syndrome. Based on neuropathology, this group of diseases has so far been classified into cerebellar cortical degenerations, spinocerebellar degenerations, cerebellar ataxias without substantial neurodegeneration, canine multiple system degeneration, and episodic ataxia. Several new hereditary ataxia syndromes are described, but most of these diseases have similar clinical signs and unspecific diagnostic findings, wherefore achieving a definitive diagnosis in these dogs is challenging. Eighteen new genetic variants associated with these diseases have been discovered in the last decade, allowing clinicians to reach a definitive diagnosis for most of these conditions, and allowing breeding schemes to adapt to prevent breeding of affected puppies. This review summarizes the current knowledge about hereditary ataxias in dogs, and proposes to add a "multifocal degenerations with predominant (spino)cerebellar component" category regrouping canine multiple system degeneration, new hereditary ataxia syndromes that do not fit in 1 of the previous categories, as well as specific neuroaxonal dystrophies and lysosomal storage diseases that cause major (spino)cerebellar dysfunction.

Cross-talk between DNA damage response and the central carbon metabolic network underlies selective vulnerability of Purkinje neurons in ataxia-telangiectasia.

Cerebellar ataxia is often the first and irreversible outcome in the disease of ataxia-telangiectasia (A-T), as a consequence of selective cerebellar Purkinje neuronal degeneration. A-T is an autosomal recessive disorder resulting from the loss-of-function mutations of the ataxia-telangiectasia-mutated ATM gene. Over years of research, it now becomes clear that functional ATM-a serine/threonine kinase protein product of the ATM gene-plays critical roles in regulating both cellular DNA damage response and central carbon metabolic network in multiple subcellular locations. The key question arises is how cerebellar Purkinje neurons become selectively vulnerable when all other cell types in the brain are suffering from the very same defects in ATM function. This review intended to comprehensively elaborate the unexpected linkages between these two seemingly independent cellular functions and the regulatory roles of ATM involved, their integrated impacts on both physical and functional properties, hence the introduction of selective vulnerability to Purkinje neurons in the disease will be addressed.

Effects of RNA M6A demethylase ALKBH5 gene deficiency on morphology and function of cerebellum in aged mice

Objective: To investigate the effects of RNA m6A demethylase ALKBH5 gene deficiency on cerebellar morphology and function in the aged mice, and to explore the role of ALKBH5 in cerebellar degeneration. Methods: Western blot was performed to detect the protein level of ALKBH5 in the cerebellum of wild-type mice of various ages. The expression of NeuN, Calbindin-D28K, MAP2, GFAP and other proteins in the cerebella of middle-aged (12-month-old) and aged (18-month-old) wild-type mice and ALKBH5-/- mice was examined using immunohistochemistry. The balance beam test and gait analysis were performed to test the balance ability and motor coordination of the mice. Results: With aging of the mice, the expression of ALKBH5 in the cerebellum increased gradually in an age-dependent manner. In the aged mice, but not middle-aged mice, the body weight, whole brain weight and cerebellum weight of ALKBH5-/- mice decreased by 15%, 10% and 21%, respectively (P<0.05). The expression of ALKBH5 in the Purkinje cells was much higher than that in other types of neural cells. Correspondingly, ALKBH5-deficiency caused 40% reduction in the number of Purkinje cells, as well as the length and density of neuronal dendrites in the aged mice (P<0.01). In addition, the time for the aged ALKBH5-/- mice to pass the balance beam was 70% longer than that of the wild type mice of the same age, with unstable gaits (P<0.01). Conclusions: Gene deficiency of RNA m6A demethylase ALKBH5 causes cerebellar atrophy, Purkinje neuron loss and damage in the aged mice. These changes eventually affect mice's motor coordination and balance ability. These results suggest that imbalanced RNA m6A methylation may lead to neurodegenerative lesions in the cerebellum of mice.

Visual oculomotor abnormalities and vestibulo‑ocular reflex dynamics in polyglutamine spinocerebellar ataxias (Review).

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurodegenerative diseases that are characterized by cerebellar ataxia. The most common types of SCAs are caused by polyglutamine (polyQ)-encoding cytosine-adenine-guanine repeat expansions. Autosomal dominant SCAs share similar pathophysiological mechanisms. The cerebellum plays an important role in the generation and control of eye movement, and neuropathological findings indicate that cerebellar degeneration is commonly present in polyQ-SCAs. As a result, various patterns of oculomotor impairment are present in most SCA subtypes. The present review summarizes the visual oculomotor abnormalities and vestibulo-ocular reflex dynamics of the most common polyQ-SCAs, as well as their genetic, clinical and neuropathological features. In conclusion, the systemic evaluation of eye movement features is useful in the differential diagnosis of polyQ-SCAs.

Immune-Mediated Cerebellar Ataxias

Autoimmune mechanisms affect the cerebellum leading to the development of cerebellar ataxias (CAs), which are termed immune-mediated cerebellar ataxias (IMCAs). IMCAs have diverse etiologies. Gluten ataxia (GA), post-infectious cerebellitis (PIC), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamate decarboxylase 65 antibody-associated CA (anti-GAD ataxia), and primary autoimmune cerebellar ataxia (PACA). In addition to these well-established entities, CAs are associated with autoimmunity against ion channels and their related proteins, synaptic adhesion proteins, transmitter receptors, glial cells, and brainstem antigens. Cell-mediated mechanisms are assumed to be involved in PCD, whereas accumulating evidence shows that anti-GAD antibodies decrease gamma-aminobutyric acid (GABA) release to elicit functional synaptic deficits. The therapeutic benefits of immunotherapies vary depending on the etiology. Early intervention is recommended when the cerebellar reserve, abilities for compensation and restoration of pathologies are preserved.

Cerebellar Hypermetabolism in a Hodgkin Lymphoma Leads to Diagnosis of Paucisymptomatic Cryptococcus neoformans Meningitis.

Malignancy-associated cerebellar hypermetabolism on [ 18 F]FDG PET/CT has 2 major causes: paraneoplastic autoimmune encephalitis and neoplasias (leptomeningeal/cerebellar metastases and primary cerebellar tumors). We present the case of a 33-year-old man with a newly diagnosed Hodgkin lymphoma and mere episodical headache, unexpectedly displaying intense cerebellar hypermetabolism on his staging [ 18 F]FDG PET/CT. Both neurolymphomatosis and paraneoplastic subacute cerebellar degeneration were ruled out by clinical presentation, MR, and repeated lumbar punctures. Instead, cerebrospinal fluid analysis unveiled a Cryptococcus neoformans meningitis, highlighting the possibility of paucisymptomatic central nervous system infections as differential diagnosis in malignancy-related cerebellar hypermetabolism in addition to (para)neoplastic causes.

Temporal Relationship between Impairment of Cerebellar Motor Learning and Deterioration of Ataxia in Patients with Cerebellar Degeneration.

Ataxia and impaired motor learning are both fundamental features in diseases affecting the cerebellum. However, it remains unclarified whether motor learning is impaired only when ataxia clearly manifests, nor it is known whether the progression of ataxia, the speed of which often varies among patients with the same disease, can be monitored by examining motor learning. We evaluated motor learning and ataxia at intervals of several months in 40 patients with degenerative conditions [i.e., multiple system atrophy (MSA), Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), SCA6, and SCA31]. Motor learning was quantified as the adaptability index (AI) in the prism adaptation task and ataxia was scored using the Scale for the Assessment and Rating of Ataxia (SARA). We found that AI decreased most markedly in both MSA-C and MSA-P, moderately in MJD, and mildly in SCA6 and SCA31. Overall, the AI decrease occurred more rapidly than the SARA score increase. Interestingly, AIs remained normal in purely parkinsonian MSA-P patients (n = 4), but they dropped into the ataxia range when these patients started to show ataxia. The decrease in AI during follow-up (dAI/dt) was significant in patients with SARA scores < 10.5 compared with patients with SARA scores ≥ 10.5, indicating that AI is particularly useful for diagnosing the earlier phase of cerebellar degeneration. We conclude that AI is a useful marker for progressions of cerebellar diseases, and that evaluating the motor learning of patients can be particularly valuable for detecting cerebellar impairment, which is often masked by parkinsonisms and other signs.

Anti-Tr/DNER Paraneoplastic Cerebellar Degeneration with Marked Cerebellar and Psychological Symptoms Responsive to Plasma Exchange (P5-5.025)

<h3>Objective:</h3> We present a patient who developed cerebellar degeneration and severe psychological symptoms leading to the diagnosis of Hodgkin’s disease and detection of anti-Tr/DNER antibodies. The patient failed to respond methylprednisolone, intravenous immunoglobulin G, rituximab, and tumor treatment but had significant improvement with plasma exchange (PLEX). <h3>Background:</h3> Paraneoplastic cerebellar degeneration accompanying Hodgkin’s disease may have its onset prior to detection of the underlying malignancy, during its course, or following treatment. The major associated autoantibody, anti-Tr, is reactive with neuronal delta/notch-like epidermal growth factor-related receptors (DNER), an autoantibody not included in all paraneoplastic testing screens. The condition characterized by progressive cerebellar injury, and response to immunosuppressive therapy and tumor treatment is generally poor. <h3>Design/Methods:</h3> <h3>Case Presentation:</h3> A 60-year-old male presented with diplopia, progressive loss of balance, and ataxia, with impaired short-term memory, confusion, and anger outbursts. Initial commercial screen for paraneoplastic autoantibodies was negative. Two months following his initial presentation he developed inguinal lymphadenopathy. He was diagnosed as having Hodgkin’s Lymphoma Stage 1B and found by a second laboratory to have anti-TR/DNER antibodies (Titer 1:3480; Reference range &lt;1:240), an antibody not included in the initial testing panel. CSF analysis was notable for a protein of 92mg/dL. MRI demonstrated normal findings for age. <h3>Results:</h3> Treatment with Doxorubicin-Bleomycin-Vinblastine-Dacarbazine (ABVD), pulse methylprednisolone, and intravenous immunoglobulin did not affect progression of neurological symptoms. Plasma exchange (PLEX), however, resulted in marked improvement. Symptoms worsened during subsequent treatment with intravenous immunoglobulins and rituximab but improved with further plasma exchange. <h3>Conclusions:</h3> Although Hodgkin’s disease is an important malignancy in paraneoplastic cerebellar degeneration, its most common associated autoantibody is not necessarily included in commercial paraneoplastic autoantibody screens, potentially leading to delay in diagnosis. Our patient’s dramatic improvement with PLEX suggests that PLEX should be considered early in treatment, or where there is poor response to other treatment modalities. <b>Disclosure:</b> Dr. Crane has nothing to disclose. Dr. Wynn has nothing to disclose. Dr. DeWitt has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Greenlee has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Medlink. Dr. Greenlee has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Sommers Schwartz Law Offices. Dr. Greenlee has received publishing royalties from a publication relating to health care. Dr. Greenlee has received publishing royalties from a publication relating to health care.

Rapidly Progressive Cerebellar Ataxia and Dementia due to Cortical Cerebellar and Thalamic Degeneration: A Case Series of Two Autopsy Confirmed Patients (P8-11.016)

<h3>Objective:</h3> To report two patients with sporadic, adult-onset ataxia with a rapidly progressive disease course and extra-cerebellar symptoms resembling prion disease. <h3>Background:</h3> Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. Cortical cerebellar atrophy (CCA), idiopathic late-onset cerebellar ataxia and sporadic adult-onset ataxia of unknown etiology have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nucleus), slowly progressive ataxia and the absence of a clear etiology. <h3>Design/Methods:</h3> We studied two patients with rapidly progressive cerebellar ataxia and dementia. We performed postmortem evaluation of the brain and whole genome sequencing, as well as analysis of AAGGG pentanucleotide repeat expansion in the <i>RFC1</i>. <h3>Results:</h3> Case 1 was a 36-year-old man with a one-year history of ataxia and dementia. Case 2 was a 41-year-old woman with a 16-month history of ataxia and dementia. Extensive studies on autoimmune etiologies and prion disease were negative in both patients. Pathological findings were consistent with CCA, but there were also degenerative changes in the thalamus of both cases. Immunohistochemistry did not show prion protein deposits. Genetic analyses did not reveal any pathogenic variants associated with cerebellar ataxia or pathologic repeat expansion in the <i>RFC1</i> gene. <h3>Conclusions:</h3> Although the underlying etiology of rapidly progressive CCA is unknown, we propose that the combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, which we refer to as rapidly progressive cerebellar cortical and thalamic degeneration (RPCCAT). <b>Disclosure:</b> Dr. Koga has nothing to disclose. Mr. Ali has nothing to disclose. Matthew Baker has nothing to disclose. Klaas Wierenga has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for BMC Medical Genomics . Dr. Dompenciel has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.

Characterizing Lewy Pathology in 231 Essential Tremor Brains from the Essential Tremor Centralized Brain Repository (S51.005)

<h3>Objective:</h3> To address several questions: (1) What proportion of essential tremor (ET) cases exhibit Lewy pathology (LP)? (2) What is the nature (i.e., type, location, severity) of that pathology? (3) How does that pathology relate to various neurodegenerative conditions (e.g., Parkinson’s disease [PD], Alzheimer’s type changes)? (4) What are the clinical correlates of that pathology? <h3>Background:</h3> The aforementioned questions have significant value in terms of furthering our understanding of the biological and mechanistic basis for ET. The Essential Tremor Centralized Brain Repository is the largest repository of prospectively-collected ET brains (n = 231). Hence, we are uniquely poised to address these questions. <h3>Design/Methods:</h3> Each brain had a complete neuropathological assessment, including assessment of LP with alpha-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. <h3>Results:</h3> Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of pathologic PD. LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of five or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. <h3>Conclusions:</h3> One-in-four ET cases had LP, a proportion that in the context of other studies among control populations seems high. LP was heterogeneous, and likely a partial function of observed clinical associations between (1) ET and PD and (2) ET and Alzheimer’s disease, as well as other factors that are unknown. There was evidence of cerebellar degeneration in ET cases both with and without LP, rather than just without. These data have value in terms of furthering our understanding of the biological and mechanistic basis for ET as well as its relatedness to other degenerative diseases. <b>Disclosure:</b> Dr. Louis has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wolters Kluwer - Merritt’s Textbook of Neurology. The institution of Dr. Louis has received research support from National Institutes of Health. Dr. Kuo has nothing to disclose. Phyllis Faust has nothing to disclose.

A Rare Case of Anti-SOX1 Antibody Positive Paraneoplastic Cerebellar Degeneration in Prostate Cancer (P5-5.030)

A Rare Case of Anti-SOX1 Antibody Positive Paraneoplastic Cerebellar Degeneration in Prostate Cancer (P5-5.030)

Anti-Ma2 Antibody Paraneoplastic Cerebellar Degeneration Associated with Renal Cell Carcinoma: A Case Report. (P8-11.013)

<h3>Objective:</h3> To highlight a unique case of Anti-Ma2 antibody paraneoplastic cerebellar degeneration (PCD) associated with renal cell carcinoma (RCC). <h3>Background:</h3> Paraneoplastic neurologic syndromes are a group of immune mediated disorders with a multitude of presentations. PCD is a rare presentation of a rapidly progressive ataxia associated with a variety of antibodies. In 0.5–1% of patients, anti-Ma2 antibody has been known to cause PCD in the setting of neoplasms. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 70-year-old male presented with three-month history of progressive gait difficulty, poor balance and recurrent falls. He had a history of metastatic RCC for which he underwent a total left nephrectomy, radiation therapy and chemotherapy with nivolumab and axitinib. Initial evaluation noted end-gaze nystagmus, limb dysmetria, truncal ataxia and wide-based gait. Chemotherapy was discontinued at the onset of symptoms. Work-up demonstrated cerebellar atrophy and cerebrospinal fluid (CSF) studies revealed mildly elevated protein and oligoclonal bands. He was hospitalized one month later for rapidly worsening ataxia. Repeat serum and CSF studies were positive for anti-Ma2 antibodies. He underwent 5 sessions of plasmapheresis with minimal improvement. Despite treatment, disease continued to progress with patient becoming wheelchair bound. Further treatment with immunotherapies were discussed, but patient elected to pursue palliative care. <h3>Conclusions:</h3> Anti-Ma2 antibodies have been well characterized in PCD in the setting of neoplasms. Immune checkpoint inhibitors (ICI) have also been associated with anti-Ma2 antibodies, causing immune related adverse events including encephalitis and cranial neuropathies. Nivolumab has been reported with cerebellar ataxia in the absence of anti-Ma2 antibodies with symptoms starting shortly after the initiation of therapy. However, symptoms improved after discontinuation of nivolumab and treatment with steroids. In our case, symptoms started almost one year after the initiation of ICI and patient continued to decline even after discontinuation of ICI. This presentation demonstrates a unique case of anti-Ma2 antibody PCD associated with RCC. <b>Disclosure:</b> Dr. Zahra has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Sivakumar has nothing to disclose. Dr. Urrea-Mendoza has nothing to disclose. Dr. Veerappan has nothing to disclose.

Anti-Yo autoimmunity in patients with post-immune checkpoint inhibitors neurological syndromes (P4-5.027)

<h3>Objective:</h3> We report for the first time the occurrence of Yo-antibodies (Abs) in the setting of post-immune checkpoint inhibitors (ICI) neurological syndromes. <h3>Background:</h3> Among Abs carrying a high risk for paraneoplastic neurological syndromes (PNS), anti-Yo-Abs are mostly detected in women with gynecological malignancies who develop a paraneoplastic cerebellar degeneration (PCD). <h3>Design/Methods:</h3> Yo-Abs were initially detected in serum and cerebrospinal fluid (CSF) samples by commercial line dots (RAVO diagnostika and Euroimmun) and further confirmed with in-house techniques: immunohistochemistry on rat brain sections, cell-based assay and Western blot for cerebellar degeneration-related 2 (CDR2) and CDR2-like (CDR2L) proteins. <h3>Results:</h3> Three patients were referred to the French national reference center for PNS: 59-year-old woman and 60-year-old man with lung adenocarcinoma, and 63-year-old woman with ovarian adenocarcinoma, all developing the first neurological symptoms within 3 months of ICI (pembrolizumab) first dose. The woman with ovarian cancer and the man with lung adenocarcinoma had a PCD, while the woman with lung cancer had a myelitis. In all patients, CSF analysis disclosed pleocytosis and brain magnetic resonance imaging was normal. Yo-Abs were retrospectively detected in pre-ICI serum samples in the patient with ovarian cancer. Management consisted of permanent ICI discontinuation (3/3) and immunomodulation, including corticosteroids (3/3), immunoglobulins (2/3), rituximab (1/3), or cyclophosphamide (1/3). No patient substantially improved (modified Rankin Score pre- and post-treatment 4). In all cases, cancer progressed after ICI discontinuation and at last follow-up (4–16 months after neurological onset) the two patients with PCD were dead and the one with myelitis was in palliative care. <h3>Conclusions:</h3> While the pre-ICI Yo-Abs positivity in the patient with ovarian cancer suggests that ICI might have triggered a latent PNS, both the unusual cancer type association (lung) in the other two patients and the atypical clinical phenotype in one of them (myelitis) poses a challenge to the classic understanding of Yo-Abs associated PNS. <b>Disclosure:</b> Dr. Farina has nothing to disclose. Veronique Rogemond has nothing to disclose. Mrs. Peter has nothing to disclose. Dr. Wucher has nothing to disclose. Dr. Villagran Garcia has nothing to disclose. Dr. DO has received research support from Agence Nationale de la Recherche (ANR) ANR-18-RHUS-0012. Géraldine Picard has nothing to disclose. Bastien Joubert, MD has nothing to disclose. The institution of Jerome Honnorat, MD, PhD has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for journal of neurology. Prof. Desestret has nothing to disclose.

Cerebellar Degeneration Causing Saccadic Dysmetria and Ocular Flutter: A Seronegative Paraneoplastic Syndrome (P4-5.015)

<h3>Objective:</h3> To report a challenging case of a woman who developed eye movement abnormalities, progressive truncal, and gait ataxia due to a paraneoplastic syndrome. <h3>Background:</h3> Progressive cerebellar degeneration is a well-known paraneoplastic syndrome. However, it can be challenging to define phenotypically and diagnose in the absence of relevant antibodies. Response to treatment is often poor. <h3>Design/Methods:</h3> Case Report. <h3>Results:</h3> A 68-year-old woman presented with several months of moderately progressive truncal, gait ataxia, followed by development of saccadic hypermetria and ocular flutter. Her metastatic small cell lung cancer was in remission, and she no longer showed bilateral cerebellar metastases on brain MRI, following treatment with chemotherapy, durvalumab, and whole brain radiation. CSF analysis revealed lymphocytic pleocytosis (8/μL), normal protein, normal glucose, and 4 oligoclonal bands. Paraneoplastic antibodies from serum and CSF were negative. She was diagnosed with a probable paraneoplastic syndrome, based on a PNS-Care score of 7. She was treated with high dose intravenous methylprednisolone and plasmapheresis, with resolution of eye movement abnormalities, and improvement of ataxia. <h3>Conclusions:</h3> Subacute development of saccadic dysmetria and ocular flutter in this case helped define a new onset cerebellar syndrome in a patient with possible residual cerebellar dysfunction from prior cerebellar metastatic disease. Saccadic hypermetria is typically caused by dysfunction of the fastigial oculomotor region (FOR). In our case, ocular flutter might have been caused by indirect instability of the brainstem network due to impairment of the FOR projections to the omnipause neurons (OPN) in the pontine saccadic burst generator area. Even in the absence of relevant antibodies and in the setting of confounders such as prior cerebellar metastases, use of checkpoint inhibitors, clinical presentation and CSF findings should raise concern for a paraneoplastic disorder. Cerebellar paraneoplastic syndromes may respond to Immunotherapy with methylprednisolone and plasmapheresis. <b>Disclosure:</b> Dr. Zampino has nothing to disclose. Dr. Figgie has nothing to disclose. Dr. Shaikh has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Serra has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen Idec. Dr. Serra has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb.

Reduction of Microvessel Number and Length in the Cerebellum of Purkinje Cell Degeneration Mice.

Degenerative effects of nerve tissues are often accompanied by changes in vascularization. In this regard, knowledge about hereditary cerebellar degeneration is limited. In this study, we compared the vascularity of the individual cerebellar components of 3-month-old wild-type mice (n = 8) and Purkinje cell degeneration (pcd) mutant mice, which represent a model of hereditary cerebellar degeneration (n = 8). Systematic random samples of tissue sections were processed, and laminin was immunostained to visualize microvessels. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in cerebellar layers. Our results in pcd mice revealed a 45% (p < 0.01) reduction in the total volume of the cerebellum, a 28% (p < 0.05) reduction in the total number of vessels and a lower total length, approaching 50% (p < 0.001), compared to the control mice. In pcd mutants, cerebellar degeneration is accompanied by significant reduction in the microvascular network that is proportional to the cerebellar volume reduction therefore does not change density of in the cerebellar gray matter of pcd mice.

Autoimmunity to voltage‐gated calcium channels

AbstractSeveral review articles on voltage‐gated calcium channels (VGCCs) classify VGCCs into five electrophysiological types and 10 genotypes. Each VGCC is distributed in different organs and specialized cells, and various organ‐specific human genetic diseases have been reported. Most of the human diseases caused by abnormalities in the VGCCs are genetic diseases. To the best of our knowledge, Lambert–Eaton myasthenic syndrome (LEMS) appears to be the only autoimmune disease for VGCCs. Approximately 90% of LEMS patients are positive for autoantibodies against P/Q‐VGCCs in the active zone of nerve endings. On the other hand, about 50% of LEMS patients a tumor‐associated neurological syndrome with small cell lung cancer. Neurological symptoms in LEMS patients include weakness of proximal limb muscles, reduced tendon reflexes, autonomic neuropathy, and in 9%–14% of patients, cerebellar ataxia, and paraneoplastic cerebellar degeneration. In the second half of this manuscript, we provide a clinical review with reference to the recently published Practical Guideline for Myasthenia gravis and LEMS 2022 in Japan.