Recent advances in diagnosis of immune-mediated cerebellar ataxias: novel concepts and fundamental questions on autoimmune mechanisms.

Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor.

Multi-omics profiling reveals dysregulated ribosome biogenesis and impaired cell proliferation following knockout of CDR2L.

BACKGROUND: Cerebellar degeneration-related (CDR) proteins are associated with paraneoplastic cerebellar degeneration (PCD) - a rare, neurodegenerative disease caused by tumour-induced autoimmunity against neural antigens resulting in degeneration of Purkinje neurons in the cerebellum. The pathogenesis of PCD is unknown, in large part due to our limited understanding of the functions of CDR proteins. To this end, we performed an extensive, multi-omics analysis of CDR-knockout cells focusing on the CDR2L protein, to gain a deeper understanding of the properties of the CDR proteins in ovarian cancer. METHODS: Ovarian cancer cell lines lacking either CDR1, CDR2, or CDR2L were analysed using RNA sequencing and mass spectrometry-based proteomics to assess changes to the transcriptome, proteome and secretome in the absence of these proteins. RESULTS: For each knockout cell line, we identified sets of differentially expressed genes and proteins. CDR2L-knockout cells displayed a distinct expression profile compared to CDR1- and CDR2-knockout cells. Knockout of CDR2L caused dysregulation of genes involved in ribosome biogenesis, protein translation, and cell cycle progression, ultimately causing impaired cell proliferation in vitro. Several of these genes showed a concurrent upregulation at the transcript level and downregulation at the protein level. CONCLUSIONS: Our study provides the first integrative multi-omics analysis of the impact of knockout of the CDR genes, providing both new insights into the biological properties of the CDR proteins in ovarian cancer, and a valuable resource for future investigations into the CDR proteins.

Paraneoplastic Cerebellar Degeneration Leading to an Early Diagnosis of Peritoneal Serous Papillary Carcinoma.

A 77-year-old female with a subacute progression of ataxia and serum anti-Yo antibodies was suspected to have paraneoplastic cerebellar degeneration (PCD). An examination of an underlying cancer showed no abnormality in the gynecological organs, but the findings did show a mass in the Douglas fossa. The mass was resected and diagnosed as stage IIB peritoneal serous papillary carcinoma (PSPC), a rare gynecologic cancer that is difficult to diagnose in the early stages. PCD was treated with intravenous immunoglobulin (IVIG). For an early diagnosis and treatment, PSPC should be included in the list of malignancies that cause PCD with anti-Yo antibodies.

Paraneoplastic cerebellar and brainstem disorders.

Paraneoplastic cerebellar and brainstem disorders are a heterogeneous group that requires prompt recognition and treatment to help prevent irreversible neurologic injury. Paraneoplastic cerebellar degeneration is best characterized by Yo antibodies in patients with breast or ovarian cancer. Tr (DNER) antibodies in patients with Hodgkin lymphoma can also present with a pure cerebellar syndrome and is one of the few paraneoplastic syndromes found with hematological malignancy. Opsoclonus-myoclonus-ataxia syndrome presents in both pediatric and adult patients with characteristic clinical findings. Other paraneoplastic brainstem syndromes are associated with Ma2 and Hu antibodies, which can cause widespread neurologic dysfunction. The differential for these disorders is broad and also includes pharmacological side effects, infection or postinfectious processes, and neurodegenerative diseases. Although these immune-mediated disorders have been known for many years, mechanisms of pathogenesis are still unclear, and optimal treatment has not been established.

Paraneoplastic neurologic syndrome associated with gynecologic and breast malignancies.

Gynecologic and breast malignancies are the cancers most commonly associated with paraneoplastic neurologic syndromes, of which the foremost is Yo [Purkinje cell antibody, type 1 (PCA-1)] paraneoplastic cerebellar degeneration. Yo syndrome affects women in the sixth decade and manifests as a subacute severe cerebellar ataxia. The association of the typical clinical picture with the detection of Yo antibodies in a patient's serum or CSF defines the diagnosis. Yo syndrome is always associated with a cancer, and the search for the underlying tumor should focus on ovarian and breast cancers and be repeated overtime if negative. The Yo autoantibodies are directed against the Yo antigens, aberrantly overexpressed by tumor cells with frequent somatic mutations and gene amplifications. The massive infiltration of these tumors by immune cells suggests that they are the site of the immune tolerance breakdown, leading to the destruction of Purkinje cells harboring the Yo antigens. Despite a growing understanding of the immunologic mechanisms, efficient therapeutic options are still lacking. Anti-Ri and antiamphiphysin syndromes are rarer and associated with breast cancers; a wide variety of other rare paraneoplastic neurologic syndromes have been described in association with gynecologic and breast malignancies that, though sharing some similarities, may have specific immune and genetics features leading to the immune tolerance breakdown.

[Blood-brain barrier breakdown and autoimmune cerebellar ataxia].

Autoimmune cerebellar ataxia is a disease entity that affects the cerebellum and is induced by autoimmune mechanisms. The disease is classified into several etiologies, including gluten ataxia, anti-glutamate decarboxylase (GAD) ataxia, paraneoplastic cerebellar degeneration, primary autoimmune cerebellar ataxia and postinfectious cerebellar ataxia. The autoimmune response in the periphery cross-reacts with similar antigens in the cerebellum due to molecular mimicry. Breakdown of the blood‒brain barrier (BBB) could potentially explain the vulnerability of the cerebellum during the development of autoimmune cerebellar ataxia, as it gives rise to the entry of pathogenic autoantibodies or lymphocytes into the cerebellum. In this review, the maintenance of the BBB under normal conditions and the molecular basis of BBB disruption under pathological conditions are highlighted. Next, the pathomechanism of BBB breakdown in each subtype of autoimmune cerebellar ataxia is discussed. We recently identified glucose-regulated protein (GRP) 78 antibodies in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome, and GRP78 antibodies induced by cross-reactivity with tumors can disrupt the BBB and penetrate anti-P/Q type voltage-gated calcium channel (VGCC) antibodies into the cerebellum, thus leading to cerebellar ataxia in this disease.

A retrospective study of autoimmune cerebellar ataxia over a 20-year period in a single institution.

BACKGROUND: It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA. METHODS: Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2 years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses. RESULTS: Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia. CONCLUSION: ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers.

A Pilot Study to Develop Paraneoplastic Cerebellar Degeneration Mouse Model.

Modeling paraneoplastic neurological diseases to understand the immune mechanisms leading to neuronal death is a major challenge given the rarity and terminal access of patients' autopsies. Here, we present a pilot study aiming at modeling paraneoplastic cerebellar degeneration with Yo autoantibodies (Yo-PCD). Female mice were implanted with an ovarian carcinoma cell line expressing CDR2 and CDR2L, the known antigens recognized by anti-Yo antibodies. To boost the immune response, we also immunized the mice by injecting antigens with diverse adjuvants and immune checkpoint inhibitors. Ataxia and gait instability were assessed in treated mice as well as autoantibody levels, Purkinje cell density, and immune infiltration in the cerebellum. We observed the production of anti-Yo antibodies in the CSF and serum of all immunized mice. Brain immunoreaction varied depending on the site of implantation of the tumor, with subcutaneous administration leading to a massive infiltration of immune cells in the meningeal spaces, choroid plexus, and cerebellar parenchyma. However, we did not observe massive Purkinje cell death nor any motor impairments in any of the experimental groups. Self-sustained neuro-inflammation might require a longer time to build up in our model. Unusual tumor antigen presentation and/or intrinsic, species-specific factors required for pro-inflammatory engagement in the brain may also constitute strong limitations to achieve massive recruitment of antigen-specific T-cells and killing of antigen-expressing neurons in this mouse model.

Paraneoplastic Cerebellar Degeneration Accompanied by Seropositivity for Anti-GAD65, Anti-SOX-1 and Anti-VGCC Antibodies Due to Small-cell Lung Cancer.

Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic neurological syndrome that is rarely accompanied by seropositivity with a combination of multiple antibodies. We herein report a 50-year-old man with PCD accompanied by small-cell lung cancer (SCLC). This patient was seropositive for anti-glutamic acid decarboxylase 65, anti-SRY-related HMG-box gene 1 and anti-voltage-gated calcium channel antibodies. After chemoradiation therapy without immunotherapy, cerebellar ataxia of the trunk and limbs markedly improved, along with a notable amelioration of SCLC. This case suggests that tumor therapy should be started immediately and that a panel of anti-neuronal antibodies should be evaluated when PCD with SCLC is suspected.

Favorable Outcomes in a Case of Non-paraneoplastic DNER Ataxia Treated with Immunotherapy.

Anti-DNER antibody is associated with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). However, recent studies reported cases absence of HD and that non-tumor anti-DNER antibody-associated ataxia was not well characterized. We present a case of acute cerebellar ataxia and nystagmus with detected anti-DNER antibody. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy. High titer of anti-DNER antibody was detected in CSF and serum. Positron emission tomography (PET) scanning was unremarkable at a 10-month follow up. The patient improved significantly after immunosuppressive therapy with intravenous steroids, immunoglobulin followed by rituximab. Our study suggest that the presence of such anti-neuronal antibodies might not come along with malignancy and that early onset non-tumor patients are more likely to have a better outcome after immunotherapy. Early diagnosis and timely immunosuppressive therapy may prove beneficial for these patients.

Immune-mediated ataxias: Guide to clinicians.

Immune-mediated cerebellar ataxias were initially described as a clinical entity in the 1980s, and since then, an expanding body of evidence has contributed to our understanding of this topic. These ataxias encompass various etiologies, including postinfectious cerebellar ataxia, gluten ataxia, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus-ataxia syndrome and primary autoimmune cerebellar ataxia. The increased permeability of the brain-blood barrier could potentially explain the vulnerability of the cerebellum to autoimmune processes. In this manuscript, our objective is to provide a comprehensive review of the most prevalent diseases within this group, emphasizing clinical indicators, pathogenesis, and current treatment approaches.

Autoimmune cerebellar ataxia associated with anti-Purkinje cells antibodies: the next frontier of neuroimmunology.

Autoimmune cerebellar ataxia (ACA) is an important cause of sporadic cerebellar ataxia. Technological innovation promotes the rapid development of cerebellar autoimmunity researches in recent years. More and more new antibodies have been proposed to be associated with ACA. Several autoantibodies against Purkinje cells (PCs) have been identified, which constitute the main components. These autoantigens are mainly located in the cytoplasm and dendrites of PCs, and exhibit a specific morphology in immunohistochemistry (IHC). Although the clinical features are relatively homogeneous, there were still some differences among different antibodies. Due to the lack of understanding of the disease and the limited detection technology, it is really difficult to diagnose and manage at present. However, unlike the most of hereditary ataxias, ACA is treatable, and even the neurological dysfunction of some patients may be reversible. Therefore, promptly identification, diagnosis and treatment may benefit some patients. Thus, this article elaborates on the clinical manifestations and laboratory characteristics of anti-PCs-antibody-associated ACA in order to help neurologists to understand ACA more comprehensively. At the same time, combining our previous exploratory work as well as the technology available, we try to propose a diagnostic strategy for ACA the text and the relevant differential diagnosis was illustrated in detail.

Anti-Zic4 Paraneoplastic Cerebellar Degeneration With Mesial Temporal Lobe Hyperintensity in a Patient With Papillary Thyroid Carcinoma: A Case Report and Review of the Literature.

Paraneoplastic cerebellar degeneration (PCD), a subtype of paraneoplastic neurological syndromes (PNSs), is a rare autoimmune neurologic syndrome that usually develops secondary to an underlying malignancy. We present a 49-year-old patient that developed PCD secondary to occult papillary thyroid carcinoma. The patient had progressive difficulty ambulating for 3 years. A neurological exam revealed signs of cerebellar syndrome. Brain magnetic resonance imaging (MRI) showed significant cerebellar atrophy and mesial temporal lobe hyperintensity. Immunological testing was highly positive for anti-CV2 and anti-Zic4 onconeural antibodies. Positron emission tomography (PET)/Computerized tomography (CT) scan revealed significant hypermetabolic uptake of F-18 fluorodeoxyglucose (FGD) by a left thyroid nodule. Histological examination of the nodule was positive for papillary thyroid carcinoma, confirming the diagnosis of PCD. A trial of high-dose methylprednisolone failed to improve the patient's symptoms. This case highlights the importance of maintaining high suspicion for PCD while investigating cases of cerebellar degeneration. Early detection is essential to prevent irreversible damage in affected patients.

A cerebellar degeneration-related protein 2-like cell-based assay for anti-Yo detection in patients with paraneoplastic cerebellar degeneration.

BACKGROUND AND PURPOSE: Commercially available tests for Yo antibody detection have low specificity for paraneoplastic cerebellar degeneration (PCD) because these assays use cerebellar degeneration-related protein 2 (CDR2) as the antigen, not CDR2-like (CDR2L). We aimed to test the hypothesis that use of a CDR2L cell-based assay (CBA), as an additional screening technique, would increase the accuracy of Yo-PCD diagnosis. METHODS: An in-house CBA to test for anti-CDR2L antibodies was developed and used to screen sera from 48 patients with confirmed anti-Yo-associated PCD. Fifteen non-Yo PCD patients, 22 patients with ovarian cancer without neurological syndromes, 50 healthy blood donors, 10 multiple sclerosis, 15 Parkinson's disease, and five non-paraneoplastic ataxic patients were included as controls. Sera were also tested by western blot analysis using recombinant CDR2 and CDR2L proteins developed in house, by the commercially available line immunoassays from Ravo Diagnostika and Euroimmun, and by the CDR2 CBA from Euroimmun. RESULTS: The CDR2L CBA identified all 48 patients with Yo-PCD. No CDR2L CBA reaction was observed in any of the control sera. The western blot technique had lower sensitivity and specificity as sera from eight and six of the 48 Yo-PCD patients did not react with recombinant CDR2 or CDR2L, respectively. CONCLUSIONS: The CDR2L CBA is highly reliable for identification of Yo-PCD. Although our findings indicate that, currently, the combination of CDR2 and CDR2L yields the most reliable test results, it remains to be evaluated if a test for single anti-CDR2L positivity will serve as a sufficient biomarker for Yo-PCD diagnosis.

Septin-3 autoimmunity in patients with paraneoplastic cerebellar ataxia.

BACKGROUND: Septins are cytoskeletal proteins with filament forming capabilities, which have multiple roles during cell division, cellular polarization, morphogenesis, and membrane trafficking. Autoantibodies against septin-5 are associated with non-paraneoplastic cerebellar ataxia, and autoantibodies against septin-7 with encephalopathy with prominent neuropsychiatric features. Here, we report on newly identified autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia. We also propose a strategy for anti-septin autoantibody determination. METHODS: Sera from three patients producing similar immunofluorescence staining patterns on cerebellar and hippocampal sections were subjected to immunoprecipitation followed by mass spectrometry. The identified candidate antigens, all of which were septins, were expressed recombinantly in HEK293 cells either individually, as complexes, or combinations missing individual septins, for use in recombinant cell-based indirect immunofluorescence assays (RC-IIFA). Specificity for septin-3 was further confirmed by tissue IIFA neutralization experiments. Finally, tumor tissue sections were analyzed immunohistochemically for septin-3 expression. RESULTS: Immunoprecipitation with rat cerebellum lysate revealed septin-3, -5, -6, -7, and -11 as candidate target antigens. Sera of all three patients reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of 149 healthy control sera was similarly reactive. In RC-IIFAs the patient sera recognized only cells expressing septin-3, individually and in complexes. Incubation of patient sera with five different septin combinations, each missing one of the five septins, confirmed the autoantibodies' specificity for septin-3. The tissue IIFA reactivity of patient serum was abolished by pre-incubation with HEK293 cell lysates overexpressing the septin-3/5/6/7/11 complex or septin-3 alone, but not with HEK293 cell lysates overexpressing septin-5 as control. All three patients had cancers (2 × melanoma, 1 × small cell lung cancer), presented with progressive cerebellar syndromes, and responded poorly to immunotherapy. Expression of septin-3 was demonstrated in resected tumor tissue available from one patient. CONCLUSIONS: Septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins.

Rapid-onset paraneoplastic cerebellar degeneration successfully treated by radiotherapy and tumorectomy.

We report the first-ever documented case of successful treatment of paraneoplastic cerebellar degeneration (PCD) with radiotherapy. A 31-year-old female presented with rapidly progressing neurological symptoms, which were revealed to be due to PCD secondary to an undiagnosed breast cancer. The cancer responded well to chemotherapy, but her neurological status continued to deteriorate, eventually progressing to complete expressive aphasia and dyssynergia with paraparesis. Due to the extraordinarily rapid progression of the disorder, a treatment with tumorectomy and radiotherapy of the whole brain was performed. This proved to be very successful, with a complete stop of the deterioration of symptoms after treatment and with a significant neurologic improvement in the following months. This case indicates that there may be a place for radiotherapy in the treatment of PCD. Current treatment options have proven insufficient and no guidelines for treatment currently exist. As such, the disorder remains associated with a very poor prognosis and often entails permanent loss of function. Radiation, with its known immunosuppressive effect and non-stochastic effects on the nervous system at the proper doses, might therefore be a valid option. However, we should note that it was in this instance combined with a removal of the primary tumor and as such, its individual efficacy cannot be considered proven.

Autoimmune Cerebellar Ataxia: Etiology and Clinical Characteristics of a Case Series from China.

Autoimmune cerebellar ataxia (ACA) is an important and potentially treatable cause of sporadic cerebellar syndrome, but studies with large sample size are limited. This study reported a large ACA series in China and described its etiology and clinical characteristics. We reviewed all ACA patients from our hospital (2013-2021) and analyzed their clinical and paraclinical features, treatment, and outcome. ACA subtypes investigated included paraneoplastic cerebellar degeneration (PCD), primary autoimmune cerebellar ataxia (PACA), anti-glutamate decarboxylase (GAD)-associated cerebellar ataxia, opsoclonus-myoclonus syndrome (OMS), Miller Fisher syndrome (MFS), and ACA-associated with autoimmune encephalitis. A total of 127 patients were identified and 40.9% were male. The median onset age was 47.0 years. Gait ataxia was the most prevalent feature followed by limb ataxia, dizziness, and dysarthria/dysphagia. Extracerebellar manifestations included pyramidal signs (28.3%) and peripheral neuropathy/radiculopathy (15.0%). ACA subtypes were PCD (30.7%), PACA (37.8%), ACA associated with autoimmune encephalitis (12.6%), anti-GAD-associated ACA (8.7%), MFS (7.1%), and OMS (3.1%). Neuronal antibodies were positive in 67.7% of patients. Brain magnetic resonance imaging was unremarkable (55.7%) or showed atrophy (18.3%) or abnormal signal intensity (26.1%, most of which was extracerebellar). Although most patients received immunotherapy, the modified Rankin scale at last follow-up was ≤ 2 in only 47.3% patients. Thirteen patients died and 24 relapsed. Compared with PACA, PCD patients were older and had poorer outcome. This study illustrates the heterogeneity in the clinical features of ACA and suggests the importance of neuronal antibody testing in ACA diagnosis. PCD and PACA are the dominant ACA subtypes, and the former has a less favorable prognosis.

The Discovery of Anti-Yo (Anti-PCA1) Antibody in Patients with Paraneoplastic Cerebellar Degeneration: Opening a Window into Autoimmune Neurological Disease.

Prior to 1982, ovarian and certain other cancers were known to have a rare complication of progressive cerebellar ataxia, a disorder characterized pathologically by severe-often total-obliteration of cerebellar Purkinje cells. However, the cause of cerebellar injury in these patients was unknown. In that year, we began studies in which sera from individuals with this disorder were reacted with frozen sections of human cerebellum. These studies revealed that patients with ovarian cancer and cerebellar degeneration had high titers of antibodies directed against cytoplasmic antigens of Purkinje cells and deep cerebellar nuclei-a previously undescribed pattern of antibody response which was subsequently found not to be present in ovarian cancer patients who remained neurologically normal. This antibody, now known as "anti-Yo" or "anti-PCA1" provides a marker for rapidly progressive cerebellar ataxia and is heavily associated with gynecological and breast malignancies. Although the role of anti-Yo antibody in cerebellar injury has not been established in living animals, in vitro studies have demonstrated that anti-Yo antibody causes Purkinje cell death in the absence of T lymphocytes. In this commentary, we describe our studies leading to initial discovery of anti-Yo antibody, discuss the relationship of this discovery to current knowledge of paraneoplastic neurological disease, and outline some important questions which remain to be resolved before we fully understand the pathogenesis and optimal treatment of this disorder.

A Systematic Review on Anti-Yo/PCA-1 Antibody: Beyond Cerebellar Ataxia in Middle-Aged Women with Gynecologic Cancer.

Current understanding of anti-Yo/PCA1 antibody-associated cerebellar ataxia is based on case reports and small case series. Our goal was to summarize clinical features, highlighting atypical presentations and gaps of knowledge. Following the PRISMA guidelines, we systematically screened Pubmed/MEDLINE, Embase, Scopus, and Web of Science from inception to April 2022 for all case reports and series concerning anti-Yo antibody-associated cerebellar ataxia. We collected data on clinical presentation, investigation findings, and treatment outcomes. Of 379 included patients, 96% were female with gynecologic cancer (82%). Among men, 87% had an associated tumor, mainly of gastrointestinal origin. The median age was 60 years old. Pancerebellar ataxia was the main clinical feature, but extracerebellar findings were frequent during the disease course. Vertigo and imbalance can be present early in the disease course in about two thirds of patients, as a prodromal phase. Although neuroimaging usually is normal or shows cerebellar atrophy, inflammatory changes may also be present. More than half of the patients reported some improvement after immunotherapy. However, despite treatment, 84% of survivors were unable to walk unassisted on follow-up. Our study provides objective data and advances in current knowledge of anti-Yo antibody-associated cerebellar ataxia such as the description of prodromal symptoms, extracerebellar findings, and its presentations in males.