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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. [ABSTRACT FROM AUTHOR]

ObjectiveCo-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known.MethodsWe performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive.ResultsAmong these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases.InterpretationTRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.

Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies represents a rare immune-mediated paraneoplastic neurological syndrome. Its diagnosis and management remain clinically challenging. Here, we present a case of PCD with confirmed anti-Yo antibodies, validated through anti-cerebellar degeneration protein 2 (CDR2) and anti-CDR2-like antibodies detection, which demonstrated a favorable response to ofatumumab therapy. The patient initially manifested with dizziness, nystagmus, dysarthria, and ataxia. Initial testing revealed weakly positive anti-Yo antibodies, accompanied by positive serum tissue-based assay result for cerebellum. Following one course of intravenous immunoglobulin and methylprednisolone pulse therapy, improvement of the patient’s dizziness was observed. Oral prednisone was prescribed for maintenance therapy. However, after discharge, the patient experienced progressive deterioration of symptoms, including worsening dizziness, dysarthria, and limb ataxia. Upon readmission to our hospital, further immunological testing confirmed the presence of anti-CDR2 and anti-CDR2-like antibodies. When a second course of methylprednisolone pulse therapy proved ineffective, treatment was switched to ofatumumab. After two doses, the patient achieved partial symptomatic relief.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are rare and often severe neurological complications of malignancies, significantly impacting patient prognosis and quality of life. They are characterized by a diverse range of onconeural autoantibodies, with further discoveries likely due to ongoing research. Among these, high-risk autoantibodies primarily target intracellular neural cell antigens. We present cases of lung cancer patients who developed limbic encephalitis and seizures at diagnosis, suggestive of PNS. Each case demonstrated distinct autoantibody profiles. Recognition of these potentially life-altering neurological sequelae, as paraneoplastic manifestations of malignancies, is crucial for physicians. PNS may precede primary cancer diagnosis and substantially affect patient presentation and overall outcome. We provide in detail the diagnostic work-up and available treatment options for these complex cases.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Among the different forms of cerebellar ataxia, autoimmune cerebellar ataxia (ACA) or immune‐mediated cerebellar ataxia (IMCA), which appears to be based on an autoimmune mechanism, has long been considered important from the viewpoint of paraneoplastic syndrome. With the expansion of the concept of immune‐mediated neurological diseases and the identification of many novel autoantibodies, ACA has recently become an important neurological syndrome. Although no definitive diagnostic criteria of ACA exist, Hadjivassilou et al suggested diagnostic criteria for primary ACA in 2020 and Dalmau and Graus showed proposed diagnostic criteria for ACA in 2022. The proposed diagnostic criteria for ACA by Dalmau and Graus emphasize the importance of antibody reliability. In the future, additional studies should be conducted to identify new antibodies associated with ACA and to clarify the importance of each antibody. Moreover, ACA is a disease for which immunological therapeutic intervention is feasible and requires early treatment to maintain cerebellar function. Many cases with ACA have reported the efficacy of immunotherapy. The concept of ACA may have the potential for further expansion and becomes increasingly important in the diagnosis of cerebellar ataxia. [ABSTRACT FROM AUTHOR]

A 57‐year‐old man presented with progressive muscle weakness in the lower limbs, with elevated anti‐P/Q‐type voltage‐gated calcium channel antibody levels. A repetitive stimulation test showed waxing with high‐frequency stimulation. He was diagnosed with Lambert–Eaton myasthenic syndrome (LEMS) and small‐cell lung cancer. After four courses of cisplatin and etoposide, computed tomography showed a decrease in tumor size and muscle weakness improved. After 3 months, the patient presented with progressive ataxic gait and dysarthria and was admitted to our hospital. Magnetic resonance imaging revealed slight cerebellar atrophy. We diagnosed the patient with paraneoplastic cerebellar degeneration (PCD)‐LEMS. The patient received intravenous immunoglobulin therapy, steroid pulse therapy, and plasmapheresis. The patient's cerebellar ataxia then improved. This represents a rare case of PCD‐LEMS after improvement of LEMS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated disorder characterized by progressive cerebellar ataxia in presence of onconeural antibodies which occurs due to an indirect effect of underlying malignancy i.e. small cell lung cancer (SCLC), breast and gynecologic cancer, and Hodgkin lymphoma. In about 50% of patients neurological manifestation of Paraneoplastic cerebellar degeneration occurs prior to detection of carcinoma. Anti-Yo Antibody is the commonest antibody present in patients with Paraneoplastic cerebellar degeneration which is associated with breast carcinoma. We describe 3 female patients with anti YO antibody mediated PCD with breast cancer. One patient had a previous diagnosis of breast cancer with post mastectomy status one year back. Two of them presented with ataxia and on further examination, breast lump was found. All three patients had symmetrical ataxia with one patient had severely debilitating ataxia and was not able to walk unassisted. Magnetic resonance imaging brain showed cerebellar atrophy in two patients while one patient had normal MRI. Anti- YO antibody was strongly positive in all the three patients. All patients were given immunotherapy (corticosteroids in 2, Intravenous immunoglobulin in 1) with 1 patient showed modest improvement These case highlights the need to consider for workup for paraneoplastic cerebellar degeneration in female patients presenting with subacute to chronic progressive ataxia, so that the tumors can be detected and treated in early stage with a good outcome.

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. [ABSTRACT FROM AUTHOR]

Abstract Background As a debilitating syndrome, paraneoplastic cerebellar degeneration (PCD) remains challenging to treat. Further, anti-Yo antibody (directed against human cerebellar degeneration-related protein 2) detection in patients with PCD is associated with unsatisfactory responses to existing therapies. Here, we present the case of a 60-year-old woman who developed PCD with anti-Yo antibodies and a submandibular gland tumor. Case presentation A 60-year-old woman presented with a 5-day history of unsteadiness of gait and inadequate coordination of her extremities, along with truncal instability. Although walking without aid was possible, dysmetria of all four limbs, trunk, and gait ataxia was observed. While routine biochemical and hematological examinations were normal, the patient’s blood was positive for anti-Yo antibodies. When the neurological symptoms deteriorated despite administration of intravenous methylprednisolone, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) images with contrast enhancement were performed, which showed a tumor in the left submaxillary gland. She underwent total left submandibular gland resection, including the tumor; histological and immunohistochemical results revealed a salivary duct carcinoma. She was administered intravenous methylprednisolone, followed by 10 plasma exchange sessions, intravenous immunoglobulins, and cyclophosphamide therapy. Following treatment, her symptoms were not alleviated, even after the reduction of anti-Yo titers. Conclusions Although tumor detection was delayed, early tumor detection, diagnosis, and PCD treatment are essential because any delay can result in the progression of the disorder and irreversible neurological damage. Therefore, we recommend that the possibility of a salivary gland tumor should be considered, and whole-body dual-modality CT, including the head and neck, and FDG-PET should be performed at the earliest for patients with well-characterized paraneoplastic antibodies when conventional imaging fails to identify a tumor.

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. [ABSTRACT FROM AUTHOR]

Rapidly progressive cerebellar ataxia is a classical paraneoplastic neurological syndrome associated with different autoantibodies and typical demographic characteristics, extracerebellar signs, tumor association, and prognosis. Anti-Tr/anti-Delta/Notch-like epidermal growth factor-related receptor (DNER) antibody is one of the associated antibodies. Given the rarity of this condition, our current knowledge is based on case reports and small case series. In order to improve our understanding of these conditions, we conducted a systematic review of the literature. Our study followed the PRISMA reporting guidelines. Studies of patients with the presence of anti-Tr/DNER antibodies in serum or cerebrospinal fluid (CSF) were included. We extract data information related to study characteristics, demographics, clinical symptoms, tumor association, neuroimaging, and cerebrospinal fluid analysis. Out of 131 records, we analyzed 17 papers, including a total of 85 patients with anti-Tr/DNER antibody–associated cerebellar ataxia. We confirmed that this disease occurred mostly in middle-aged males. Isolated cerebellar ataxia was the most common presentation. Extracerebellar features were rare (8%). Ninety-one percent of the patients presented an associated tumor, being Hodgkin lymphoma the most common. Abnormal neuroimaging patterns included cerebellar atrophy (19%) and cerebellar hypersignal (6%). Cerebrospinal fluid was inflammatory in 64% of the patients. Oncological response was complete in 88%, but neurological prognosis was poor with only 41% of the patients presenting significant neurological improvement at the last follow up. Anti-Tr/DNER antibodies should be tested in rapid progressive cerebellar ataxia. Oncological response is excellent; however, many patients do not improve from their cerebellar ataxia. [ABSTRACT FROM AUTHOR]

An 82-year-old man presented with acute progressive disturbance of consciousness. We suspected autoimmune limbic encephalitis because of abnormal magnetic resonance imaging findings in the bilateral temporal lobes and cerebrospinal fluid pleocytosis. The patient tested positive for anti-Tr/Delta/Notch-like epidermal growth factor-related receptor (DNER) antibodies, and a tissue biopsy revealed complications of anaplastic large cell lymphoma. Typically, anti-Tr/DNER antibody-associated paraneoplastic neurological syndrome presents with cerebellar ataxia and is complicated by Hodgkin lymphoma (HL). However, there are rare cases that present only with LE and are complicated by tumors other than HL; therefore, aggressive antibody measurement and search for tumors are important.

The endoplasmic reticulum (ER) relies on the microtubule cytoskeleton for distribution and remodelling of its extended membrane network, but how microtubule-based motors contribute to ER organization remains unclear. Using biochemical and cell-based assays, we identify cerebellar degeneration-related protein 2 (CDR2) and its paralog CDR2-like (CDR2L), onconeural antigens with poorly understood functions, as ER adaptors for cytoplasmic dynein-1 (dynein). We demonstrate that CDR2 is recruited by the integral ER membrane protein kinectin (KTN1) and that double knockout of CDR2 and CDR2L enhances KTN1-dependent ER sheet stacking, reversal of which by exogenous CDR2 requires its dynein-binding CC1 box motif. Exogenous CDR2 expression additionally promotes CC1 box-dependent clustering of ER sheets near centrosomes. CDR2 competes with the eEF1Bβ subunit of translation elongation factor 1 for binding to KTN1, and eEF1Bβ knockdown increases endogenous CDR2 levels on ER sheets, inducing their centrosome-proximal clustering. Our study describes a novel molecular pathway that implicates dynein in ER sheet organization and may be involved in the pathogenesis of paraneoplastic cerebellar degeneration., Competing Interests: The authors declare no competing financial interests.

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 neurological syndromes (PNS) are rare presentations of an underlying oncological disease and more unusual during an oncological disease. They most likely present in small-cell lung carcinomas and thymomas, but present in

Background: As a debilitating syndrome, paraneoplastic cerebellar degeneration (PCD) remains challenging to treat. Further, anti-Yo antibody (directed against human cerebellar degeneration-related protein 2) detection in patients with PCD is associated with unsatisfactory responses to existing therapies. Here, we present the case of a 60-year-old woman who developed PCD with anti-Yo antibodies and a submandibular gland tumor.Case Presentation: A 60-year-old woman presented with a 5-day history of unsteadiness of gait and inadequate coordination of her extremities, along with truncal instability. Although walking without aid was possible, dysmetria of all four limbs, trunk, and gait ataxia was observed. While routine biochemical and hematological examinations were normal, the patient's blood was positive for anti-Yo antibodies. When the neurological symptoms deteriorated despite administration of intravenous methylprednisolone, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) images with contrast enhancement were performed, which showed a tumor in the left submaxillary gland. She underwent total left submandibular gland resection, including the tumor; histological and immunohistochemical results revealed a salivary duct carcinoma. She was administered intravenous methylprednisolone, followed by 10 plasma exchange sessions, intravenous immunoglobulins, and cyclophosphamide therapy. Following treatment, her symptoms were not alleviated, even after the reduction of anti-Yo titers.Conclusions: Although tumor detection was delayed, early tumor detection, diagnosis, and PCD treatment are essential because any delay can result in the progression of the disorder and irreversible neurological damage. Therefore, we recommend that the possibility of a salivary gland tumor should be considered, and whole-body dual-modality CT, including the head and neck, and FDG-PET should be performed at the earliest for patients with well-characterized paraneoplastic antibodies when conventional imaging fails to identify a tumor. [ABSTRACT FROM AUTHOR]

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.

Paraneoplastic cerebellar degeneration (PCD) is a rare neuroimmunological disease that may accompany tumors. In this article, we present a patient with progressive gait difficulty who was diagnosed with PCD and, in a rare comorbidity, with papillary thyroid carcinoma (PTC) following malignancy screening. A 46-year-old male patient reported having experienced poor balance for 2 years. A neurological examination revealed nystagmus, intention tremor, and ataxia, and anti-thyroid peroxidase and anti-thyroglobulin levels were found to be elevated. A brain MRI showed significant cerebellar atrophy in the superior vermis. Malignancy screening for PCD was performed, and thyroid ultrasonography revealed a nodule in the left lobe, while PET/CT detected elevated focal F-18 fluorodeoxyglucose uptake in the thyroid. Onconeuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-Tr, anti-PPCA-2, anti-Ma, anti-CV-1, and anti-ANNA-3) were negative. Pathologic examination of the thyroid revealed PTC, for which the patient was treated with 0.4 g/kg intravenous immunoglobulin and referred to the medical oncology department. This case demonstrates that clinicians must be alert to the rare comorbidity of PCD and PTC.

Moreover, CD8 T-cell infiltration was marked as shown by the CD4:CD8 T-cell ratio (1.03), lower than what is usually observed in cerebrospinal fluid (2.2-3.4) and blood (1.5-1.9) in controls, meningitis and multiple sclerosis [14], in keeping with preferential CD8 T-cell recruitment, especially in the Purkinje cell layer where the CD4:CD8 ratio was 0.8. Keywords: CD8 T cells; cerebellitis; CTLA-4 inhibitor; immune checkpoint inhibitors; ipilimumab; paraneoplastic cerebellar degeneration EN CD8 T cells cerebellitis CTLA-4 inhibitor immune checkpoint inhibitors ipilimumab paraneoplastic cerebellar degeneration 1 5 5 02/03/22 20220215 NES 220215 We report a rapidly progressive and fatal CD8 T-cell-mediated cerebellitis after ipilimumab (cytotoxic T-lymphocyte-associated protein 4 inhibitor) for small cell lung cancer. CD8 T-cell-mediated cerebellitis directed against Purkinje cell antigen after ipilimumab for small cell lung cancer A patchy CD8 T-cell infiltrate spatially corresponded to areas of Purkinje cell loss, with occasional CD8 polarisation towards Purkinje cells. [Extracted from the article]

Paraneoplastic neurological syndrome (PNS) is a neurological picture that occurs in patients with cancer, does not occur with the direct effects of the underlying tumor, cannot be explained by metastasis and side effects of cancer treatment, and is accepted to occur by mechanisms of autoimmune origin. The most common PNS, paraneoplastic cerebellar degeneration (PCD) is a neurological picture that occurs due to autoimmune causes related to breast or gynecological cancers. Before the diagnosis of cancer, the patient may apply with cerebellar complaints and the diagnosis can be reached through autoantibodies such as anti-Yo. Here, a case that presented with PCD before being diagnosed with malignancy and had much better surveillance than known cases in terms of prognosis is presented. [ABSTRACT FROM AUTHOR]

Abstract Background Paraneoplastic cerebellar degeneration (PCD) is a devastating paraneoplastic syndrome that occasionally occurs in patients with Hodgkin lymphoma (HL). Anti-Ma2 is a well-characterized onconeuronal antibody and one of the causes of PCD. There has been only one previous report of anti-Ma2-associated paraneoplastic syndrome as a complication of HL. Here we present a rare case of anti-Ma2-associated PCD in a patient with nodular lymphocyte-predominant HL (NLPHL). Case presentation A 77-year-old man with a 3-month history of gait instability and a 2-month history of oscillopsia was referred to our hospital for further investigation. On examination, his cognition was normal. He had nystagmus in all directions of gaze; specifically, he had horizontal and rotatory nystagmus in the primary position, downbeat nystagmus after right, left, and up gaze, and upbeat nystagmus after down gaze. Although his limb ataxia was mild, his trunk ataxia was so pronounced that he was unable to walk without support. We strongly suspected paraneoplastic syndrome and tested for neuronal autoantibodies. The anti-Ma2 antibody was strongly positive in the blood and cerebrospinal fluid but other antineuronal autoantibodies were negative. Computed tomography showed an enlarged lymph node in the right axilla but no masses. Biopsy confirmed a diagnosis of NLPHL. The NLPHL cells stained with anti-Ma-2 antibody in the cytoplasm, suggesting these abnormal cells contained protein that was cross-reactive with Ma-2. Conclusions To the best of our knowledge, this is the first case of anti-Ma2-associated PCD in a patient with NLPHL that was confirmed using immunostaining of the lymph node tissue with anti-Ma2 antibody. Our case confirms an association between anti-Ma2-associated PCD and NLPHL.

Melanoma metastasis from an unknown primary cancer has an incidence of 3.2% among melanoma patients. Furthermore, paraneoplastic neurological syndromes (PNS) are rare, occurring in 1–3% of patients with malignancies. Paraneoplastic cerebellar degeneration (PCD) is one of the classic PNS and is characterized by acute or subacute onset of ataxia and/or presence of onconeural antibodies. A 61-year-old male with ataxia, vertigo, and headache later developed dysarthria, multidirectional nystagmus, hyperactive delirium, auditory hallucinations, psychomotor agitation, and myoclonus. Toxicological, metabolic, infectious, and autoimmune etiologies were assessed and reported negative. An osteolytic lesion was observed in the right iliac crest via computed tomography (CT). A positron emission tomography-CT reported increased fluorodeoxyglucose uptake of a right iliac and right inguinal ganglion. After biopsy of the right inguinal ganglion, a BRAF mutation-positive melanoma metastasis from an occult primary cancer was diagnosed. Dermatologic, ophthalmologic, and endoscopic gastrointestinal assessment did not reveal a primary malignant melanoma. The patient’s movement disorders and neuropsychiatric symptoms improved with quetiapine, prednisone, azathioprine, and cyclophosphamide. Oncological management was conducted with MAPK pathway inhibitors (i.e., dabrafenib and trametinib). Movement disorders associated with neuropsychiatric symptoms are complex to diagnose. PNS are rare and often associated with antibodies against neural antigens expressed by the tumor. The case presented above describes a patient with a BRAF-positive malignant melanoma metastasis from an occult primary associated with PCD – to the best of our knowledge, the first reported in the literature.

Abstract Background Cerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early. Case presentation We present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia. Conclusion Paraneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease.

Introduction: PCD (paraneoplastic cerebellar degeneration) is a neurological disorder caused by immunemediated injury to cerebellar Purkinje cells. The symptoms of PCD can precede the diagnosis of underlying gynecological malignancies. The following case highlights the atypical and rare onset of gynecological cancer with paraneoplastic syndrome and emphasizes the need for comprehensive assessment and early detection. Case Report: We report the case of a 49-year-old woman with progressive symptoms of dysarthria, gait instability, and dysmetria after a diarrheal illness. On examination, there was evidence of horizontal nystagmus and an absence of superficial abdominal reflexes. Blood tests showed the presence of antinuclear antibodies = 159UI/ml and positive anti-Yo antibodies. MRI of the head showed left parietal convexity meningioma. Vascular demyelination lesions suggested mild to moderate cerebellar atrophy. The patient underwent a CT of the thorax, abdomen and pelvis that revealed a highly suspicious tubo-ovarian lesion consisting of a 66/35-mm left adnexal mass. After reviewing the investigations, it has been decided that a gynecological examination was necessary to further assess the adnexal mass. It raised the suspicion of an adnexal malignant tumor, which could explain the paraneoplastic syndrome. Surgery was performed via a Pfannenstiel incision, and an intraoperative frozen section diagnosis of fallopian tube carcinoma was made. At inspection, the surgeon found a tumor of the left fallopian tube, of 6/4 cm, highly suspicious of malignancy. A left adnexectomy was performed and the pathology result came back positive for malignancy. The operation was completed with total hysterectomy with right adnexectomy, multiple peritoneal biopsies and an omentectomy. The final histopathology report provided the diagnosis of high-grade serous carcinoma of the left fallopian tube. The postoperative evolution was favorable and the patient started adjuvant treatment. She is currently undergoing chemotherapy, with a slight remission of the neurologic symptoms. Discussions : Typical neurological symptoms in cancer patients are common due to direct tumor invasion of the nervous system or neurotoxicity from chemotherapy. In under 1% of cases, an autoimmune response that targets the neuronal tissue is developed. Numerous antineuronal antibodies are associated with PCD, anti-Yo antibodies being one of them. In our case, PCD has evolved gradually over 7 months, leaving the patient with severe pancerebellar dysfunction. Conclusions: It is important for healthcare providers to be aware that persistent unexplained neurological symptoms can be associated with an underlying malignancy. By recognizing the symptoms of PCD, early cancer diagnosis can be made, leading to a faster treatment and an improved prognostic. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are rare presentations of an underlying oncological disease and more unusual during an oncological disease. They most likely present in small-cell lung carcinomas and thymomas, but present in <1% of the gynecological neoplasms. Acknowledging the pathophysiology is essential for management, explaining its clinical presentation, and future research. We present a patient with an underlying gynecological cancer that during her disease developed a PNS with an unusual autoantibody (anti-CV2/CRMP5) mediating the disease. We report a case of a 62-year-old female diagnosed with ovarian cancer who in the course of her disease developed neurological symptoms associated with cerebellar degeneration. After ruling out differential diagnoses such as metastases, a PNS was suspected and studied, in which anti-CV2/CRMP5 antibodies were positive. With her clinical presentation, radiological features, autoantibody positivity on cerebrospinal fluid, and an underlying oncological disease, cerebellar degeneration was diagnosed. The pathophysiology of PNS is not fully understood; therefore, its diagnosis and management are complex. Diagnosis is based on clinical presentation and specific antibodies associated. Unfortunately, patients have a bad prognosis and diminished quality of life, and therefore a multidisciplinary approach is needed. It is important to mention that the presentation of PNS does not mandatorily appear before the diagnosis of cancer, and multiple cases have been reported in which patients with an underlying oncological disease develop these syndromes. As medical oncologists and neurologists, we must consider and study these syndromes as a possible etiology in cases with an underlying cancer who develop neurological symptoms in the course of their disease. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.

Paraneoplastic cerebellar degeneration (PCD) is a rare neuroimmunological disease that may accompany tumors. In this article, we present a patient with progressive gait difficulty who was diagnosed with PCD and, in a rare comorbidity, with papillary thyroid carcinoma (PTC) following malignancy screening. A 46-year-old male patient reported having experienced poor balance for 2 years. A neurological examination revealed nystagmus, intention tremor, and ataxia, and anti-thyroid peroxidase and anti-thyroglobulin levels were found to be elevated. A brain MRI showed significant cerebellar atrophy in the superior vermis. Malignancy screening for PCD was performed, and thyroid ultrasonography revealed a nodule in the left lobe, while PET/CT detected elevated focal F-18 fluorodeoxyglucose uptake in the thyroid. Onconeuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-Tr, anti-PPCA-2, anti-Ma, anti-CV-1, and anti-ANNA-3) were negative. Pathologic examination of the thyroid revealed PTC, for which the patient was treated with 0.4 g/kg intravenous immunoglobulin and referred to the medical oncology department. This case demonstrates that clinicians must be alert to the rare comorbidity of PCD and PTC. [ABSTRACT FROM AUTHOR]

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We report the effect of intravenous immunoglobulin (IVIG) against paraneoplastic cerebellar degeneration (PCD) in a case of progressive ovarian cancer. Our patient developed PCD soon after postoperative chemotherapy and became bedridden. After undergoing IVIG, however, symptoms dramatically improved, and unexpectedly the remaining tumors were confirmed to have completely disappeared. When PCD is diagnosed, IVIG treatment should be attempted to reduce neuropathy regardless of its degree and the state of the cancer. It may also have further potential benefits that should be considered.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

Paraneoplastic neurologic syndromes are a subgroup of diseases due to indirect cytotoxic effects of the immune system on specific brain structures rather than the mass effect itself. Paraneoplastic anti-Yo antibody mediated subacute cerebellar degeneration is characterised by an insidious onset, a characteristic neurologic syndrome of cerebellar dysfunction, normal or near/normal brain imaging on MRI, and gynaecologic malignancies identified by thorough investigation in middle aged post-menopausal women. Despite various aggressive treatments available, the prognosis is often considered poor. We present two cases with classical findings consistent with paraneoplastic subacute cerebellar degeneration and give literature review.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease. [ABSTRACT FROM AUTHOR]

Background: Cerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early.Case Presentation: We present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia.Conclusion: Paraneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease. [ABSTRACT FROM AUTHOR]

Melanoma metastasis from an unknown primary cancer has an incidence of 3.2% among melanoma patients. Furthermore, paraneoplastic neurological syndromes (PNS) are rare, occurring in 1–3% of patients with malignancies. Paraneoplastic cerebellar degeneration (PCD) is one of the classic PNS and is characterized by acute or subacute onset of ataxia and/or presence of onconeural antibodies. A 61-year-old male with ataxia, vertigo, and headache later developed dysarthria, multidirectional nystagmus, hyperactive delirium, auditory hallucinations, psychomotor agitation, and myoclonus. Toxicological, metabolic, infectious, and autoimmune etiologies were assessed and reported negative. An osteolytic lesion was observed in the right iliac crest via computed tomography (CT). A positron emission tomography-CT reported increased fluorodeoxyglucose uptake of a right iliac and right inguinal ganglion. After biopsy of the right inguinal ganglion, a BRAF mutation-positive melanoma metastasis from an occult primary cancer was diagnosed. Dermatologic, ophthalmologic, and endoscopic gastrointestinal assessment did not reveal a primary malignant melanoma. The patient's movement disorders and neuropsychiatric symptoms improved with quetiapine, prednisone, azathioprine, and cyclophosphamide. Oncological management was conducted with MAPK pathway inhibitors (i.e., dabrafenib and trametinib). Movement disorders associated with neuropsychiatric symptoms are complex to diagnose. PNS are rare and often associated with antibodies against neural antigens expressed by the tumor. The case presented above describes a patient with a BRAF-positive malignant melanoma metastasis from an occult primary associated with PCD – to the best of our knowledge, the first reported in the literature. [ABSTRACT FROM AUTHOR]