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.

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.

[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.

Cerebellar leptomeningeal enhancement: An imaging finding of rapidly progressive Purkinje cell cytoplasmic autoantibody type 1 paraneoplastic cerebellar syndrome.

Purkinje cell cytoplasmic autoantibody type 1 (PCA1), also known as anti-Yo, is a 'high-risk' paraneoplastic antibody, associated with rapidly progressive cerebellar syndrome. In patients with this syndrome, various MRI abnormalities have been documented, including atrophy in the cerebellum and brainstem, T2 hyperintensity in the brainstem and spinal cord, and cranial nerve enhancement. This report introduces an imaging finding, cerebellar leptomeningeal enhancement, which was observed in all three cases at early stages. Despite neurological deterioration, all patients underwent immunotherapy, and subsequent follow-up MRI revealed resolution of the leptomeningeal enhancement, suggesting that this feature is distinct from meningeal carcinomatosis.

Cerebellar progressive multifocal leucoencephalopathy identified by the shrimp sign.

Progressive multifocal leucoencephalopathy (PML) is a demyelinating disease caused by the John Cunningham (JC) virus, which may get reactivated under certain immunosuppressive states such as AIDS, immunomodulatory therapy and haematological malignancies. PML has been reported rarely even in immunocompetent individuals where no immunodeficiency was present. PML characteristically involves periventricular and juxtacortical white matter. Isolated cerebellar or brainstem PML may be seen rarely. We present a case of a man in his 70s who presented with rapidly progressive cerebellar ataxia, ptosis and bipyramidal signs. Investigations excluded a direct viral cerebellar infection, acute disseminated encephalomyelitis, paraneoplastic cerebellar degeneration or any structural cerebellar lesion. MRI PET study revealed the classical shrimp sign which raised the possibility of cerebellar PML, and the same was confirmed by a positive JC virus PCR in the cerebrospinal fluid. Our patient had no known immune-compromising state, but further workup revealed a low CD4 count suggestive of idiopathic CD4 lymphopenia. The case illustrates the importance of the shrimp sign on MRI, the possibility of cerebellar involvement of PML as well as the need to consider a differential diagnosis of PML even in individuals with no obvious immunocompromised state.

Ovarian mass Presenting as Paraneoplastic cerebellar degeneration with peripheral neuropathy and anti-Yo antibody.

Paraneoplastic neurological syndromes (PNS) are a group of disorders with diverse neurological manifestations that are observed in patients with various types of cancer. Any portion of the nervous system can be affected by these syndromes, which are brought on by processes other than metastasis, direct tumour spread or chemotherapy side effects. An immune-mediated attack on the cerebellar Purkinje cells and consequent cerebellar symptoms define paraneoplastic cerebellar degeneration(PCD), a subtype of the PNS. Axonal or demyelinating paraneoplastic peripheral neuropathies are both possible. Here, we describe the case of a middle-aged woman who presented with subacute-onset cerebellar symptoms and peripheral neuropathy, was discovered to have a positive anti-Yo antibody, and was later detected to have an ovarian mass. This case illustrates the significance of considering a paraneoplastic aetiology in patients with otherwise unexplained neurological manifestations and initiating an appropriate workup and early treatment for the primary malignancy.

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.

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.

Anti-Ma2 Antibody-Mediated Paraneoplastic Cerebellar Degeneration and Myeloneuropathy Secondary to Lymphoma.

ABSTRACT: A 61-year-old woman with a history of untreated low-grade B-cell lymphoma presented with blurry vision, unsteadiness, and worsening pain on touching skin of the upper trunk was enrolled. Blurry vision was attributed to oscillopsia from downbeat nystagmus, which later evolved into macrosaccadic oscillations. MRI brain and spine showed mild, longitudinally extensive T2 hyperintensity in the central gray matter of the spinal cord extending from the medulla to T11 level. Serum paraneoplastic panel was negative; however, she had very high titers of anti-Ma2 antibodies in cerebrospinal fluid. The diagnosis of paraneoplastic neurological syndrome was made. Empiric treatment with high dose of intravenous steroids followed by intravenous immunoglobulin infusions did not improve her symptoms. An extensive search for an underlying tumor commenced and was initially unrevealing. However, two-month follow-up positron emission tomography scan showed increased uptake in a right pulmonary nodule, which when biopsied confirmed diagnosis of extranodal marginal zone lymphoma. The final diagnosis was anti-Ma2 antibody-mediated paraneoplastic cerebellar degeneration and myeloneuropathy secondary to lymphoma.

CDR2 and CDR2L line blot performance in PCA-1/anti-Yo paraneoplastic autoimmunity.

Background: Purkinje cytoplasmic autoantibody type 1 (PCA-1)/anti-Yo autoimmunity is a common high-risk paraneoplastic neurological disorder, traditionally attributed antigenically to cerebellar degeneration-related protein 2 (CDR2), predominantly affecting women with gynecologic or breast adenocarcinoma. Single-modality CDR2 testing may produce false-positive results. We assessed the performance characteristics of the more recently purported major PCA-1/Yo antigen, CDR2-like (CDR2L), side by side with CDR2, in a line blot format. Methods: CDR2 and CDR2L were tested in six specimen groups (serum and cerebrospinal fluid (CSF)). Group 1, PCA-1/Yo mouse brain indirect immunofluorescence assay (IFA) positives; Group 2, PCA-1/Yo IFA mimics; Group 3, suspected CDR2 line blot false positives; Group 4, consecutive patient samples tested for neural antibodies over 1 year; Group 5, healthy subject serums; and Group 6, polyclonal (non-specific) immunoglobulin G (IgG)-positive serums. Results: Group 1: Of 64 samples tested, all but two were CDR2 positive (both CSF samples) and all were CDR2L positive. In individual patients, CDR2L values were always higher than CDR2. The two "CDR2L-only" positives were CSF samples with low titer PCA-1/Yo by IFA with serum negativity but with typical clinical phenotype. Group 2: All 51 PCA-1/Yo mimics were CDR2/CDR2L negative. Group 3: Nine samples [six of 1289 (0.47%) serums and three of 700 CSF samples (0.43%) were PCA-1/Yo IFA negative/CDR2 positive; two of the six available (serums from the same patient) were also CDR2L positive; the other four CDR2L negative had low CDR2 values (17-22). Group 4: Twenty-two patients had unexpected CDR2 or CDR2L positivity; none had tissue IFA positivity. Eleven of the 2,132 serum (0.5%) and three of the 677 CSF (0.4%) samples were CDR2 positive; median value was 19 (range, 11-48). Seven of the 2,132 serum (0.3%) and three of the 677 CSF (0.4%) samples were CDR2L positive; median value was 18 (range, 11-96). Group 5: All 151 healthy serum samples were negative. Group 6: One of the 46 polyclonal serum samples was CDR2L positive. Optimum overall performance was accomplished by requiring both CDR2 and CDR2L positivity in serum (sensitivity, 100%; and specificity, 99.9%) and positivity for CDR2L in CSF (sensitivity, 100%; and specificity, 99.6%). Conclusion: CDR2L provides additional PCA-1/anti-Yo sensitivity in CSF, and dual positivity with CDR2 provides additional specificity assurance in serum. Combining antigen-specific and tissue-based assays optimizes PCA-1/anti-Yo testing.

Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.

OBJECTIVE: Co-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. METHODS: We 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. RESULTS: Among 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. INTERPRETATION: TRIM9/67-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.

Anti-Yo paraneoplastic cerebellar degeneration in a patient with stage IV ovarian adenocarcinoma during bevacizumab maintenance therapy.

Anti-Yo paraneoplastic cerebellar degeneration (PCD) is a rare autoimmune neurological syndrome characterised by cerebellar symptoms and frequently associated with gynaecological malignancies. While typically preceding the diagnosis of the malignancy, rarely it may present later in the disease course, heralding a recurrence prior to biochemical or radiological confirmation. Disease management is challenging and prognosis remains poor.We present the case of a woman with stage IV ovarian adenocarcinoma who developed anti-Yo PCD 16 months post malignancy diagnosis while receiving bevacizumab maintenance therapy. We review the literature and outline the difficulties in diagnosis and the frequently refractory nature of PCD to available treatments.

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

ABSTRACT: 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.

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.

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.