Anti-Yo–associated paraneoplastic cerebellar degeneration revealing appendiceal adenocarcinoma: a case report with complete neurological recovery

Paraneoplastic syndromes are secondary conditions to the systemic effects of cancer. Among these, paraneoplastic cerebellar degeneration (PCD) is one of the most common neurological forms. PCD is characterized by immune-mediated damage to Purkinje cells and progressive cerebellar atrophy. Exercise has already been suggested as a non-pharmacological strategy to counteract cachexia, one of the most prevalent paraneoplastic syndromes. However, the impact of physical training on PCD has not yet been investigated. In this study, male BALB/c mice were assigned to four experimental groups. Two groups (T+) were inoculated with C26 tumor fragments and either underwent a 4-week endurance training protocol (TR) or remained sedentary (SED). The remaining two groups (T−) were subjected to the same training or sedentary conditions. Tumor groups were sacrificed at the onset of cachexia to assess the impact of proactive endurance training. Cachexia onset was confirmed during the third week through body weight loss and reduced grip strength analyses. Preliminary histological analysis revealed that the overall cerebellar area was comparable across groups. Interestingly, the Purkinje cell body circularity index and layer thickness were significantly reduced in SED T+ mice and restored in TR T+ animals. Among cerebellar regions, the flocculonodular lobe -crucial for postural and oculomotor regulation- was the most impacted, yet also the one where training provided the strongest effect in preserving Purkinje cell soma size. Since ZIC4 is one of the transcription factors targeted by the autoimmune response in PCD, we evaluated its expression and localization using both immunohistochemistry and immunofluorescence. ZIC4 expression was reduced in the Purkinje cells of SED T+ mice, but training was able to protect Purkinje cells from any autoimmune attack during tumour development. We also assessed the expression of PSD95, a common marker used for the immunolabeling of the post-synaptic side of excitatory synapses. The very low expression of the PSD95 protein in SED T+ mice suggested that the tumour mass affected the synaptic plasticity, while endurance training again preserved synaptic integrity. Altogether, these results suggest an important role of training in the protection of cerebellum damage. Further studies are needed to clarify the role of exercise in protecting the stimulating synapses of the efferent fibers of the cerebellar cortex.

BackgroundWe present a 66‐year‐old female with persistent subacute vertigo lasting 3 weeks, along with a 15 kg weight loss. Her medical history included rheumatoid arthritis, type 2 diabetes, gastroesophageal reflux disease, hypertension, anxiety, and depression. Initially, she was discharged from the emergency department and referred to a neurology outpatient clinic. Six months later, during a follow‐up examination, she exhibited opsoclonus, tongue fasciculations, dysmetria with bilateral intentional tremor, tactile hypoesthesia in the limbs, and significant ataxia.MethodHospitalized for further evaluation, she underwent extensive testing. Magnetic Resonance Imaging (MRI) revealed cerebellar atrophy. Cerebrospinal fluid (CSF) analysis showed oligoclonal bands and an IgG index of 6.2, while other results were normal. Pulse therapy with methylprednisolone failed to improve her symptoms. A chest CT scan revealed a left axillary lymph node (1.4 cm x 1.4 cm), and breast MRI was classified as BI‐RADS 5. A wholebody PET‐CT scan showed hypermetabolic activity in the lymph node, suggesting malignancy.ResultThe patient underwent a left lymph node biopsy, and immunohistochemical analysis revealed: positive CK 7 (SP 52), negative CK 20 (Ks 20.8), positive GATA‐3 (L50‐823), weakly positive estrogen receptor (ER) in 2% of cells, negative progesterone receptor (PR), indeterminate C‐erbB‐2, and a Ki‐67 proliferative index of 50%. These findings confirmed metastasis from primary breast carcinoma.ConclusionThe diagnosis of paraneoplastic syndrome with cerebellar degeneration secondary to breast cancer was established. Paraneoplastic neurological syndromes, triggered by autoimmune responses to tumors or metastases, may present months or even years before or after cancer diagnosis. Early recognition and treatment are essential not only to manage neurological symptoms but also to identify and treat the underlying malignancy. This case underscores the importance of comprehensive clinical evaluation for differential diagnosis of neurological syndromes.

Abstract BACKGROUND Paraneoplastic cerebellar degeneration (PCD) is a rare but debilitating autoimmune neurological syndrome often associated with gynecological malignancies, particularly ovarian cancer. PCD may precede the diagnosis of the underlying tumor, and its early recognition is crucial to improving patient outcomes. METHODS We present a case of a 61-year-old woman from Nepal who developed progressive slurred speech and unsteady gait. Initial neurological work-up, cerebrospinal fluid analysis, and serum biomarkers were inconclusive for metastasis or infection. Further investigations, including imaging, histopathology, and immunohistochemistry, were conducted. RESULTS The patient was found to have elevated CA-125 and a strongly positive anti-Yo antibody. Imaging revealed recurrent pelvic masses with metastases. Biopsy confirmed metastatic ovarian adenocarcinoma. Brain MRI later showed cerebellar atrophy and T2/FLAIR hyperintensities. The patient was diagnosed with paraneoplastic cerebellar degeneration secondary to metastatic ovarian carcinoma. CONCLUSION This case underscores the significance of considering paraneoplastic syndromes in patients with unexplained cerebellar symptoms. Timely evaluation and recognition of PCD can facilitate early cancer detection, allowing for earlier intervention and potentially limiting irreversible neurological damage.

Abstract Paraneoplastic syndromes (PNS) are effects of cancer associated with pathogenic immune-mediated antibodies expressed by tumor cells. We present a case of a 74-year-old male with Merkel cell carcinoma on lenvatinib plus pembrolizumab who presented with gait instability and frequent falls. MRI brain and total spine unremarkable. CSF revealed elevated nucleated cells (13), protein (61 mg/dL), and myelin basic protein (6). Serum neurofilament light chains (NfL) were markedly elevated at 141 pg/mL. After treatment with five days of high dose IVMP followed by two days of IVIG for presumed ICI-induced cerebellitis, the patient’s truncal ataxia resolved. One month later, while tapering oral prednisone, symptoms recurred with severe orthostatic hypotension, prompting an additional dose of IVIG. Due to limited improvement, rituximab (375 mg/m2) was administered, leading to the resolution of symptoms. Paraneoplastic evaluation showed significantly elevated anti-Hu antibodies in the CSF (titers >1:1024) and serum (titers 1:30720) resulting in a diagnosis of anti-Hu associated paraneoplastic cerebellar degeneration (PCD) and dysautonomia. A severe sensorimotor axonal polyneuropathy with a proximal to distal gradient of involvement was identified on EMG. Despite aggressive immunosuppression and physical therapy, symptoms returned with progressive dysarthria, dysphagia, and pronounced functional deterioration. Repeat MRI brain/spine stable. NfL (26 pg/mL) and anti-Hu antibodies (titers 1:15360) in the serum had improved. Although reduced, inflammatory markers persisted in the CSF. In the context of clinical instability and ongoing inflammation, three subsequent doses of rituximab were administered, without response. A recent PET scan showed cancer remission. He started cyclophosphamide (750 mg/m2) and aggressive rehabilitation with the Curren Foundation. This case is rare and illustrates a prolonged recovery in a patient with anti-Hu PNS and Merkel cell carcinoma. We shed light on the importance of suspecting PNS to avoid misdiagnosis. Our case opens discussion regarding the perceived risk of PNS in patients being treated with ICI.

Background: Paraneoplastic cerebellar degeneration (PCD) is a rare neurological disorder caused by tumor-mediated antibodies targeting the cerebellum, often leading to irreversible cerebellar damage. The most common antibody implicated in PCD is anti-Purkinje cell cytoplasmic antibody type-1, associated with malignancies such as breast, gynecological, and lung cancers. Symptoms often include dizziness, imbalance, progressive ataxia, and other cerebellar signs/symptoms, but early presentations may mimic acute vestibular syndrome, thus complicating diagnosis.Purpose: To present a case of PCD and demonstrate how objective vestibular test results facilitated the management of the patient’s medical care.Research Design: Case report.Case Presentation: A 67-year-old female with a history of left breast cancer presented with acute dizziness, imbalance, and left-sided lower-extremity weakness. The patient was referred for objective vestibular testing at the request of her internal medicine doctor.Results: Vestibular testing revealed continuous down-beating nystagmus and abnormal video head impulse test (vHIT) findings of the posterior canals only. Findings and history raised concern for central vestibular origin. Subsequent neurological evaluations revealed progressive cerebellar dysfunction. After a long medical journey, anti-Yo antibodies were detected, confirming a diagnosis of PCD.Conclusions: PCD can present with early vestibular symptoms, such as vertigo and dizziness, and as a result of damage to Purkinje cells in the cerebellum. This damage extends to the central vestibular system structures, which can lead to down-beating nystagmus and impaired vestibular-ocular reflex function as evident by vHIT findings. Early vestibular testing can play a role in the diagnosis, particularly when accompanied by a detailed cancer history.Clinical Relevance Statement: Given the rapid disease progression of PCD, it is crucial for clinicians conducting vestibular testing to understand signs of central nervous system involvement and refer patients promptly for neurological evaluation.

Background and ObjectivesThe aim of this study was to describe 2 patients with paraneoplastic cerebellar degeneration (PCD) treated with autologous hematopoietic stem cell transplantation (AHSCT).MethodsOff-label AHSCT was performed at Hospital Clinic Barcelona, including stem cell mobilization (cyclophosphamide, filgrastim), plasma exchange, and a nonmyeloablative regimen (cyclophosphamide, antithymocyte globulin, rituximab [RTX]).ResultsA 38-year-old woman developed anti-Yo–associated PCD 17 months after treatment of a gynecologic cancer (without evidence of tumor recurrence). Despite treatment with steroids and RTX, she became unable to walk. AHSCT resulted in progressive improvement, no longer needing assistance to walk 9 months after AHSCT. Tumor recurrence, without neurologic worsening, was identified 16 months after AHSCT, and chemotherapy was restarted. At the last follow-up (46 months), she continues on chemotherapy without neurologic deterioration. A 48-year-old man developed PCD associated with Tr/delta/notch-like epidermal growth factor–related receptor antibodies. Axillary lymph node biopsy demonstrated Hodgkin lymphoma. Chemoradiation resulted in complete tumor response, but cerebellar ataxia worsened despite treatment with steroids and IV immunoglobulins. Ten months after cerebellar symptom onset, he underwent AHSCT resulting in neurologic improvement. At the last follow-up, 39 months after AHSCT, he remains independent in activities of daily living.DiscussionIn our experience, AHSCT is worth to be considered in patients with progressive PCD refractory to conventional oncological and immunotherapy treatments.Classification of EvidenceThis is a single observational study without controls and provides Class IV evidence.

The ER relies on the microtubule cytoskeleton for the organization of its extended membrane network, but how microtubule-based motors contribute 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 in human cancer cells 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.

Abstract Abstract: Background: Paraneoplastic cerebellar degeneration (PCD), also known as Anti-Yo antibody syndrome, is a rare neurodegenerative manifestation described in patients with malignant tumors, including breast cancer. In these patients, the diagnosis of breast cancer usually follows the onset of neurologic symptoms and can be made months to years after symptom onset, most commonly through PET scan or CT whole body scans. Case presentation: We present the case of a 51-year-old female undergoing neurologic work up for suspected multiple sclerosis (MS) after experiencing sudden onset severe neurologic deficits to include diplopia, dysarthria, gait instability, and extremity paresthesias. As part of her evaluation, CT chest was obtained which revealed an incidental left breast mass. Diagnostic mammogram and subsequent core needle biopsy lead to the diagnosis of an ER/PR negative, HER2 positive invasive ductal carcinoma (IDC). During this time her neurologic symptoms were not responding to MS treatment regimens and further imaging was inconsistent with MS. In the setting of a newly confirmed breast malignancy, she underwent work up for a paraneoplastic syndrome to include PCA1/Anti-Yo antibodies. She was found to have significantly elevated levels of PCA1 (anti-Yo antibodies) consistent with PCD. She underwent neoadjuvant chemotherapy with TCHP, followed by partial mastectomy with sentinel lymph node biopsy, with minimal improvement in her neurologic symptoms. Surgical pathology revealed no evidence of residual IDC, negative margins, and no evidence of axillary metastasis – ypT0N0. To date she has completed adjuvant radiation therapy and remains on adjuvant Herceptin and Perjeta. Unfortunately, the patient’s symptoms have persisted despite breast cancer treatment. She has additionally undergone four cycles of plasmapheresis and IVIG treatments, with no significant improvement noted to date. Conclusions: Anti-Yo antibodies detected at significantly elevated levels causing a paraneoplastic syndrome of the brain is a rare manifestation and a very uncommon complication of breast cancer. The elevation of Anti-Yo antibodies has been observed in only 1.6% of breast cancer cases, with few documented instances of associated neurologic symptoms. This patient is one of the few rare cases to manifest this neoplastic syndrome and develop severe neurologic symptoms. While an uncommon complication of breast cancer, providers should consider investigating PCD in patients presenting with new-onset neurologic degenerative symptoms alongside a recent breast cancer diagnosis. Additionally, it has also been reported that over-expression of HER2 is frequently seen in patients with elevated levels of PCA1/Anti-Yo antibodies, as in our case. Citation Format: Ashley Montgomery, Ismail Jatoi, Carissia Calvo-Strube. The diagnosis of Anti-Yo antibody mediated paraneoplastic syndrome, a rare neurodegenerative disorder in a patient with invasive breast cancer, a case report [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-08-24.

A 56-year-old male presented with complaints of insidious onset difficulty in speech and head tremors for 2 years and imbalance while walking for 1 year. He did not have autonomic dysfunction and had a negative family history. The cerebrospinal fluid examination was normal and the workup for autoimmune disorders was negative. Brain magnetic resonance imaging showed mild superior cerebellar atrophy. The serum paraneoplastic antibody panel showed anti-Sry-like high mobility group box (SOX1) antibodies positivity. He was treated with steroids and steroid-sparing immunosuppressants resulting in mild improvement. Extensive workup for underlying malignancy was negative. Our case illustrates a small subset of individuals with anti-SOX1 antibody positivity who also exhibit neurological symptoms indicative of paraneoplastic cerebellar degeneration without having any underlying tumor and responded to immunotherapy.

Paraneoplastic neurological syndromes (PNS) are a complex spectrum of clinical syndromes that are associated with underlying malignancies. Majorly being immune-mediated, these syndromes are characterized by the presence of specific paraneoplastic antibodies that are either directed against intracellular (onconeuronal) or extracellular (surface or junctional) antigens. Syndromes associated with the occurrence of onconeuronal antibodies have poor prognoses. The spectrum of neurological manifestations includes limbic encephalitis, paraneoplastic cerebellar degeneration, rhombencephalitis, myelitis, optic neuropathy, cranial neuropathies, plexopathy and polyneuropathy. This review presents a comprehensive overview of these manifestations including their imaging features, associated malignancies and antibodies, differential diagnoses and recommended further evaluation.

Anti-Yo (PCA1) Antibody Associated Paraneoplastic Cerebellar Degeneration (PCD) in Primary Occult Breast Cancer (OBC). (P3-8.009)

Rationale:Paraneoplastic syndromes occur in 10% to 20% of all malignancies, with paraneoplastic neurological syndromes in less than 1% of all malignancies. In small cell lung cancer (SCLC), paraneoplastic manifestations are more common, affecting up to 5% of cases. Common manifestations include syndrome of inappropriate antidiuretic hormone secretion, Cushing’s syndrome due to adrenocorticotropic hormone secretion, paraneoplastic cerebellar degeneration, and Lambert-Eaton myasthenic syndrome. Paraneoplastic acute motor and sensory polyneuropathy is an exceptionally rare but severe complication, necessitating timely diagnosis and management.Patient concerns:A 55-year-old male with an 80 pack-year history of smoking presents to the hospital with a 3-week history of fevers, productive cough, dyspnoea, and wheeze. He had no significant comorbidities.Diagnoses:Extensive radiological investigations revealed a large mass at the right hilum compressing on the right lower bronchus with metastatic adrenal deposits. Biochemical investigations confirmed syndrome of inappropriate antidiuretic hormone secretion, and histology identified SCLC.Interventions:Despite initiating a combination chemotherapy with carboplatin and etoposide, the patient developed progressive motor paralysis and sensory loss over 4 days, leading to a diagnosis of paraneoplastic acute motor and sensory polyneuropathy.Outcomes:He deteriorated rapidly and died 14 days after symptom onset due to respiratory failure, underscoring the aggressive nature of paraneoplastic syndromes.Lessons:Paraneoplastic syndromes, particularly in SCLC, pose significant diagnostic and therapeutic challenges. This case highlights the importance of early recognition and prompt multidisciplinary intervention, which may improve outcomes despite the low incidence of these severe complications. Treating cancer with appropriate systemic chemotherapy or suppression of the immune response alleviates neurological symptoms and improves prognosis.

Utility of cerebellar inhibition in paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome (PCD-LEMS): diagnosis and follow-up

Neurological immune-related adverse events can manifest as paraneoplastic neurological syndrome (PNS), especially in patients with small-cell lung cancer (SCLC). We herein report a 73-year-old man with SCLC treated with an immune checkpoint inhibitor (ICI) combined with chemotherapy. Although the chemo-immunotherapy induced a favorable response to SCLC, he later developed acute cerebellar ataxia. He was diagnosed with paraneoplastic cerebellar degeneration associated with anti-Sry-like high mobility group box 1 (SOX1) autoantibody. The antibody was also identified in serum collected at the diagnosis of SCLC and before ICI administration, which retrospectively suggested that the patient was at risk of ICI-induced PNS. J. Med. Invest. 72 : 172-176, February, 2025.

Paraneoplastic cerebellar degeneration - raising awareness for early diagnosis.

Paraneoplastic cerebellar degeneration (PCD) is a rapidly progressive, immune-mediated syndrome characterized by the degeneration of Purkinje cells, often associated with the presence of antibodies targeting intracellular antigens within these cells. These autoantibodies are implicated in the induction of cytotoxicity, leading to Purkinje cell death, as demonstrated in in vitro models. However, the precise roles of antibodies and T lymphocytes in mediating neuronal injury remain a subject of ongoing research, with T cells appearing to be the main effectors of cerebellar injury. Notably, at least 50% of PCD cases involve anti-Yo autoantibodies, also referred to as anti-PCA1 (Purkinje cell antigen 1) antibodies, which specifically target cerebellar degeneration-related protein 2 (CDR2) and its paralogue, CDR2-like (CDR2L). Another recognized antigen is CDR 34, a 34 kDa Purkinje cell antigen characterized by tandem repeats and a B-cell epitope; its detection in non-cerebellar tissues necessitates further in situ hybridization studies. Onconeural antigens are expressed in both Purkinje cells and tumour cells, where they localize in the cytoplasm and associate with membrane-bound and free ribosomes, playing critical roles in regulating transcription and calcium homeostasis. Recent studies suggest that the breakdown of immune tolerance is linked to genetic alterations in tumour cell antigens, leading to the formation of neoantigens that can elicit autoreactive T cells, which may underscore the function of Yo antibodies. In vitro studies indicate that anti-Yo antibodies can induce cell death independent of T lymphocytes. The disease progresses by initial lymphocytic infiltration, followed by a rapid loss of Purkinje cells without significant inflammation. However, in vivo models showcase that anti-Yo PCD is primarily T-cell mediated, with antibodies serving as biomarkers rather than direct effectors of neuronal death. This review examines the mechanisms underlying PCD, focusing on the roles of CDR2 and CDR2L in tumour development and their potential role in the degeneration of cerebellar Purkinje neurons. A comprehensive understanding of these processes is essential for advancing diagnostic, prognostic, and therapeutic strategies for PCD and associated malignancies.

Paraneoplastic cerebellar degeneration (PCD) typically presents via acute to subacute cerebellar ataxia, dysarthria, and ocular dysmetria, resulting from tumor-induced autoimmunity against the cerebellum. In most cases, symptoms of PCD show months before a diagnosis of cancer. Therefore, it is important for clinicians to investigate the primary tumor in PCD cases in order to treat both conditions concurrently. Herein, we report a case of PCD associated with an anti-Yo antibody, leading to a diagnosis of left fallopian tube adenocarcinoma.

ABSTRACTA 62‐year‐old man was diagnosed with paraneoplastic cerebellar degeneration (PCD) at a previous hospital due to cerebellar ataxia, positive serum SOX‐1 antibodies, and small cell lung cancer. Although the tumor has shrunk by chemotherapy, the cerebellar ataxia progressed and left him unable to walk. Lambert–Eaton myasthenic syndrome (LEMS) was suspected, because nerve conduction studies showed that reduced compound muscle action potential amplitudes disproportionate to muscle weakness. PCD‐LEMS with SOX‐1 antibodies was diagnosed on the basis of waxing by high‐frequency repetitive nerve stimulation test and high P/Q‐type voltage‐gated calcium channel antibody levels. Immunoglobulin therapy and 3,4‐diaminopyridine contributed to improved activities of daily living by improving muscle weakness masked by cerebellar symptoms. In patients with SOX‐1 antibodies, investigating for tumors and LEMS is necessary, even if muscle weakness is not noticeable.

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.