Paraneoplastic Cerebellar Degeneration (PCD) associated with PCA-1 antibodies in established cancer patients.

INTRODUCTION: Paraneoplastic cerebellar degeneration (PCD) is a rare set of neurological disorders arising from tumor-associated autoimmunity against antigens within the cerebellum. Anti-Purkinje cell cytoplasmic antibody 1 (PCA-1), or anti-Yo, is the most commonly linked antibody and is classically associated with breast and ovarian cancers. METHODS: Medical records of patients at our institution who developed PCA-1 associated PCD were reviewed. Clinical information, including cancer history, cancer-directed treatment, and serum and CSF titers of PCA-1 antibody were extracted. CASES: We report a series of cases of PCA-1 associated PCD in patients with known breast or ovarian cancer diagnosis not receiving immunotherapy. These cases highlight aspects of PCA-1 paraneoplastic syndrome such as triggering by cytotoxic chemotherapy or surgery, the possibility of tumor recurrence and the association with development of a second cancer. DISCUSSION: Diagnosis of the syndrome requires neurological workup with lumbar puncture (LP) with cerebrospinal fluids (CSF) studies, serum and CSF paraneoplastic antibody panel, and neuroimaging. Inpatient admission for prompt workup and initiation of treatment is recommended. Treatment most commonly includes immunosuppression with corticosteroids, plasmapheresis, and/or intravenous immune globulin (IVIG); however, we postulate that other immune modulating treatments may warrant consideration. CONCLUSION: These cases highlight the need for early recognition of the syndrome in patients receiving nonimmune based chemotherapy, for prompt workup and treatment.

Anti-Ma-associated paraneoplastic cerebellar degeneration in a patient with nodular lymphocyte-predominant Hodgkin lymphoma: a case report.

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.

[Paraneoplastic subacute degeneration of the cerebellum in non-small cell lung cancer and positive anti-Tr3 antibodies]. / Paraneoplastische subakute Degeneration des Kleinhirns bei nichtkleinzelligem Bronchialkarzinom und positiven Anti-Tr3-Antikörpern.

Neurological disorders can occur before the diagnosis of a malignoma is set. These disorders are induced by a misguided immune response with antibodies against intracellular or cell surface antigens. One of the most common paraneoplastic diseases is the subacute degeneration of the cerebellum. In most of the cases antibodies against Anti Hu, CRMP5/CV2, Amphiphysin and Ma/Ta are found and small cell bronchial carcinoma, breast cancer and lymphoma are diagnosed. We report about a 67 years old man with cerebellar symptoms and a weight loss of 10 kg who was treated in our clinic. After our diagnostic work up we found a non small cell cancer and diagnosed a subacute degeneration of the cerebellum as a paraneoplastic disorder. We found a high positive titer for Anti-Tr3 antibodies while the rest of the paraneoplastic antibodies described as typically associated with the subacute degeneration of the cerebellum were negative. The Anti-Tr3 antibodies are usually found in patients with Hodgkin and less often Non-Hodgkin disease. After initiation of a tumor specific therapy and intravenous immunoglobulin therapy the cerebellar symptoms decreased. In future follow up examinations we will see if the anti-Tr3 antibodies were associated with the non small cell bronchial carcinoma or if a lymphoma will occur in our patient.

[A Case of Rectal Colon Cancer with Paraneoplastic Cerebellar Degeneration].

A case complicated with colorectal and prostate cancers in paraneoplastic(subacute)cerebellar degeneration(PCD)is extremely rare. We report a retrospective case of rectal carcinoma with paraneoplastic cerebellar degeneration. A 79-year-old man with Parkinson's disease was unable to walk because of paralysis. Brain MRI showed cerebellar atrophy. He was admitted to our hospital for anal bleeding and was diagnosed with colon cancer. An associated diagnosis of PCD was made. After resection, his paralysis and dysarthria were resolved to the extent of beingable to walk and speak fluently. Brain MP-RAGE showed no findings suggestive of metastasis or atrophy. He was treated surgically, which resulted in a transient improvement in PCD symptoms. Per blood testing, cytokines IL-6 and IL-10 were lower postoperatively. Immunosuppressive levels of myeloid- derived suppressor cells(MDSCs)were lower compared with the preoperative values. Thus, innate immunocompetence and resolution of paralysis followed the surgical intervention.

Inpatient rehabilitation performance of patients with paraneoplastic cerebellar degeneration.

OBJECTIVE: To evaluate the functional improvement of rehabilitation inpatients with paraneoplastic cerebellar degeneration. DESIGN: Retrospective review. SETTING: Referral-based hospitals. PARTICIPANTS: Cancer rehabilitation inpatients (N=7) admitted to 3 different cancer centers with a diagnosis of paraneoplastic cerebellar degeneration. INTERVENTION: Medical records were retrospectively analyzed for demographic, laboratory, medical, and functional data. MAIN OUTCOME MEASURE: FIM. RESULTS: All 7 patients were white women (median age, 62y). Primary cancers included ovarian carcinoma (n=2), small cell lung cancer (n=2), uterine carcinoma (n=2), and invasive ductal breast carcinoma (n=1). Mean admission total FIM score was 61±23.97. Mean discharge total FIM score was 73.6±29.35. The mean change in total FIM score was 12.6 (P=.0018). The mean length of rehabilitation stay was 17.1 days. The mean total FIM efficiency was .73. Of the 7 patients, 5 (71%) were discharged home, 1 (14%) was discharged to a nursing home, and 1 (14%) was transferred to the primary acute care service. CONCLUSIONS: To our knowledge, this is the first study to demonstrate the functional performance of a group of rehabilitation inpatients with paraneoplastic cerebellar degeneration. Despite the poor neurologic prognosis associated with this syndrome, these patients made significant functional improvements in inpatient rehabilitation. When appropriate, inpatient rehabilitation should be considered. Further studies with larger sample sizes are needed.

Paraneoplastic cerebellar degeneration as the first evidence of malignancy: a case report.

Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated paraneoplastic disorder affecting the cerebellum. PCD associated with ovarian malignancy is a rare occurrence with fewer than 100 cases reported in published work. PCD patients express anti-Yo antibody, one of the anti-onconeuronal antibodies which is most likely associated with gynecologic or breast malignancies. In this report, we present the case of a 65-year-old postmenopausal woman presenting with acute symptoms of PCD as a first sign of ovarian malignancy.

Paraneoplastic cerebellar degeneration caused by ovarian clear-cell carcinoma.

Paraneoplastic cerebellar degeneration is a paraneoplastic neurological syndrome caused by the remote effect of certain systemic cancers and is characterized by subacute cerebellar symptoms. A 62-year-old woman suffering from unidentified cerebellar symptoms was admitted to our hospital. Paraneoplastic cerebellar degeneration was suspected and ovarian cancer was detected after the systemic examination for malignancy. The symptoms of vertigo and dysarthria were improved a little after surgical operation and treatments of γ-globulin, steroid pulse and tacrolimus hydrate. The cerebellar symptoms of paraneoplastic cerebellar degeneration are often evident prior to detection of malignancy. It is important to perform systemic examination for malignancy in case of unidentified cerebellar symptoms.

Paraneoplastic neurologic syndrome associated with gynecologic and breast malignancies.

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

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

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

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

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

Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease.

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome associated with lung cancer, breast adenocarcinoma,ovarian adenocarcinoma, and Hodgkin disease. It is rarely seen in pediatrics. We report a case of a 10-year-old boy with a 2-year prodrome that led to a diagnosis of PCD in association with stage IV Hodgkin disease. He received radiation and chemotherapy for his Hodgkin disease with resolution of his lymphoma. Based on promising data in adults on the efficacy of rituximab over other immuno suppressive agents in paraneoplastic disorders, he was treated with rituximab with marked improvement of the cerebellar syndrome.

Anti-Yo antibody associated with occult fallopian tube carcinoma.

This is the case report of a 61-year-old woman who presented with progressive diplopia and ataxia. Her cerebrospinal fluid revealed high titers of anti-Yo (PCA-1) antibody and a magnetic resonance imaging with contrast showed cerebellar degeneration. Extensive imaging workup was negative for malignancy and she was otherwise asymptomatic. Given the association between anti-Yo antibodies and gynecologic malignancies, she underwent a bilateral salpingo-oophorectomy and cancer staging. Extensive section of the fimbriated end of the fallopian tube revealed a stage 1, microscopic serous adenocarcinoma. After surgery, her anti-YO titers fell and plans were made for adjuvant chemotherapy. Her neurologic symptoms are not expected to substantially improve, illustrating the urgent need for early surgical investigation in cases of paraneoplastic syndrome, even in the absence of imaging evidence of a lesion.

Anti-Ri-associated paraneoplastic cerebellar degeneration. Report of a case and revision of the literature.

Paraneoplastic cerebellar degeneration associated with anti-Ri antibodies mainly presents with opsoclonus-myoclonus-ataxia. We report here the case of a patient with anti-Ri-antibody paraneoplastic syndrome, who presented four years after treatment for small-cell lung cancer (SCLC) with oscillopsia and gait disorder. On neurological examination vertical nystagmus, ataxic gait and postural tremor of all four limbs was detected. He died one year after the onset of the symptoms because of a acute exacerbation of his severe chronic obstructive pulmonary disease. No SCLC relapse or new cancer has been detected during the one-year follow-up period.To our knowledge, our patient is the first case of anti-Ri associated disorder with oscillopsia and vertical nystagmus as the initially prominent clinical features. The findings of this case study support the variability of anti-Ri-antibody-associated paraneoplastic syndrome. Further studies must be directed to better characterize the mechanisms underlying this syndrome. Finally, paraneoplastic neurological syndromes should be kept in mind also when a neoplastic disease is not demonstrated.

Rare case of paraneoplastic cerebellar degeneration secondary to high-grade serous carcinoma of tubo-ovarian origin.

This case describes a 69-year-old woman, who presented with rapidly progressive cerebellar symptoms and unintentional weight loss. Full neurological assessment excluded space-occupying lesions, vascular accidents and infection. Surprisingly, a chest, abdomen and pelvis CT showed a left hemipelvis mass, which was subsequently biopsied. A high-grade serous carcinoma of tubo-ovarian origin was found, diagnosing paraneoplastic cerebellar degeneration (PCD) secondary to this. The exact mechanism is not known, but is thought to be immune-mediated. In cases of PCD, after cancer treatment, the neurological disability stabilises to a severe level and will unfortunately be lifelong. Our patient continues to make great progress with intensive rehabilitation for her ongoing balance issues. Early recognition of PCD can lead to a prompt diagnosis of the underlying malignancy and hence subsequent management. This can at least limit the extent of the neurological disability of the disease and increase the survival rate from cancer.

Functional analysis of CD8+ T cell responses to the onconeural self protein cdr2 in patients with paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) is linked to an immune response against cerebellar degeneration related antigen 2 (cdr2) co-expressed in tumor and Purkinje neurons. Here, comprehensive immune-assessment assays were used to analyze CD8(+) T cells from 7 PCD patients, but no evidence was found of CD8(+) T cells specific for either of two previously described cdr2 epitopes (cdr2-1 and cdr2-2). In contrast, viral-specific CD8(+) T cells from healthy volunteers and PCD patients were measurable. These findings are inconsistent with an obligate role for cdr2-1- or cdr2-2-specific CD8(+) T cells in the pathogenesis of PCD.

Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications.

BACKGROUND: To investigate the neuropsychological outcome of children treated with surgery and posterior fossa irradiation for localized infratentorial ependymoma. METHODS: 23 patients (age 0.3 - 14 years at diagnosis) who were treated with local posterior fossa irradiation (54 Gy) underwent one (4 patients) or sequential (19 patients) neuropsychologic evaluation. The last evaluation was performed at a median of 4.5 (1 to 15.5) years after RT. RESULTS: Mean last full scale IQ (FSIQ), verbal IQ (VIQ) and PIQ were 89.1, 94.0, and 86.2 respectively. All patients had difficulties with reading, and individual patients showed deficits in visuospatial, memory and attentional tasks. There was no trend for deterioration of intellectual outcome over time. All 5 children with IQ scores < or = 75 were under the age of four at diagnosis. There was a significant association between the presence of cerebellar deficits and impaired IQ (72.0 vs 95.2, p < 0,001). The absence of hydrocephalus was an indicator of better neuropsychologic outcome (mean FSIQ of 102.6 vs 83.9, p = 0.025). CONCLUSION: Within the evaluated cohort, intellectual functions were moderately impaired. Markedly reduced IQ scores were only seen with early disease manifestation and treatment, and postoperative neurological deficits had a strong impact on intellectual outcome.

A case of paraneoplastic cerebellar ataxia secondary to renal cell carcinoma.

A 64-year-old female patient presented with acute cerebellar ataxia. After ruling out vascular, infectious, metastatic, demyelinating, and medication etiologies, a paraneoplastic origin for her illness was determined. A renal mass was discovered and found to be renal cell carcinoma. Her symptoms resolved after a radical nephrectomy. Physicians should consider the diagnosis of paraneoplastic neurologic syndromes whenever a thorough evaluation fails to explain neurologic abnormalities.