IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration.

Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo-self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely α4 integrin and IFN-γ. Mice with PCD were treated with anti-α4 integrin antibodies or neutralizing anti-IFN-γ antibodies at the onset of neurological signs. Although blocking α4 integrin had little or no impact on disease development, treatment using the anti-IFN-γ antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-γ by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti-IFN-γ antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders.

Paraneoplastic cerebellar degeneration in a patient with anaplastic non-Hodgkin's lymphoma.

A 31-year-old man presented with a subacute cerebellar syndrome of unknown aetiology. Investigations including a paraneoplastic antibody screen were negative and a working diagnosis of possible vasculitis was concluded. After 1 month, he re-presented with worsening of his symptoms and a neck lump. He was diagnosed with anaplastic lymphoma kinase, negative non-Hodgkin's lymphoma and paraneoplastic cerebellar syndrome. A more extensive paraneoplastic antibody screen found patient to be Tr (delta/notch-like epidermal growth factor-related receptor) antibody positive. After a period of chemotherapy and steroid treatments, his symptoms are now stable in terms of cerebellar function. This case report summarises a very rare diagnosis of paraneoplastic cerebellar degeneration with a positive onconeuronal antibody associated with anaplastic non-Hodgkin's lymphoma.

Anti-Yo positive and late-onset paraneoplastic cerebellar degeneration associated with ovarian carcinoma: A case report.

RATIONALE: Paraneoplastic cerebellar degeneration (PCD) is a rare nonmetastatic neurological complication often associated with ovarian, breast, and other gynecologic cancers. Anti-Yo is one of the antionconeural antibodies found in patients with PCD. It primarily emerges before a malignancy is detected. PATIENT CONCERNS: In this report, we describe an unusual case involving a patient who exhibited anti-Yo-positive PCD 1 year after being diagnosed with ovarian cancer. DIAGNOSES: Histopathology of the resected tissues and Antineuronal antibody testing. INTERVENTIONS: The patient was treated with intravenous immunoglobulin (IVIG, 1 g/d) for 1 week and a large-dose of methylprednisolone (0.4 g/kg/d) for 5 days. At the same time, underlying complications were prevented actively, and the peripheral nerves were protected. OUTCOMES: Although most patients with anti-Yo-positive PCD do not improve after treatment, our patient significantly improved after receiving active and effective treatment.

Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration in a female patient with pleural malignant mesothelioma.

Paraneoplastic cerebellar degeneration is a rare non-metastatic complication of malignancies. It presents with acute or subacute onset of ataxia, dysarthria and intention tremor. Paraneoplastic cerebellar degeneration is most commonly associated with malignancies of the ovary, breast and lung. The anti-Yo (anti-Purkinje cells) antibodies that specifically damage the Purkinje cells of the cerebellum are found in the serum and cerebrospinal fluid. Anti-Yo-related paraneoplastic cerebellar degeneration is most commonly found in women with gynecological and breast cancers, but it is reported in other malignancies. Patients with paraneoplastic syndromes most often present with neurologic symptoms before an underlying cancer is detected. We report a case of anti-Yo-related paraneoplastic cerebellar degeneration associated with pleural malignant mesothelioma in a 51-year-old female patient. She presented to our department with a 2-week history after the last chemotherapy of progressive dizziness related to head movement, nausea, vomiting, ataxia and unsteady gait. A western blot assay was negative for anti-Hu, anti-Ri, anti-Ma2, anti-CV2 and anti-amphiphysin paraneoplastic antibody markers but positive for anti-Yo. In conclusion, we report a case of paraneoplastic cerebellar degeneration in a patient with pleural malignant mesothelioma because of the rarity of this neurologic presentation after the diagnosis of malignant mesothelioma and of the association with anti-Yo antibodies.

[Synchronous appearance and improvement with anticancer chemotherapy of paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome complicated with small cell lung cancer].

A 62-year-old man who had suffered from instability of gait and double vision for two months was admitted to our hospital because of weakness of the extremities and ataxia of the extremities and trunk. Chest X-rays and CT scans showed enlargement of the left hilar lymph nodes and a nodular shadow in the left lung. Transbronchial biopsy revealed small cell lung cancer. We diagnosed the patient with two conditions: paraneoplastic cerebellar degeneration (PCD), based on cerebellar ataxia, the presence of Hu antineuronal antibodies, and the absence of cerebellar atrophy and malignancy; and Lambert-Eaton myasthenic syndrome (LEMS), based on weakness of the extremities, the presence of P/Q-type voltage-gated calcium channel antibodies, and waxing in the evoked electromyogram. Anticancer chemoradiation therapy that was started within three months of symptom onset resulted in reductions in size of the hilar lymph nodes and the nodule. Concurrently, cerebellar ataxia, weakness of the extremities, and double vision all disappeared. Anticancer chemotherapy is effective against LEMS while usually less effective against PCD. Early commencement of anticancer chemotherapy is recommended for the treatment of PCD with LEMS.

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.

Bipolar disorder associated with paraneoplastic cerebellar degeneration: a case report.

We Present a case report of a patient who suffers from Paraneoplastic cerebellar degeneration (PCD) secondary to which the patient, a young woman, developed Bipolar Affective Disorder. Here we focus on the mental health aspects of this case.

Effective immunosuppressant therapy with cyclophosphamide and corticosteroids in paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated phenomenon often associated with cancer of the ovarian. Hitherto, tumor dissection is the mainstay in therapy while immunomodulatory treatment regimes often fail. Here we report on an 86 year old female patient who developed a severe pancerebellar syndrome. Clinical course, onconeural (anti-Yo) antibodies and detection of ovarian cancer suggest the assumption of PCD as the most probable diagnosis. We initiated a high-dose course of corticosteroids followed by a single dose of cyclophosphamide (600 mg/day). Surprisingly patient's condition improved and stabilized within days subsequent to cyclophosphamide application. This case demonstrates the benefit of immunosuppressive therapy in an anti-Yo positive patient with severe PCD secondary to an ovarian cancer.

[A case of paraneoplastic cerebellar degeneration associated with small cell lung cancer showing marked response to intravenous immunoglobulin].

BACKGROUND: Paraneoplastic cerebellar degeneration (PCD), one of the paraneoplastic neurological syndromes (PNS), develops a subacute cerebellar dysfunction and its neurological prognosis is poor in most cases. Because it is considered to be immune-mediated, immunosuppressive therapy may be effective, but its past outcomes are not constant. CASE: A 59-year-old woman presented with deteriorating cerebellar manifestations such as ataxic gait, nausea, and dysarthria. Chest CT revealed a nodule in the upper lobe of the right lung, and small cell lung cancer was diagnosed by transbronchoscopic lung biopsy and sputum cytology. Although known antineuronal antibodies were not detected, no other causative diseases were recognized, so PCD associated with SCLC was diagnosed. The cerebellar manifestations improved remarkably with immediate intravenous immunoglobulin (IVIG) therapy. SCLC showed complete response (CR) after chemoradiotherapy, and the neurological symptoms have not worsened at present. CONCLUSION: Treatment with IVIG at the early stage may lead to the improvement of PCD and is worth attempting.

Neurologic improvement after high-dose intravenous immunoglobulin therapy in patients with paraneoplastic cerebellar degeneration associated with anti-Purkinje cell antibody.

Paraneoplastic cerebellar degeneration (PCD) is a rare syndrome associated with systemic malignancies, most in lung and ovarian cancer. Cerebellar ataxia has previously been associated with the presence of anti-Purkinje cell antibodies (anti-Yo) in the serum and cerebrospinal fluid and responses to therapy are uncommon. We reported two patients were identified with delayed onset of PCD associated with high titer of CSF anti-Yo (1:30,000, 1:320 U/ml) and a marked elevation of tumor markers for ovarian cancer (CA-125 17,700 ng/ml, 43 ng/ml) titer 1 year and 6 months prior to discovery of the carcinoma. Both developed subacute onset of severe ataxia, dysarthria, tremor, nystagmus with progression to severe debilitation (wheelchair bound or bedridden status). One of these patients also developed dysphagia that required PEG tube feeding. They were treated with six cycles of intravenous immunoglobulin (IVIG) 0.4 gm/kg/day x 5 days, every 4-6 weeks in conjunction with combination chemotherapy of Taxol and Carboplatin after the surgical resection of ovarian cancer. In each case, a significant improvement of neurological deficits were seen after the third cycle of IVIG, approximately 4 months after initiation of treatment. This type of delayed response is contrary to the previous reports. Both patients could ambulate without assistance in correlation with dramatic decrease in anti-Yo titer (1:80, 1:320 U/ml) and CA-125 (11 ng/ml, 8 ng/ml). This is a first report of benefit from IVIG in patients with late onset of PCD, which showed a delayed response with significant neurological improvement.

[Chemotherapy treatment for anti-Hu paraneoplastic syndrome without active malignancy]. / Traitement par chimiothérapie d'un syndrome neurologique paranéoplasique anti-Hu sans cancer actif associé

INTRODUCTION: Anti-Hu associated paraneoplastic neurological syndromes are rare and characterized by poor prognosis. The research and treatment of a related cancer, a small-cell lung cancer most of the time, remains the best therapeutic strategy. CASE REPORT: We describe the clinical course of a paraneoplastic subacute sensory neuronopathy associated with anti-Hu antibodies in a male smoker treated by an early chemotherapy active against a small-cell lung cancer although no tumor could be found at repeated evaluations. In spite of this treatment, the neurological state deteriorated with the appearance of a cerebellar degeneration, and limbic encephalitis which resulted in a loss of autonomy. A small-cell lung cancer was found and treated 65 months after the onset of the neurological symptoms. The treatment of the underlying malignancy, when it can be found, is still considered as the optimal treatment for paraneoplastic neurological syndromes. Although no tumor could be found, we treated our patient with an empirical chemotherapy active against the most frequent malignancy associated to anti-Hu syndrome in a smoker man, without any improvement. CONCLUSION: Active and repeated research for a cancer related to an anti-Hu neurological syndrome and its treatment are undispensable. For our patient without any identified cancer empirical chemotherapy treatment was unable to stop neurological worsening. When no tumor can be identified by conventional imaging techniques, an early FDG-PET scan should be considered and then repeated if normal.

Paraneoplastic cerebellar degeneration preceding the diagnosis of Hodgkin's lymphoma.

Paraneoplastic cerebellar degeneration (PCD) can present as a severe and (sub)acute cerebellar syndrome. PCD can accompany different kinds of neoplasms including small cell lung cancer, adenocarcinoma of the breast and ovary, and Hodgkin's lymphoma. A 34-year-old patient is described with acute dysarthria, gait ataxia and diplopia. Despite extensive laboratory and radiological evaluations in this patient with rapidly deteriorating cerebellar syndrome, the diagnosis of a paraneoplastic syndrome was only made after several months, when an anti-Tr antibody was detected in his serum. The search for Hodgkin's disease as concomitant disorder was then started and resulted in stage II B disease. The patient was successively treated with six courses of etoposide, bleomycin, vinblastine and dexamethasone and radiotherapy, which resulted in a complete remission of the Hodgkin's disease. After starting therapy the cerebellar degeneration stabilised. The pathogenesis of neuronal damage in central nervous system paraneoplastic disorders such as the one we describe is not completely understood. Antitumour therapy is assumed to be the important cornerstone in stabilising the neurological condition. Improvement of the cerebellar syndrome in anti-Tr autoantibody paraneoplastic disease is a rare achievement. Early recognition of the concomitant disorders (anti-Tr autoantibody disease and Hodgkin's lymphoma) is of crucial importance.

Subacute cerebellar degeneration as paraneoplastic syndrome: initial symptom of breast cancer with HER2 overexpression.

We report the case of a patient with subacute cerebellar degeneration presenting as paraneoplastic syndrome, preceding the final diagnosis of breast cancer. The tumor had high HER2 overexpression, so a weekly regimen of paclitaxel/trastuzumab was started after surgery of the primary breast tumor. Negativity of specific antineuronal antibodies and clinical stabilization of the patient was achieved after 12 cycles of treatment. The interest of this case is the unusual presentation and the targeted therapeutic approach that has been used.

Probably anti-Tr associated paraneoplastic cerebellar degeneration as initial presentation of a squamous cell carcinoma of the lung.

Paraneoplastic cerebellar degeneration (PCD) is the most frequent paraneoplastic syndrome affecting the brain. Until now, anti-Tr associated PCD was only seen in patients with Hodgkin's disease. We report a male patient who presented with a progressive ataxia, affecting predominantly the lower limbs and a cerebellar dysarthria. Extensive diagnostic approach initially showed no evidence of tumor. The patient was found to have anti-Tr antibodies in his serum. Fourteen months after onset of symptoms a whole body PET-scan showed a pathological focus at the right hilus of the lungs. A mediastinoscopy was performed and peribronchial node sampling was done. The anatomopathological analysis revealed a non-well differentiated squamous cell carcinoma. This is the first report about the association between an anti-Tr associated PCD and squamous cell carcinoma.

Paraneoplastic neurological syndrome: patient with anti-Yo antibody and breast cancer: a case report.

Presented here is the case of a paraneoplastic cerebral degeneration (PCD) in a female patient with breast cancer and the indication of anti-Yo antibodies in the cerebrospinal fluid (CSF) and serum. The patient's primary indications were dizziness and a severe gait ataxia. The indication of anti-Yo antibodies led to the conclusion of the existence of a paraneoplastic cerebral degeneration. The antibodies in question are anti-Purkinje-cell autoantibodies acting against the antigens common to tumor and Purkinje cells which occur in association with a certain percentage of breast or ovarian cancers. The diagnosis of the primary tumor, that is clinically undetectable with conventional imaging processes, is performed with the aid of positron emission tomography (PET) to detect the presence of axillary lymph node metastases. The micro-invasive mammary carcinoma was able to be localized with the aid of MR mammography and, after MR mammography marking, was removed. The patient subsequently received adjuvant treatment with epirubicine and cyclophosphamide. This treatment failed to influence the paraneoplastic neurological symptoms.