Paraneoplastic cerebellar degeneration as a manifestation of metastatic recurrent carcinoma breast: rare scenario.

Carcinoma breast presenting with paraneoplastic cerebellar degeneration is a rare scenario. We report a case of a 52-year-old woman, which is a follow-up case of completely treated carcinoma breast presenting with paraneoplastic cerebellar degeneration which, on investigation, revealed metastatic disease with recurrence at previous scar site and metastasis to contralateral axilla. The patient was given pulse methyl prednisolone therapy and underwent wide local excision of nodule and right axillary lymph node dissection with 14 cycles of trastuzumab and paclitaxel as adjuvant therapy. However, there was no detectable change in neurological symptoms at 6-month follow-up postoperatively. This case report highlights the need for clinicians to be aware of all possible presentations of carcinoma breast and its recurrence, including rare manifestations as in this case.

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults.

IMPORTANCE: Classic Purkinje cell cytoplasmic antibody type 1 (PCA-1, or anti-Yo) paraneoplastic cerebellar ataxia has a poor prognosis, yet little has been published otherwise regarding treatment responses and outcomes among patients with autoimmune cerebellar ataxia. OBJECTIVES: To investigate treatment responses and outcomes in adults with autoimmune cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS: A cohort study conducted at Mayo Clinic, Rochester, Minnesota, included 118 patients who had ataxia, were 18 years or older, were seropositive for at least 1 neural autoantibody, had received at least 1 immunotherapy or cancer therapy, and had neurologist-reported outcomes documented from January 1, 1989, through December 31, 2013. Data were collected from May 14, 2013, through August 9, 2014, and analyzed from August 9, 2014, through April 27, 2015. Responses to immunotherapy (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressants) and ambulatory outcomes were compared between different subgroups. Subgroups were classified as paraneoplastic vs nonparaneoplastic disorders; neuronal nuclear and/or cytoplasmic (NNC) antibody positivity vs plasma membrane protein (PMP) antibody positivity; and glutamic acid decarboxylase 65-kDa isoform (GAD65) antibody positivity vs PMP antibody positivity. MAIN OUTCOMES AND MEASURES: Response to therapy and ambulatory ability, with univariate logistic regression and Kaplan-Meier analyses. RESULTS: Inclusion criteria were met by 118 patients. Median age at onset of neurologic symptoms was 58 (range, 27-83) years, and 87 patients (73.7%) were women. Median duration from symptom onset to last follow-up was 25 (range, 2-223) months. Sixty-three patients had paraneoplastic and 55 patients had nonparaneoplastic ataxic disorders. Eighty-one patients were seropositive for NNC antibodies (most commonly PCA-1 [anti-Yo], antineuronal nuclear antibody type 1 [anti-Hu], and GAD65 antibody); 22 patients, for neural PMP receptor or ion channel antibodies (most commonly targeting P/Q- or N-type voltage-gated calcium channels); and 15 patients, for antibodies from both categories. Neurologic improvements occurred in 54 patients (with a robust change in ambulatory ability in 22) attributable to immunotherapy; univariate regression analysis revealed that improvements were significantly more common among patients with nonparaneoplastic disorders (P = .03) and those with exclusively PMP antibodies (P = .02). Kaplan-Meier analyses revealed that progression to wheelchair dependence occurred significantly faster among patients with NNC antibody positivity only (P = .02), although those with GAD65 autoimmunity progressed to wheelchair dependence at a rate similar to those with PMP autoimmunity (P = .92). CONCLUSIONS AND RELEVANCE: Although autoimmune ataxia is usually severe, treatment responses can be gratifying, particularly in patients with nonparaneoplastic disorders and in those harboring autoantibodies directed against GAD65 or neural PMPs.

Degeneración cerebelosa paraneoplásica en cáncer ginecológico: descripción de 3 casos / Paraneoplastic cerebellar degeneration in gynecological cancer: A report of 3 cases

Fundamento y objetivo. La degeneración cerebelosa paraneoplásica (DCP) es una complicación neurológica infrecuente que aparece en pacientes con cáncer y se asocia a diferentes autoanticuerpos. La DCP asociada a anticuerpos anti-Yo ocurre más frecuentemente en pacientes con cáncer ginecológico. El uso de un método diagnóstico que permita su detección precoz y una adecuada conducta terapéutica no están establecidos. Métodos. Se describen 3 casos clínicos correspondientes a pacientes que comenzaron con disfunción cerebelar subaguda y anticuerpos anti-Yo positivos. Tras el diagnóstico y tratamiento del proceso oncológico y el cuadro neurológico, se realizó un seguimiento clínico para evaluar la evolución del síndrome neurológico. Resultados. Se realizaron estudios de imagen complementarios para descartar un cáncer ginecológico. La tomografía por emisión de positrones/tomografía computarizada con fluorodesoxiglucosa (FDG-PET/TC) fue la única exploración de imagen que sospechó la lesión primaria en todos los casos. El estudio histológico confirmó carcinoma de ovario en 2 casos y carcinoma de trompa en un caso. Las pacientes fueron tratadas mediante cirugía radical y quimioterapia adyuvante. Se administraron corticoides sin observar ninguna mejoría del síndrome neurológico. Conclusión. El tratamiento oncológico no modificó los síntomas neurológicos. La FDG-PET/TC puede ser útil en algunos casos de DCP en los que las exploraciones de imagen convencionales no identifican la neoplasia subyacente (AU)

Background and objective. Paraneoplastic cerebellar degeneration (PCD) is a rare neurological complication that develops in patients with cancer and is associated with different antibodies. PCD associated with anti-Yo antibodies usually occurs in patients with gynecological cancer. There is no diagnostic method that would allow early detection and appropriate treatment. Methods. We describe three patients who presented with subacute cerebellar dysfunction and positive anti-Yo antibodies. After diagnosis and treatment, the patients were monitored to evaluate persistence of the neurological syndrome. Results. Imaging studies were performed when gynecologic cancer was suspected. In all patients, fluorodeoxyglucose-positron emission tomography/tomography computerized (FDG-PET/TC) was the only imaging test that led to suspicion of the primary lesion. Histological examination confirmed the diagnosis of ovarian carcinoma in two patients and carcinoma of the horn in the third patient. All patients underwent radical surgery and subsequent chemotherapy. Corticosteroids were administered with no improvement of the neurological syndrome in any of the patients. Conclusion. Oncologic treatment does not improve neurological symptoms. FDG-PET/TC with fluorodeoxyglucose could be useful in cases of PCD in which conventional imaging tests do not identify the underlying malignancy (AU)

Degeneración cerebelosa paraneoplásica como presentación de un carcinoma de mama oculto / Paraneoplastic cerebellar degeneration as the form of presentation of an occult breast carcinoma

La degeneración cerebelosa paraneoplásica (DCP) es un síndrome poco frecuente y de difícil diagnóstico. Suele presentarse meses o años antes de la aparición de una neoplasia curable y, menos frecuentemente, ocurre en pacientes con una neoplasia conocida o como forma de recidiva. Su asociación con el cáncer de mama es poco frecuente. Presentamos el caso de una paciente de 59 años que desarrolló una DCP, sin identificación del tumor primario. Tras casi año y medio de seguimiento y estudio, se diagnosticó un carcinoma ductal infiltrante de mama, mediante pruebas de imagen, que hasta el momento habían sido rigurosamente normales(AU)

Paraneoplastic cerebellar degeneration (PCD) is an uncommon and difficult-to-diagnose syndrome. This syndrome usually presents months or years before a curable neoplasm develops and, less frequently, in patients with a known or recurrent tumor. The association of PCD with breast cancer is very rare. We present the case of a 59-year-old woman who developed a PCD, without identification of the primary tumor. After almost a year and a half of follow-up, an infiltrating ductal breast carcinoma was diagnosed with imaging tests, which had previously been strictly normal(AU)

Isolated ZIC4 antibodies in paraneoplastic cerebellar syndrome with an underlying ovarian tumor.

OBJECTIVE: To describe a patient with paraneoplastic cerebellar syndrome and the uncommon association of isolated ZIC4 antibodies and ovarian cancer. DESIGN: Case report and review of the literature. SETTING: Hospitalized care, follow-up in private practice. PATIENT: A 60-year-old woman with severe paraneoplastic cerebellar syndrome and an underlying ovarian adenocarcinoma. INTERVENTIONS: Neurological examination, lumbar puncture, laboratory tests, radiological imaging, and histological examination. MAIN OUTCOME MEASURES: Clinical course and titer of anti- ZIC4 antibodies in serum. RESULTS: Laboratory and cerebrospinal fluid tests revealed the isolated presence of ZIC4 antibodies. Screening results for small cell lung carcinoma were negative, while abdominal computed tomographic scan was suggestive of ovarian adenocarcinoma, which was confirmed by histological examination. Glucocorticosteroid administration and chemotherapy led to complete remission of paraneoplastic cerebellar degeneration. CONCLUSION: To the best of our knowledge, this is the first case of paraneoplastic cerebellar degeneration in a patient with isolated ZIC4 antibodies associated with ovarian adenocarcinoma.

Blood-brain barrier breakdown and cerebellar degeneration in the course of experimental neoplastic disease. Are circulating Cytokine-Induced Neutrophil Chemoattractant-1 (CINC-1) and -2alpha(CINC-2alpha) the involved mediators?

Cerebellar degeneration belongs to indirect effects of malignancy on the nervous system. Although the involvement of immune system is accepted as a hypothesis of its pathology, the clinical observations of ineffective immunomodulatory therapy suggest complex pathomechanisms, which await elucidation. The aim of this study was to prove the blood-brain barrier integrity, its relation to cerebellar degeneration and the role of circulating Cytokine-Induced Neutrophil Chemoattractant-1 (CINC-1) and Cytokine-Induced Neutrophil Chemoattractant-2alpha (CINC-alpha) in indirect effects of experimental malignancy. Two transplantable neoplasms: breast cancer (BC) and Morris hepatoma (MH) in rats were used in the study. The blood-brain barrier breakdown was clearly proved in the course of both malignancies. We observed also morphological signs of cerebellar degeneration in both models, with linear loss of Purkinje cells and homogenization changes more pronounced in breast cancer bearing rats. We have found a significant decrease of CINC-1 concentration in serum of rats with growing MH, however BC had no effect on CINC-1 concentration. Changes in serum CINC-2alpha concentrations in BC did not reach the level of significance, however in MH bearing rats the concentrations increased three weeks after tumour transplantation. In conclusion, we may state that the development of cerebellar degeneration as an indirect effect of experimental neoplasm can result from blood-brain barrier (BBB) breakdown and possible passage of neurotoxic factors. The decreased serum concentration of CINC-1 as neuroprotective agent and increased CINC-2alpha in late stage of MH may be considered for their contribution to cerebellar degeneration.

Neuro-ophthalmologic manifestations of paraneoplastic syndromes.

Paraneoplastic syndromes with neuro-ophthalmologic manifestations may involve the central nervous system, cranial nerves, neuromuscular junction, optic nerve, uvea, or retina. Most of these disorders are related to immunologic mechanisms presumably triggered by the neoplastic expression of neuronal proteins. Accurate recognition is essential to appropriate management.

Ataxic vs painful form of paraneoplastic neuropathy.

OBJECTIVE: To characterize the clinicopathologic features of ataxic and painful forms of paraneoplastic neuropathy. METHODS: Clinical, electrophysiologic, and histopathologic findings were assessed in 17 patients with paraneoplastic neuropathy. RESULTS: Clinical features can be categorized into two groups: one group (13 patients) with predominantly deep sensory disturbance and a second group (4 patients) with predominantly superficial sensory disturbance. The former group showed severe sensory ataxia and predominantly large myelinated fiber loss in the sural nerve. The latter group showed marked pain, in particular, severe mechanical hyperalgesia, and predominantly small myelinated and unmyelinated fiber loss. Nerve conduction assessment indicated an axonal neuropathy pattern in both groups, while sensory action potentials were more markedly diminished in the sensory ataxic form. Anti-Hu antibodies were detected in half of the patients in both groups. Treatment for cancer was effective to improve or stabilize neuropathic symptoms in some cases from both groups. Immunotherapy was effective only for a short time. CONCLUSIONS: Paraneoplastic neuropathy can be characterized into two groups by the presence of sensory ataxia or severe spontaneous pain and severe mechanical hyperalgesia. Preferential small myelinated and unmyelinated fiber loss correlated to the cases of severe pain.

Eye movements as a marker for cerebellar damage in paraneoplastic neurological syndromes.

Cerebellar disturbances can induce a variety of motor deficits, ranging from severe ataxia to mild deficits of fine motor control. Although motor disturbances appear as an important clinical feature in many neurological disorders, mild disturbances are often difficult to assess properly. Eye movement recordings using video-oculography in a group of patients with a paraneoplastic neurological disorder revealed subtle saccadic and smooth pursuit deficits when compared to controls. We conclude that an easy quantification of eye movement control may assist in the diagnosis and follow-up of mild motor disturbances in patients with neurological disorders, especially when such signs are not overt during clinical neurological examination.

Paraneoplastic cerebellar degeneration: Yo-expressing tumor revealed after a 5-year follow-up with FDG-PET.

We report a patient with anti-Yo associated paraneoplastic cerebellar degeneration (PCD) whose tumor was demonstrated 5 years after developing PCD and had strong expression of Yo (cdr2) antigen. Review of this case along with clinical series and studies of tumor growth rates question the effectiveness of the anti-tumor immune response. These studies and similar cases suggest that the tumor may trigger the anti-Yo immune response at microscopic stages of development. An overwhelming majority of anti-Yo positive patients eventually develop a detectable malignancy, which argues in favor of a poorly effective or non-sustained anti-tumor immune response.

Cerebellar hypermetabolism in paraneoplastic cerebellar degeneration.

A 51 year old man with paraneoplastic cerebellar degeneration from gastric adenocarcinoma showed cerebellar hypermetabolism and increased perfusion on brain FDG-PET scan and SPECT during the acute stage of his illness. The patient underwent subtotal gastrectomy. The intensity of the hypermetabolism had decreased markedly on follow-up FDG-PET 3 months later following two cycles of chemotherapy. We suggest that the cerebellar hypermetabolism may have been due to an acute inflammatory process associated with an immunological reaction.

Speech and language findings associated with paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) is an autoimmune disease that can be associated with cancer of the breast, lung, and ovary. The clinical presentation of PCD commonly includes ataxia, visual disturbances, and dysarthria. The speech disturbances associated with PCD have not been well characterized, despite general acceptance that dysarthria is often part of the initial presentation. A retrospective study was conducted of the speech, language, and swallowing concerns of patients with PCD evaluated at the Mayo Clinic in Rochester, MN, between 1990 and 2001. Prospective speech and language assessments were then conducted with 5 patients who had PCD. While ataxic dysarthria was the most common speech diagnosis, a spastic component was recognized frequently enough to suggest that the subacute (days to weeks) emergence and progression of an ataxic or mixed ataxic-spastic dysarthria in the setting of a more diffuse cerebellar ataxia should raise suspicions about PCD and justify further investigation of a possible immune-related etiology.

Immunological features of neurological paraneoplastic syndromes.

Neurological paraneoplastic syndromes are a rare group of disorders that occur in 1-2% of people with malignancy. They are usually caused by an immune response, triggered by and directed against a tumour, that cross-reacts with protein expressed by the peripheral or central nervous system. Any part of the nervous system can be affected and patients often develop severe and permanent disability. Diagnosis can be difficult as in two-thirds of patients the neurological problems appear up to 5 years before the tumour manifests. However, certain of these syndromes are often associated with specific serum autoantibodies that can be useful both in diagnosis of the neurological syndrome and in focusing the search for a particular tumour. Thus, these antibodies can allow earlier identification and treatment of cancer and, potentially, a reduction in morbidity and mortality. It was only in the 1980s that the first anti-neuronal autoantibodies were characterized and their associations with clinical syndromes and tumours defined. Further antibodies have been isolated over the past 20 years and novel pathogenic mechanisms for several syndromes have been recognized. For example, voltage-gate ion channels seem to be a common target for autoantibodies involved in peripheral nerve diseases such as the Lambert-Eaton myasthenic syndrome and neuromyotonia (Isaacs' syndrome). However, the place of most paraneoplastic antibodies in the pathogenesis of central syndromes is yet to be fully elucidated.

Effect of a paraneoplastic cerebellar degeneration-associated neural protein on B-myb promoter activity.

In this study, we have shown that a paraneoplastic cerebellar degeneration (PCD)-associated antigen, pcd17, binds to a cell cycle-related protein, MRG15. MRG15 derepresses the E2F-responsive B-myb promoter. The pcd17 antigen inhibits the derepression of the B-myb transcriptional activity by MRG15, and, as a result, pcd17 represses the promoter. Delivery of anti-Purkinje cell antibodies (anti-Yo) into the cells inhibits the repression of B-myb promoter activity by pcd17. Because derepression of the B-myb promoter has been implicated in neuronal death, the results suggest the possible role of the antibodies in the pathogenesis of PCD.