anti-Purkinje Cell Antibodies Research Articles

A rare case of paraneoplastic cerebellar ataxia secondary to Gynaecological malignancy

We report on a rare case of paraneoplastic syndrome (PS) that was discovered on completion of diagnostic work up to be a fallopian tube carcinoma. A 65year old female, presented with 1 month history of imbalance, gait instability, incoordination of right upper limb, vertigo and vomiting. Cerebrovascular accident and drug intoxication was excluded. Indicative of further diagnosis of paraneoplastic syndrome was presence of adnexal mass in pelvis with identification of onconeural anti-Yo antibodies, detection of which leads to the confirmation of diagnosis. The anti- Yo (Anti-Purkinje cell) antibodies that specifically damage Purkinje cells of the cerebellum. Anti- Yo related paraneoplastic cerebellar degeneration is most commonly found in women with gynecological and breast cancers.

Paraneoplastic cerebellar syndromes associated with antibodies against Purkinje cells

ABSTRACTThe paraneoplastic cerebellar syndrome presents as severe neuroimmunological disease associated with malignancies. Antibodies against antigens expressed by tumor cells cross-react with proteins of cerebellar Purkinje cells leading to neuroinflammation and neuronal loss. These antineuronal antibodies are preferentially investigated by serological analyses while examination of the cerebrospinal fluid is only performed infrequently.We retrospectively investigated 12 patients with antineuronal antibodies against Purkinje cells with a special focus on cerebrospinal fluid.Our results confirm a subacute disease with a severe cerebellar syndrome in 10 female patients due to anti-Yo antibodies associated mostly with gynecological malignancies. While standard cerebrospinal fluid parameters infrequently revealed pathological results, all patients presented oligoclonal bands indicating intrathecal IgG synthesis. Analyses of anti-Yo antibodies in cerebrospinal fluid by calculating the antibody specific index revealed intrathecal synthesis of anti-Yo antibodies in these patients. In analogy to anti-Yo syndrome, an intrathecal production of anti-Tr antibodies in one patient who presented with a paraneoplastic cerebellar syndrome was detected. In an additional patient, anti-Purkinje cell antibodies of unknown origin in the cerebrospinal fluid but not in serum were determined suggesting an isolated immune reaction within the central nervous system (CNS) and underlining the importance of investigating the cerebrospinal fluid.In conclusion, patients with a cerebellar syndrome display a distinct immune reaction within the cerebrospinal fluid including intrathecal synthesis of disease-specific antibodies. We emphasize the importance of a thorough immunological work up including investigations of both serum and cerebrospinal fluid.

Anti-Yo antibody uptake and interaction with its intracellular target antigen causes Purkinje cell death in rat cerebellar slice cultures: a possible mechanism for paraneoplastic cerebellar degeneration in humans with gynecological or breast cancers.

Anti-Yo antibodies are immunoglobulin G (IgG) autoantibodies reactive with a 62 kDa Purkinje cell cytoplasmic protein. These antibodies are closely associated with paraneoplastic cerebellar degeneration in the setting of gynecological and breast malignancies. We have previously demonstrated that incubation of rat cerebellar slice cultures with patient sera and cerebrospinal fluid containing anti-Yo antibodies resulted in Purkinje cell death. The present study addressed three fundamental questions regarding the role of anti-Yo antibodies in disease pathogenesis: 1) Whether the Purkinje cell cytotoxicity required binding of anti-Yo antibody to its intraneuronal 62 kDa target antigen; 2) whether Purkinje cell death might be initiated by antibody-dependent cellular cytotoxicity rather than intracellular antibody binding; and 3) whether Purkinje cell death might simply be a more general result of intracellular antibody accumulation, rather than of specific antibody-antigen interaction. In our study, incubation of rat cerebellar slice cultures with anti-Yo IgG resulted in intracellular antibody binding, and cell death. Infiltration of the Purkinje cell layer by cells of macrophage/microglia lineage was not observed until extensive cell death was already present. Adsorption of anti-Yo IgG with its 62 kDa target antigen abolished both antibody accumulation and cytotoxicity. Antibodies to other intracellular Purkinje cell proteins were also taken up by Purkinje cells and accumulated intracellularly; these included calbindin, calmodulin, PCP-2, and patient anti-Purkinje cell antibodies not reactive with the 62 kDa Yo antigen. However, intracellular accumulation of these antibodies did not affect Purkinje cell viability. The present study is the first to demonstrate that anti-Yo antibodies cause Purkinje cell death by binding to the intracellular 62 kDa Yo antigen. Anti-Yo antibody cytotoxicity did not involve other antibodies or factors present in patient serum and was not initiated by brain mononuclear cells. Purkinje cell death was not simply due to intraneuronal antibody accumulation.

Anti-Yo antibody, associated with paraneoplastic cerebellar degeneration, specifically produces Purkinje cell death by binding to the 62 kDa intracellular Yo antigen

Paraneoplastic cerebellar degeneration accompanying breast and gynecological cancers is frequently accompanied by an autoantibody response, termed anti-Yo or anti-Purkinje cell antibody (APCA), which reacts with cytoplasmic antigens of cerebellar Purkinje cells. In Western blots of Purkinje cell lysates anti-Yo recognizes antigens of 62kDa and, in many but not all patients, 34kDa. Despite its close association with paraneoplastic cerebellar degeneration, however, the role of anti-Yo antibody in the pathogenesis of cerebellar injury has been uncertain.

Carbonic anhydrase‐related protein VIII antibodies and paraneoplastic cerebellar degeneration

Carbonic anhydrase‐related protein <scp>VIII</scp> antibodies and paraneoplastic cerebellar degeneration

Anti-Purkinje cell antibody as a biological marker in attention deficit/hyperactivity disorder: A pilot study

An autoimmune hypothesis has been suggested for several disorders in childhood. The aim of the study was to clarify the role of the cerebellum in ADHD and to evaluate the possible association between anti-Yo antibodies and ADHD. The presence/absence of antibodies was tested by indirect immunofluorescence assay on 30 combined subtype ADHD children, on 19 children with other psychiatric disorders (Oppositional-defiant and Conduct Disorders, Dyslexia) and 27 healthy controls.Results showed a significant positive response to the anti-Yo antibody immunoreactivity in the Purkinje cells of the cerebellum of ADHD children, compared with the control group and the psychiatric non-ADHD children. This association points to an immune dysregulation and the involvement of the cerebellum in ADHD.

Opsoclonus: Clinical and immunological features

BackgroundOpsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. MethodsWe recorded eye movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. ResultsIn all patients but one the opsoclonus resolved within 2weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4–10Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. ConclusionsThe clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus.

Encephalitis in the Pediatric Population

1. Stephen J. Falchek, MD* 1. *Division of Pediatric Neurology, Alfred I. duPont Hospital for Children/Thomas Jefferson University, Wilmington, DE, and Philadelphia, PA. * Abbreviations: ADEM: : acute disseminated encephalomyelitis CEP: : California Encephalitis Project CNS: : central nervous system CPP: : cerebral perfusion pressure CSF: : cerebrospinal fluid HSV: : herpes simplex virus IVIG: : intravenous immune globulin MS: : multiple sclerosis PCR: : polymerase chain reaction WNV: : West Nile virus Management of encephalitis, which can be fatal, requires understanding of a broad range of causative agents, pathophysiologic mechanisms, clinical syndromes, and outcomes. After completing this article, readers should be able to: 1. Know the many causes of encephalitis, including infectious, parainfectious, and noninfectious disorders. 2. Recognize the clinical features of encephalitis. 3. Be able to conduct a diagnostic investigation of a patient with encephalitis by using clinical and laboratory criteria. 4. Know the anticipated clinical course of different types of encephalitis. 5. Be familiar with the modalities used to treat encephalitis. 6. Understand the factors that influence the outcome in a patient who has encephalitis. The broad definition of the term “encephalitis,” that is, inflammation of the brain , necessitates acknowledgment of the enormous inclusivity of the topic. The most common interpretation of the term implies a direct invasion of the brain by an infectious pathogen, most commonly, viral, fungal, or parasitic. The topic also includes examples of meningitis mediated by bacteria or other agents, which can produce extrameningeal symptoms such as lethargy or seizures, in which case, the combined term “meningoencephalitis” is used. There are also many examples of encephalitis not due to direct central nervous system (CNS) infections. Inflammatory processes due to an acute or chronic illness can result in an acute immune-mediated encephalitis, such as acute disseminated encephalomyelitis (ADEM), lupus cerebritis, and paraneoplastic syndromes. Agents or conditions that produce slowly progressive CNS symptoms, such as tertiary syphilis or “slow viruses” (the prion protein encephalopathies), also are considered examples of encephalitis. Table 1 lists only a limited number of the many pathogens and pathologic conditions that can cause either acute or subacute encephalitis. In this discussion, …

A Case Report of Plasmapheresis Treatment in a Patient With Paraneoplastic Cerebellar Degeneration and High Anti‐Yo Antibody Titers

A patient with paraneoplastic cerebellar degeneration due to anti-Purkinje cell antibodies (anti-Yo) arising from ovarian carcinoma with metastases was treated with three plasmapheresis (PP) series (a total of 22 PP treatments) over one year and was monitored by repeated otoneurological testing, balance tests and clinical investigations. Blood samples for antibody titers were checked on several occasions. Initially there was a weak clinical response and significantly improved test results regarding the caloric response, as well as a possible effect on visual suppression of the vestibulo-ocular reflex after caloric ear irrigation. After the first series of PP treatment, new metastases were found. A half year later there was a progressive course with increasing general symptoms. Serology tests showed continuously high titers of anti-Yo antibody, although somewhat lower after PP. We thus report a minor and short-lived effect of PP, possibly inhibited by the natural course of metastatic disease.

Unusual MRI abnormalities in anti-Yo positive "pure" paraneoplastic cerebellar degeneration

Sirs: anti-Yo or anti-Purkinje Cell Antibody (PCA) is one of the commonest onco-neural antibodies recognized within the CNS. The associated paraneoplastic cerebellar degeneration (PCD) is a clearly defined syndrome with over 200 reported cases in the literature [6]. Magnetic resonance imaging (MRI) is “remarkably unremarkable” in anti-Yo associated PCD although cerebellar atrophy can be seen early in the course of the disease [7, 8]. The negative imaging in anti-Yo positive PCD contrasts PCD associated with other onconeural antibodies, notably anti-Hu but also with anti-Ma2, anti-CV2, and with antibody negative PCD. In such cases PCD occurs in the setting of a more widespread encephalomyelitis and may demonstrate multifocal MRI and functional imaging abnormalities [2, 3, 5]. To date there are no reports demonstrating MRI evidence of cerebellar or extra-cerebellar inflammation in a living patient with anti-Yo associated PCD. A 62 year-old right-handed woman presented with a two-week history of predominantly left-sided limb ataxia, dysarthria and weight loss. Over four weeks in the hospital, her ataxia became generalized with symmetrical limb involvement, horizontal nystagmus, truncal ataxia, and scanning dysarthria. She had normal cognition and no evidence of sensory neuropathy. Initial MRI brain scan was normal. CSF demonstrated a lymphocytic pleocytosis (WBC 9/mm3) and oligoclonal bands. Despite normal serum tumor markers and clear CT imaging of chest, abdomen, and pelvis, Positron Emission Tomography (PET) revealed a hypermetabolic area in the left pelvis, which was subsequently investigated at laparoscopy. Anti-neuronal antibody screening was positive for anti-Yo antibodies and negative for anti Hu, Ri, Ma, Tr and PCA2. A small poorly differentiated ovarian adenocarcinoma was found and bilateral salpingo-oophorectomy performed. A second MRI scan was performed six weeks after onset of symptoms due to clinical deterioration with anti-neuronal antibody status yet unknown. This demonstrated an abnormality in the right medial temporal lobe. This was hyperintense on FLAIR and enhanced with gadolinium (Fig. 1). No cerebellar abnormalities were seen. Following surgical treatment of the tumor, a follow-up scan (at 12 weeks) showed resolution of the medial temporal lobe changes but demonstrated a focal right cerebellar hyperintensity on gadolinium enhanced T1-MRI (Fig. 1). There was no meaningful clinical improvement in her ataxia following surgery and chemotherapy for the tumor. This patient’s case is clinically typical of anti-Yo associated PCD demonstrating a purely cerebellar syndrome with subacute progression resulting in severe disability over 10 weeks. The evolving MRI abnormalities are atypical for the disorder. We believe they represent inflammation. Inflammatory changes have been demonstrated radiologically in other reports of PCD but never in association with anti-Yo [3, 5]. It has been suggested that an inflammatory phase precedes cerebellar atrophy in PCD and that this may even precede clinical presentation [8]. The MRI of the brain was normal at two weeks from symptom presentation. The follow-up scan at six weeks showed right mesial temporal abnormality but no cerebellar change. MRI following resection of the tumor showed resolution of the temporal abnormality but a new focal cerebellitis. No immunosuppressive drugs were given over this period. Although non-inflammatory etiologies such as infection, ischemia, or metastasis could account for the MRI lesions of the cerebellum and temporal lobe in a patient with cancer, the appearance and evolution of this patient’s MRI abnormalities are not consistent with such differentials. Pathologic change in anti-Yo associated PCD is generally restricted to the cerebellum with cortical atrophy and selective Purkinje cell loss. Inflammatory cells may occasionally be seen in the leptomeninges or in the dentate nucleus. In one post mortem study inflammatory changes were noted in the medulla and pons, corresponding to the known expression of the PCA/Yo antigen (a 62 kDa cytoplasmic protein) in cerebellar and brainstem neurons [4, 9]. Therefore it is possible that anti-Yo could be responsible for mesial temporal inflammation. LETTER TO THE EDITORS

Homer 3 autoimmunity in subacute idiopathic cerebellar ataxia

Few adult patients present with an irreversible subacute cerebellar ataxia of unknown cause.1,2 The subacute evolution and the presence of CSF pleocytosis suggest a possible immune-mediated pathogenesis. In this study, we characterize the antigen of a new anti-Purkinje cell antibody identified in a patient with idiopathic subacute cerebellar ataxia.1,2 A 65-year-old woman presented in October 2000 with a week history of vertigo and vomiting. She denied symptoms of previous infectious disease. Neurologic examination revealed dysarthria, horizontal nystagmus, and severe limb and gait ataxia. Routine blood analysis, thyroid hormones, antineuronal antibodies (Hu, Yo, Ri, Ma1 and 2, CV2, Tr, GAD, and amphiphysin), brain MRI, colonoscopy, esophagogastroscopy, and CT of the chest and abdomen were normal or negative. CSF showed 27 lymphocytes/mm3 with a CSF IgG index of 1.4 (n < 0.7). She did not improve after treatment with steroids. At the last evaluation in June 2006, the cerebellar syndrome was unchanged with no cancer clinically evident. Immunohistochemistry was performed as described.3 Cerebellum samples from normal rats or mice and Homer 3–deficient mice (gift of Dr. Paul F. Worley) were subjected to standard immunoblot procedures.3 …

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.

Induction of humoral responses specific for paraneoplastic cerebellar degeneration-associated antigen by whole recombinant yeast immunization

Paraneoplastic cerebellar degeneration (PCD) is a potent autoimmune disorder in which antigen-driven responses toward the onconeural antigen are assumed to occur in patients. Yeast cell wall has adjuvant capacity and provides immunostimulatory effects of the antigen expressing in viable cells. The recombinant yeast expressing the PCD-associated antigen may become an immunogen for inducing PCD-associated autoimmunity in mice. We attempted to induce autoimmune responses with whole recombinant yeast expressing PCD-associated antigen. SJL/J strain of mouse is found to be a responder to the major epitope on the antigen for anti-Purkinje cell antibodies, and whole recombinant yeast could induce cellular and humoral autoimmune responses in vivo ion SJL/J mice. The immunization technique based on the recombinant yeast expressing a PCD-associated antigen provides a new tool for analyzing the underlying immunological pathomechanisms of PCD.

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.

Paraneoplastic cerebellar degeneration with ovarian endometroid carcinoma

Paraneoplastic cerebellar degeneration with ovarian endometroid carcinoma

Induction of Cytotoxic T Lymphocytes Specific for Paraneoplastic Cerebellar Degeneration-associated Antigen in vivo by DNA Immunization

Paraneoplastic cerebellar degeneration associated with gynecological and breast malignancies (PCD) is known to develop autoantibodies and autoreactive cytotoxic T lymphocytes (CTLs) specific for a cytoplasmic protein of Purkinje cells PCD17/cdr2, in the blood of patients. The functional roles of these antibodies and CTLs in the pathogenesis of PCD are unknown. Induction of immune response to this antigen in experimental animals should be useful to clarify the immune mechanisms in PCD patients. We immunized Balb/c mice with naked DNA, which is encoded human PCD17 neural protein in an eukaryotic expression plasmid under control of CMV promoter, and explored whether or noth humoral and cell-mediated immune responses against PCD17 could be induced in vivo. We show that DNA immunization with nake pcd17 cDNA could induce autoantibodies against the cytoplasmic protein of Purkinje cells and CTLs could lyse syngenic myeloma cells pulsed with H-2K-restricted PCD17 peptide. In spite of the generation of anti-Purkinje cell antibodies and PCD17-specific CTLs in vivo, neither clinical nor pathological changes consistent with significant cerebellar degeneration have been detected.

Autoantibodies in Childhood Post-Varicella Acute Cerebellar Ataxia

Anti-Purkinje cell antibodies have been reported in cerebellar ataxia following Epstein-Barr virus (EBV) infection. We investigated autoantibody responses, including anti-Purkinje cell antibodies, and the clinical course in eight children who developed post-varicella ataxia, five of their siblings with uncomplicated varicella, one child with post-EBV ataxia, two children with acute disseminated encephalomyelitis (ADEM) and one with neuroblastoma associated ataxia, and in age and gender matched controls. Autoantibodies were tested by indirect immunofluorescence (IIF) on cryopreserved cerebrum and cerebellum sections. Other autoantibodies were measured by conventional IIF protocols using HEp-2 cells as a substrate. Antibodies to myelin associated glycoprotein (MAG), asialo-GM1, beta2 glycoprotein 1, cardiolipin and myelin basic protein (MBP) were measured by ELISA. Three of eight children with acute post-varicella ataxia, one child with post-EBV ataxia, one child with ADEM and one child with uncomplicated varicella, had high titer autoantibodies (>1/160) that reacted with cerebrum and cerebellar tissue. This reactivity was not seen in one child with ADEM, in one with neuroblastoma and ataxia, in the remainder of the children with uncomplicated varicella or age and gender matched controls. Autoantibodies were not seen in CSF from two children with post-varicella ataxia. The punctate staining seen on cerebrum and cerebellum sections co-localized with rabbit antibodies to the centrosome protein pericentrin. All patients with strong reactivity with cerebrum and cerebellar tissue by IIF had elevated levels of anti-MAG that was not confirmed by absorption assay. No reactivity was seen with asialo-GM1, MBP, beta2 glycoprotein 1 or cardiolipin. None of the sera had autoantibodies directed against endosomes, the Golgi complex, or the paraneoplastic autoantigens Hu and Yo. Some children with post-viral ataxia develop antibodies that have strong reactivity with cerebral and cerebellar tissue. Some of the antigenic reactivity co-localized with the centrosome protein pericentrin.

Paraneoplastic cerebellar degeneration as the first evidence of cancer: A case report

Paraneoplastic cerebellar degeneration (PCD) is the most frequently seen paraneoplastic syndrome affecting the brain. PCD is most commonly associated with cancers of the ovary, breast, and lung. The anti-Purkinje cell antibodies (anti-Yo) that specifically damage the Purkinje cells of the cerebellum are found in the patient's serum and cerebrospinal fluid. The typical presentation of PCD includes limb and truncal ataxia, often along with dysarthria. This report describes the case of a 47-year-old woman without significant medical history who developed new onset of unsteady gait, headache, and vertigo. The imaging studies suggested rhombencephalitis. The patient initially responded to corticosteroid treatment. Unfortunately, her gait ataxia worsened and she developed dysarthria, neither of which responded to increasing dosages of corticorsteroids. Extensive imaging studies showed no evidence of tumor, but the patient was found to have positive anti-Yo antibodies and elevated cancer antigen 125 (CA-125). Pathology results from exploratory laparotomy revealed stage III C adenocarcinoma of the ovary. This case demonstrates that PCD may be the presenting symptom of an occult malignancy. The pathogenesis, diagnosis, and treatent of PCD, and its rehabilitation implications, are reviewed.

A patient with breast cancer and paraneoplastic cerebellar syndrome associated with anti-Purkinje cell antibodies: Response to CMF chemotherapy

A 41-year-old lady underwent a left mastectomy and axillary clearance in 1992, for T 2N 0 breast cancer. She remained well until December 1995, when she presented with a rapidly progressive cerebellar ataxia. Full investigations for metastatic disease were negative. A clinical diagnosis of paraneoplastic cerebellar degeneration was confirmed by a high titre of anti-Purkinje cell antibodies. She was treated with cyclophosphomide, methotrexate and 5-fluorouracil. The improvement in neurological symptoms was dramatic and has been maintained by further hormone manipulation (ovarian ablation). The patient now leads a normal life without medication.

1-39-04 Paraneoplastic cerebellar degeneration associated with anti-purkinje cell antibody (anti-yo syndrome)

1-39-04 Paraneoplastic cerebellar degeneration associated with anti-purkinje cell antibody (anti-yo syndrome)