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The pathogenesis of Yo-mediated paraneoplastic cerebellar degeneration (PCD) is unclear. We applied cerebrospinal fluid and serum from PCD patients as well as CDR2 and CDR2L antibodies to neuronal tissue, cancer cell lines, and cells transfected with recombinant CDR2 and CDR2L to elucidate which is the major antigen of Yo antibodies. We found that Yo antibodies bound endogenous CDR2L, but not endogenous CDR2. However, Yo antibodies can bind the recombinant CDR2 protein used in routine clinical testing for these antibodies. Because Yo antibodies only bind endogenous CDR2L, we conclude that CDR2L is the major antigen of Yo antibodies in PCD. ANN NEUROL 2019;86:316-321.

Central nervous system (CNS) inflammation occurs in a large number of neurological diseases. The type and magnitude of CNS inflammation, as well as the T-cell contribution, vary depending on the disease. Different animal models of neurological diseases have shown that T cells play an important role in CNS inflammation. Furthermore, recent studies of human neurological disorders have indicated a significant role for T cells in disease pathology. Nevertheless, how individual T-cell subsets affect neuronal survival, damage and/or loss remains largely unclear. In this review we discuss the processes by which T cells mediate either beneficial or deleterious effects within the CNS, with emphasis on the direct interaction between T cells and neurons, as occurs in multiple sclerosis, paraneoplastic cerebellar degeneration, and viral encephalitis. The therapeutic approaches targeting T cells and their mediators as treatment for neurological diseases are also described here.

Aims As cystatin C (CysC) is involved in some forms of neurodegeneration, we investigated the possible relationship between CysC and multiple system atrophy (MSA), including its parkinsonian (MSAp) and cerebellar (MSAc) phenotypes. Methods Cystatin C gene (CST3) haplotypes were determined by PCR followed by KspI digestion in 50 MSA patients and 108 controls. CST3 and cathepsins B, D and L1 mRNA levels were studied in frozen post-mortem caudate nucleus and cerebellar samples of eight MSAp, four MSAc and 18 control brains and analysed by the ΔΔCt method. CysC immunohistochemistry was performed on three MSAp, three MSAc and three control cerebella. Additionally, determination of CST3 and cathepsins B, D and L1 mRNA levels and immunohistochemistry for CysC were carried out in cerebella from three patients with paraneoplastic cerebellar degeneration, three with spinocerebellar ataxia (type 3, SCA3) and three with cerebellar ischaemia (CI). Results In the set of blood samples, the CST3 B-haplotype was associated with MSAp (OR 4.86, confidence interval 1.84–13.3). High CST3 mRNA levels were found in MSAp caudate nuclei [expression change: 3.08 (2.98–3.18)] and MSAc cerebella [expression change: 2.44 (2.14–2.88)]. In the latter there was CysC over-expression in Purkinje cells, Bergmann glia and dentate nucleus neurones. No cathepsin increase was detected in MSA cerebella. High mRNA levels of CST3 and cathepsins B and L1 were observed in SCA3 and CI brains. Conclusions CysC changes are differentially present in the parkinsonian and cerebellar forms of MSA and may play an important role in the pathogenesis of this neurodegenerative condition.

Background Previously, we identified a brain-type creatine kinase antibody to be associated with paraneoplastic cerebellar degeneration using a proteomic approach. Immunohistochemistry showed that this antibody reacted with both mouse cerebellar neurons and bladder cancer tissues. Furthermore, we detected this antibody in sera from two paraneoplastic cerebellar degeneration patients with small cell lung cancer and one lymphoma patient. In total, we detected four paraneoplastic cerebellar degeneration patients. Aim To confirm the new onconeural antibody, we investigated whether this autoantigen is expressed in both human cerebellum and cancer tissues (small cell lung cancer of lymphoma). Methods We examined sera from two paraneoplastic cerebellar degeneration patients with small cell lung cancer, one lymphoma patient and a patient with sensory-motor neuropathy as paraneoplastic neurological syndrome by western blotting and enzyme-linked immunosorbent assay to explore creatine kinase brain-type antibody expressions in these cancer cells as well as in the human cerebellum. Sera from the patients without paraneoplastic cerebellar degeneration were used as controls. In addition, we examined the serum from a patient with sensory-motor neuropathy as paraneoplastic neurological syndrome by western blot. Results The mean serum values of creatine kinase brain-type antibodies in paraneoplastic cerebellar degeneration patients with small cell lung cancer were significantly higher than those of small cell lung cancer patients without paraneoplastic cerebellar degeneration. Immunohistochemistry detected this autoantigen expression in both abovementioned specimens. We also detected this antibody in the serum in sensory-motor neuropathy as paraneoplastic neurological syndrome. Conclusion Our study showed that this antibody was produced in four paraneoplastic cerebellar degeneration patients, and that this autoantigen expression was evident in human cerebellum and cancer. These findings show that creatine kinase brain-type antibody might be a novel antibody associated with paraneoplastic neurological syndrome.

Paraneoplastic neurological syndromes (PNS) are defined as all non-metastatic neurological complications of cancer in which no other etiologies, such as vascular, infectious or metabolic, were determined. Recently, Sry-like high-mobility group box (SOX1) antibody associated with PNS has been described, and is associated with Lambert–Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration and paraneoplastic peripheral neuropathy invariably in the background of underlying small-cell lung cancer. A 75-year-old man was admitted to our neurology clinic at Hacettepe University Hospital, Sihhiye, Ankara, Turkey with complaints of imbalance and memory impairment that had started 2 months earlier and progressively increased. Neurological examination showed a state of delirium in the background of rapid progressive dementia and severely truncal ataxia. Cranial magnetic resonance imaging was unremarkable; however, in further investigations, thoracic tomography yielded bilateral hilar lymphadenopathy, and paraneoplastic antibody investigations resulted in positive SOX1 antibody. The following thoracic excisional lymph node biopsy investigations supported the diagnosis of non-small-cell lung cancer and paraneoplastic cerebellar degeneration associated with SOX1 antibody in the background of non-small-cell lung cancer. Adjuvant chemotherapy was started, but the patient deteriorated, which prevented proper plasmapheresis therapy. He died in the second month of admission as a result of severe sepsis leading to septic shock. Here, we show the second case diagnosed with PNS in association with non-small-cell lung cancer. We note the importance of SOX1 antibody as a marker for PNS, and suggest that investigations of this antibody be carried out in larger case studies.

It is widely believed that paraneoplastic neurological syndromes with antibodies against intracellular antigens are a cytotoxic T-cell-mediated disease triggered in the process of cancer immunity. During this process, coactivation of a humoral immune mechanism is elicited, and autoantibodies against onconeural antigens are produced. These onconeural proteins are usually located in the neuronal cytoplasm or nucleus, and are not targets of antibody-mediated neuronal damage. Greenlee et al. asserted that the anti-Yo antibody had a direct effect on Purkinje cell apoptosis, which conflicts with the commonly believed view.

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.

Background Paraneoplastic syndromes are of interest to psycho-oncologists because they may be misdiagnosed initially as primary psychiatric disorders and can have profound neuropsychiatric and psychosocial sequelae. Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic syndrome which destroys Purkinje cells of the cerebellum and causes trunk and limb ataxia, dysarthria, diplopia, and vertigo, which often precede the diagnosis of cancer. Anti-Yo PCD is a devastating syndrome that significantly worsens prognosis in terms of functional ability and survival. Methods We present the case of a woman with progressive cerebellar deficits, which were misdiagnosed for several months before breast cancer and anti-Yo antibodies were discovered. Results PCD may be misdiagnosed as a primary psychiatric disorder. Results of neuropsychological assessment in this case found subtle attentional dysfunction but relatively preserved cognitive functioning in other domains. Discussion The literature relating to PCD and psychiatric manifestations of cerebellar disease are reviewed. The limitations of our current understanding of non-motor cerebellar function are highlighted, asserting the need for further study in this area. Copyright © 2013 John Wiley & Sons, Ltd.

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.

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.

A 53-year-old-male patient was admitted to the Hiroshima University Hospital in August 2001, with a history of progressive cerebellar ataxia, notable by standing and gait disturbances. Brain computed tomography (CT) and magnetic resonance imaging (MRI) showed no signs of ischemic damage. Two weeks later, left axillary lymphadenopathy developed. The pathological finding was Hodgkin's disease (HD; a classical malignant lymphoma in an early stage). Serum antibodies against Purkinje's cells (anti-Tr antibody) were detected by immunohistochemical study. Thus, we diagnosed this as paraneoplastic cerebellar degeneration (PCD) associated HD. We immediately carried out chemotherapy (ABVD therapy), radiotherapy with 20-30 Gy, steroid pulse and intravenous immunoglobulin (IVIg) without neurologic improvement. The patient was subsequently treated by double filtration plasmapheresis (DFPP), leading to a marked improvement of standing and gait disturbances and to a reduction of autoantibodies, which became undetectable. We conclude that DFPP might be useful in treating patients with cerebellar ataxia, and should be considered as a therapeutic choice for it.

Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects.

A patient presented with symptoms of cerebellar degeneration and nephrotic syndrome. A work-up at that time failed to reveal an underlying disease; however, 20 months later Hodgkin's disease was diagnosed. Hodgkin's lymphadenopathy developed 2 wk after prednisone therapy for the nephrotic syndrome had been discontinued. Systemic polychemotherapy resulted in complete remission of both Hodgkin's disease and nephrotic syndrome, while the neurological deficit persisted. Patients with unexplained cerebellar degeneration and/or nephrotic syndrome demand extensive evaluation for the presence of Hodgkin's disease, and steroid therapy may delay diagnosis.

Patients with paraneoplastic cerebellar degeneration (PCD) offer the opportunity to explore the mechanisms underlying tumor immunity and immune-mediated neuronal degeneration. Cytotoxic T lymphocytes (CTLs) specific for the PCD onconeural antigen cdr2 found in the blood of patients with PCD are likely to be effectors of PCD tumor immunity. Here, we suggest a role for CTLs in the autoimmune destruction of Purkinje neurons. More than 75% of the cells obtained from the cerebrospinal fluid (CSF) of PCD patients were CD3+ alphabeta T cells. In patients with active/progressive disease, 20% to 40% of CSF cells were activated T cells, and the CD4+ helper cells were Th1-type cells. Three PCD patients were given tacrolimus, a specific inhibitor of activated T cells, which markedly reduced these cells in the CSF. Tacrolimus also reduced the number of activated cdr2-specific CTLs in the peripheral blood, but did not lead to tumor recurrence. We suggest that activated cdr2-specific CTLs in the CSF contribute to Purkinje degeneration in PCD, and that tacrolimus therapy may benefit patients with paraneoplastic neurological disease and other T cell-mediated autoimmune neurological disorders.

The detection of 14-3-3 protein in cerebrospinal fluid by immunoblotting is useful for the diagnosis of Creutzfeldt-Jakob disease (CJD). We found 14-3-3 protein in 10 of 80 (12.5%) patients with paraneoplastic neurological disorders (PNDs), whose presenting symptoms may mimic those of CJD. In 47 of 48 CJD patients, the 14-3-3 protein was detected as a single band, and it was detected as a double band in 1 patient. The double-band pattern was observed in 9 of 10 14-3-3 protein-positive patients with PNDs. The 14-3-3 protein assay may be positive in PND patients, but the immunoblotting pattern distinguishes most PND samples from those of CJD.

Whether P/Q-type voltage-gated calcium channel (VGCC) antibodies are present in the serum of patients with paraneoplastic syndromes other than the Lambert-Eaton myasthenic syndrome (LEMS) and tumors other than small-cell lung cancer (SCLC) is controversial. Using a commercially available radioimmunoprecipitation assay kit, we examined the sera of 93 patients with paraneoplastic syndromes of the central nervous system (CNS), including 27 patients with paraneoplastic cerebellar degeneration (PCD) associated with tumors other than SCLC and 66 SCLC patients with paraneoplastic encephalomyelitis and sensory neuronopathy (PEM/SN). All PCD sera from patients with tumors other than SCLC were negative for P/Q-type VGCC antibodies. Eight of 66 (12%) SCLC patients with PEM/SN had P/Q-type VGCC antibodies; 4 had LEMS and the other 4 had no symptoms of LEMS or they were overlooked and, therefore, not examined electrophysiologically. In patients with paraneoplastic syndromes of the CNS, the detection of P/Q-type VGCC antibodies supports the diagnosis of LEMS; in our series, only 6% of patients with SCLC and PEM/SN may have had a false positive antibody result, or undiagnosed LEMS.

Paraneoplastic neurological syndromes in patients with Hodgkin's disease are rare findings. Subacute, paraneoplastic cerebellar degeneration or autonomic dysfunctions were described before. In some of these cases, autoantibodies against central or peripheral nervous system structures were found in serum and CSF. We present a 30-year-old white male who developed a progredient, clinical and electrophysiological distal sensomotoric neuropathy. Six months after the beginning of the neurological disturbances, Hodgkin's disease (Stadium III BE) was diagnosed. Other reasons for neuropathy, such as direct impairment of the peripheral nervous system by tumor masses or drug-induced neuropathy, were excluded. Cerebrospinal fluid (CSF) analysis showed a mild pleocytosis, elevated total protein (9.8 g/l) and identical oligoclonal bands in serum and CSF. Blood-CSF barrier damage was detected by Reiber formula. Indirect immunofluorescence and western blot analysis demonstrated an autoantibody against peripheral and central nervous system structures in serum and CSF. Although the autoantibody responded to a 38-40 kDa-protein in western blot and showed nuclear staining of myenteric plexus and Purkinje cell nuclei in the immunofluorescence test, this antibody was shown to be not identical to anti-Hu. An intrathecal synthesis of the antineuronal antibody was detected by antibody specificity index. Tumor therapy, plasmapheresis and treatment with intravenous immunoglobulins did not improve the neuropathy. According to our knowledge this is the first case of antineuronal antibody-associated sensomotoric neuropathy in Hodgkin's disease.

BACKGROUND Paraneoplastic cerebellar degeneration (PCD) is a remote effect of cancer most frequently associated with carcinoma of the ovary or lung. In many patients, antibodies to Purkinje cells are found. Progressive, incapacitating cerebellar dysfunction occurs in most cases, and no treatment has produced even a transient response in any significant proportion of patients. METHODS A woman age 81 years with recurrent ovarian carcinoma and PCD, confirmed clinically, radiologically, and serologically, was treated with 5 exchanges of 1 plasma volume each, followed by intravenous immunoglobulin at a dose of 1g/Kg−1 body weight daily for 2 days. RESULTS Several weeks after the treatment, the patient had significant improvement of her dizziness, tremor, and dysmetria. She refused maintenance therapy and began to deteriorate neurologically 3 months after the treatment. CONCLUSIONS Although this is only a single case report, the authors believe that the dire prognosis of PCD and the lack of effective therapy warrant a trial of this combined treatment early in the course of the disease. Confirmatory evidence of the efficacy of such an approach would be welcomed. Cancer 1996;78:2153-6.

Anti-Purkinje cell antibodies (APCA), believed to be markers of paraneoplastic cerebellar degeneration in females, have been identified in the serum of 3 men with subacute sensory neuronopathies and no evidence of tumors 5 years after the onset of the neurological signs. By indirect immunohistochemistry on sections of rat cerebellum and dorsal root ganglia, the patients' IgG bound to the cytoplasms of both Purkinje cells and dorsal root ganglia neurons. By western blot analysis on whole human cerebellum and whole human dorsal root ganglia homogenates, the IgG from 2 patients bound to a 62-kd protein in both homogenates and the IgG from 1 patient bound to a 110-kd protein in the cerebellum homogenate only. Yo autoantibody test was negative in all patients. Our study provides evidence that non-anti-Yo APCA may be associated with subacute sensory neuronopathies and are not necessarily markers of an underlying tumor. The previously described anti-Yo APCA has only occurred in females with cancer.

A 52-kd neural antigen was reported to be recognized by anti-Purkinje cell antibodies in serum of a patient with paraneoplastic cerebellar degeneration associated with uterine carcinoma. In this study, we demonstrate that this neural antigen is recognized by antibodies known as anti-Purkinje cell antibody type I (PCAb Type I) and anti-YO. The latter's antigen is reported to be specific for the 62- to 64-kd antigen CDR62. Assuming that the 52-kd and 62- to 64-kd antigens share a common epitope(s) recognized by all of these antibodies, we examined the antigenic region on the 52-kd protein by immunoblots with deletion fragment proteins of the recombinant 52-kd protein. A major epitope was localized in the region of amino acid residues 94 to 133 of the 52-kd protein, which is the site of a leucine zipper motif. The potential pathogenicity of PCAb Type I is discussed.

Cerebellar ataxia is a frequent finding among patients seen in neurological practice and may result in a wide variety of aetiologies, both acquired and genetic. Inherited ataxia is a large and important subgroup of the ataxic disorders, and includes metabolic ataxias, autosomal recessive degenerative ataxias, autosomal dominant spinocerebellar ataxias (SCAs), X-linked and maternally inherited ataxias. Hereditary ataxia is reviewed in this article and acquired ataxias are covered in the accompanying article. Hereditary conditions account for the majority of ataxic syndromes in children and one-third to one-half of patients with adult-onset ataxic syndromes. Classification by mode of inheritance is a useful way of organizing the hereditary ataxias for both clinical and research purposes, and this approach will be used in this article. Key Concepts Understand that there are a wide variety of different inherited causes of ataxia. Some patients without a family history of ataxia still have the disorder on the basis of a genetic mutation. Nucleotide expansion disorders are a common cause of dominantly inherited cerebellar ataxia. The majority of these diseases result from a toxic gain-of-function mechanism and they demonstrate genetic anticipation, wherein intergenerational expansion leads to disease with earlier onset and often more severe symptom. Friedreich ataxia is the most common inherited cause of ataxia. It results from decreased expression of the Frataxin protein due to a nucleotide repeat expansion in a noncoding region. A variety of mitochondrial disorders are associated with ataxia as one of the number of neurologic and systemic symptoms. These diseases result from mutations in either nuclear DNA in genes involved in mitochondrial function or in mitochondrial DNA itself. Wilson disease is a disorder of copper metabolism that can present with dystonia, ataxia or neuropsychiatric symptoms and is also associated with liver failure. Early treatment can be curative. Defects in DNA repair underlie many childhood onset forms of inherited ataxia. Keywords: spinocerebellar ataxia; neurodegeneration; mitochondrial disorders; DNA repair; polyglutamine disorders

Of the remote effects of cancer on the neurologic system, paraneoplastic cerebellar degeneration (PCD), characterized by global cerebellar dysfunction, is second only to paraneoplastic neuropathies in frequency. Recent evidence, including the finding of anti-Purkinje cell (now termed anti-Yo) antibodies directed against specific protein antigens shared by Purkinje's and tumor cells, supports an autoimmune etiology for this disorder. Increasingly, a link between breast cancer and PCD is being recognized. The authors report a case, as well as a comprehensive overview, of 62 women with breast cancer and PCD, identified through a Medline (National Library of Medicine, Washington, DC) computer search (1966 to 1991) and comprehensive reference follow-up of the medical literature. The current understanding of the pathophysiology of PCD, with particular emphasis upon those features both salient and unique to breast cancer, is discussed. Whereas PCD will affect only a small number of patients with breast cancer, recognition of this syndrome is important. Anti-Purkinje cell (anti-Yo) antibody titers are now commercially available through several reference laboratories, and a serum anti-Purkinje cell antibody titer will assist in establishing the diagnosis. Presence of consistent symptoms and elevated titers of anti-Yo antibodies should prompt a search for an otherwise occult, and potentially treatable, malignancy. Only therapy initiated early in the patient's course appears to be of benefit. Finally, investigations into the pathogenesis of this syndrome may shed further light upon other diseases presumed secondary to autoimmune dysfunction.

The components of protein phosphorylation systems (protein kinases, protein phosphatases, and their phosphoprotein substrates) are highly enriched in neuronal cells compared with other cell types. We exploited this relative neuronal enrichment of protein phosphorylation system components to develop a general assay technique for putative protein kinase substrates (phosphoproteins) in human cerebrospinal fluid. Using this cerebrospinal fluid phosphoprotein assay, we have detected a putative protein kinase C substrate protein of apparent Mr 60 kd in 6 of 14 patients with paraneoplastic cerebellar degeneration but not in any of 55 patients with a variety of other neurological diseases. Phosphoproteins in cerebrospinal fluid may provide novel and unique markers for the diagnosis or staging of neuronal diseases as well as offer potential insights into the biochemical characterization of affected neuronal populations.

We isolated a complementary DNA clone encoding a 52-kd protein recognized by an anti-neuronal cell antibody in serum from a patient with paraneoplastic cerebellar degeneration associated with uterine carcinoma. The recombinant protein expressed in prokaryotic cells was specifically recognized by the anti-neuronal cell antibody from the patient, and its molecular weight was identical to that of antigenic proteins in the cerebellum. The deduced protein consisted of 450 amino acids dominated by hydrophilic residues, the calculated relative molecular mass was 51,238, and the predicted value of the isoelectric point was 4.99. This complementary DNA sequence and the deduced protein sequence have not been reported previously, and the sequences showed no homologies with the complimentary DNA or the amino acid sequences in the GenBank, EMBL, or NBRF databases, including the complementary DNA for a 34-kd cerebellar protein (CDR34) that is recognized by an anti-Purkinje cell antibody. Unexpectedly, the transcript of this gene was detected not only in the cerebellum and the brain stem but also in an extraneural tissue, the intestine.

Paraneoplastic cerebellar degeneration typically begins with rapidly progressive ataxia of the trunk and extremities. Antineuronal antibodies are found in about half the patients. The most specific autoantibody is an anti-Purkinje cell antibody found in women with gynecologic tumors. Even after the tumor is removed, the cerebellar deficit persists in most patients.

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.

Background: Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. Objectives: An overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. Methods: Many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A–C were possible, but good practice points were agreed by consensus. Recommendations: The nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3–6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.

Evidence supports the hypothesis that autoimmune mechanisms are operational in the etiopathogenesis of certain neurologic paraneoplastic syndromes (PNSs), including paraneoplastic encephalomyelitis (PEM) and paraneoplastic cerebellar degeneration (PCD). The antibodies (Anti-Hu and Anti-Yo), the antigens (Hu and Yo), and complementary DNA clones encoding Hu and Yo, central to PEM and PCD, respectively, have been isolated. In contrast, the antigens, and antibodies if any, involved in autoimmune cochleovestibular dysfunction remain unknown. The temporal bone histopathology and neuropathology of 2 patients, 1 with PEM and 1 with PCD, who developed signs and symptoms of cochleovestibular dysfunction, are reviewed and contrasted to the literature. It is concluded that both auditory and vestibular symptomatology and pathologic alterations can be seen in association with neurologic PNSs and that studies using the antigens and antibodies involved in neurologic PNSs may provide a new perspective on the investigation of autoimmune cochleovestibular dysfunction.

Paraneoplastic cerebellar degeneration (PCD) is a common cause of subacute cerebellar ataxia caused by widespread loss of the Purkinje cells of the cerebellum. PCD diagnosis can be confirmed by detection of onconeural antibodies that may also indicate the underlying tumor type [1]. Most onconeural antibodies associated with PCD recognize intracellular antigens in Purkinje cells [2]. These antigens are supposed to induce, besides the antibody synthesis, an antigen-specific cytotoxic T-cell attack that probably is responsible of the Purkinje cell death and limited response to treatment [3,4]. The most common onconeural antibody in PCD is the Yo antibody that associates with breast and ovarian cancer [4]. In a previous case report, we identified a new antibody, targeting the intracellular Purkinje cell protein carbonic anhydrase-related protein VIII (CARPVIII), in a patient with PCD and melanoma [5]. We provide further evidence for the association of CARP VIII antibodies with PCD by demonstrating a second patient with these antibodies, who had an ovarian adenocarcinoma and developed cerebellar ataxia. A 69-year-old female patient presented with an ovarian papillary serous cystadenocarcinoma with infiltration of the omentum and peritoneal carcinomatosis that was resected and treated with chemotherapy for one year. The patient had been in remission for 4 years when she was admitted to hospital with the clinical presentation of cerebellar ataxia since 2 weeks, with vertigo, instability, headache, and vomiting that did not improve upon symptomatic treatment. Neurological examination revealed vertical nystagmus, dysarthria, intention tremor of the upper extremities, and gait ataxia. The brain MRI was normal. Abdomen CT scan detected a paraaortic adenopathy that was confirmed in a biopsy as recurrency of the ovarian adenocarcinoma. Lumbar puncture showed pleocytosis (290 cells/µl, 94% lymphocytes) and elevated protein concentration (67mg/dl), with normal glucose levels, oligoclonal bands were not tested. The serum was investigated for onconeural and surface receptor antibodies by tissue-based assays and immunoblot [6]. The tissue-based screening revealed an anti-Purkinje cell antibody of the IgG1 subclass that stained the soma, dendrites, and axons of Purkinje cells as well as synaptic terminals in the deep cerebellar nuclei (Fig. 1A, B). Currently, three different anti-Purkinje cell antibodies are associated with this staining pattern and PCD: anti-PKCgamma, described in two patients with adenocarcinomas [7], anti-ARHGAP26, reported in four patients, including one with ovarian cancer [8,9,10], and anti-CARP VIII [5]. To further characterize our antibody, we performed an immunoblot with electrophoretically separated extracts of rat cerebellum. As controls we used serum of the first published CARP VIII patient [5] and a serum of a healthy individual. The patient’s antibody detected a protein band with a molecular mass of approximately 29 kDa and was identical to the band detected by the serum with CARP VIII antibodies (data not shown). Moreover, we stained filters with purified phage plaques resulting in the specific expression of CARP VIII, and control phage plaques (which do not result in expression of CARP VIII) with the patient’s serum, a commercial CARP VIII antibody (Millipore, Billerica, MA, USA), and serum from a healthy individual (Fig. 1C). The patient’s antibody and the commercial anti-CARP VIII antibody stained phage plaques expressing CARP VIII, whereas control plaques remained negative. In addition, we performed a competitive inhibition of immunohistochemistry, where we first incubated the rat brain section either with the patient’s serum (Fig. 1D) or a control serum (Fig. 1E) and subsequently with biotinylated anti-CARP VIII IgG, obtained from the first published case [5]. The biotinylated anti-CARP VIII antibody immunoreacted with the brain section preincubated with the negative control, but not with the section pre-incubated with the patient’s serum, indicating that the antibodies of this patient competed for the same epitopes recognized by the IgG of the patient with CARP VIII antibodies. Other antibodies such as GAD65 and classical onconeural antibodies Hu, Yo, Ri, Ma1/2, amphiphysin, SOX1, and CV2/CRMP5 screened by a commercial immunoblot (Ravo Diagnostika, GmbH, Freiburg, Germany) were negative. Moreover, no surface receptor antibodies (LGI1, CASPR2, NMDAR, AMPAR, GABA(B)R, DPPX, mGluR1, mGluR5, GlyR) were detectable. Immunohistochemical analysis of the biopsy material with a commercial anti-CARP VIII antibody demonstrated robust expression of CARP VIII in the tumor cells (Fig. 1F, G). Despite of treatment with chemotherapy and intravenous immunoglobulin the cerebellar syndrome worsened over the following 6 months and the patient became wheelchair restricted and developed a worsening of dysarthria. Brain MRI showed a progressive cerebellar atrophy compared to the previous image. The tumor remained in remission until last follow-up of 9 months. Figure 1 Characterization of CARP VIII antibody We report the second patient with CARP VIII antibodies who also developed PCD. However, unlike the previously reported patient the underlying tumor was an ovarian carcinoma that expressed CARP VIII. CARP VIII is related to the family of carbonic hydrases (CA), a group of enzymes that catalyze CO2 hydration. CARP VIII differs from this group in lacking the classical CA activity due to the absence of zinc-binding histidine residues [11]. Human CARP VIII is preferentially expressed in the brain, mainly in Purkinje cells [11,12]. Beyond Purkinje cells, little or no expression of CARP VIII has been described in adult human tissue. However, in cancer cells, the protein becomes strongly upregulated and has been described in different tumor types, including colorectal and non-small-cell lung carcinoma, where it was associated with higher proliferation and invasive properties, suggesting a role in tumor growth [12,13]. By immunohistochemistry, CARP VIII immunoreactivity has been detected in 15% of a series of melanomas and 3% of ovarian cancers (www.proteinatlas.org). The upregulation of the otherwise neuron-restricted CARP VIII in tumor cells likely contributes in breaking immune tolerance triggering the development of CARP VIII antibodies and the expression in different forms of cancer explains its association with more than one tumor type. The cerebellar ataxia of our patient occurred at the time of tumor recurrence. Although PCD usually antedates the tumor diagnosis, it is not unusual that the clinical symptoms arise with the recurrence of the tumor, which might be explained by a dedifferentiation of tumor cells and/or change of antigen-presentation [4]. Unfortunately, in our case no tissue of the first tumor biopsy is available to test whether CARP VIII initially was negative but turned positive during tumor progression. The role of CARP VIII antibodies in disease evolution is unclear. CARP VIII is an intracellular protein, thus, the cerebellar degeneration is most likely T cell mediated and the patient’s antibodies, although of the IgG1 subclass and thus capable of activating complement, are not directly pathogenic. This is supported by the poor response to IVIg in both, the first and our CARP VIII patient, and probably neither plasma exchange nor other B cell targeting strategies might lead to a benefit, although more patients are needed to determine treatment response and prognosis [14]. However, the diagnosis of CARP VIII antibodies prompted early tumor diagnosis and removal. Unfortunately the clinical evolution was not favourable, as it usually happens in patients with anti-Hu and -Yo antibodies [4]. Our case confirms the association of CARP VIII antibodies with PCD and expands the spectrum of underlying tumors. Systematic screening for CARP VIII antibodies will detect more cases of this new paraneoplastic syndrome and can facilitate diagnosis and treatment of these patients. The possibility of CARPVIII antibodies should be considered in patients with strong suspicion of PCD and who do not have antibodies against other most common onconeural antibodies [1].