Ophthalmoplegia associated with the anti-Ri antibody.

Anti-Ri antibodies most often occur in patients with breast cancer and typically are associated with the paraneoplastic syndrome of opsoclonus-myoclonus-ataxia. This study reports a patient with diplopia and ophthalmoplegia. She had anti-Ri antibodies, and despite an exhaustive search for malignancy at presentation, breast cancer was not detected for six months.     

Anti-Ri-associated paraneoplastic cerebellar degeneration and breast cancer: an autopsy case study

Several antineuronal antibodies are associated with paraneoplastic cerebellar degeneration. Anti-Ri is one of these antibodies in some cases but it is more commonly associated with paraneoplastic opsoclonus myoclonus in the context of gynecological neoplasia. Anti-Ri autoantibodies are thought to be directed against onconeural antigens, NOVA-1 and NOVA-2, that are expressed by the tumor as well as by neurons. The results of the treatment of both syndromes have been disappointing, although aggressive multimodality immunosuppressive treatments have been used. There are few cases of anti-Ri paraneoplastic cerebellar degeneration and none has been pathologically studied. We report the pathological study of a patient who died from anti-Ri-positive paraneoplastic cerebellar degeneration associated with breast cancer only confirmed at autopsy.     

Clinical and pathological advances on central nervous system paraneoplastic syndromes.

In the last decade, several features have improved our knowledge of CNS paraneoplastic syndromes. Patients with paraneoplastic cerebellar degeneration (PCD) and breast or ovarian cancer, but not with other tumors, harbor an antibody against Purkinje cells (called anti-Yo). Clinical features of anti-Yo positive and negative PCD are similar but the latter may have a less progressive clinical course with occasional remissions. In addition to the association of opsoclonus with neuroblastoma, this syndrome has been identified in patients with breast or small-cell lung cancer (SCLC). Patients with opsoclonus and breast cancer have an antineuronal antibody (called anti-Ri) not present if opsoclonus is associated with SCLC or neuroblastoma. Paraneoplastic encephalomyelitis (PEM) is almost always associated with SCLC. Most patients present with sensory neuronopathy, limbic or brainstem encephalitis but involvement of multiple levels is usual. An antibody (called anti-Hu) against neuronal nuclear antigens is present in patients with PEM and SCLC. Autopsy studies demonstrate deposits of anti-Hu specific IgG in the neurons and a predominance of T cells in the inflammatory infiltrates. Treatment of the tumor and immunosuppressors are effective in opsoclonus whereas patients with PCD or PEM with circulating antibodies do not improve.     

Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors

BACKGROUND: Antiamphiphysin antibodies react with a 128-kd protein found in synaptic vesicles.They were first described in patients with paraneoplastic stiff-man syndrome and breast cancer, but studies suggest that they can also occur in patients with other tumors and neurological disorders. OBJECTIVE: To determine if antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. PATIENTS AND METHODS: Of 2800 serum samples tested by routine immunohistochemical procedures on sections of paraformaldehyde-fixed rat brain for the detection of autoantibodies associated with paraneoplastic neurological syndromes, 5 were selected because of labeling suggestive of antiamphiphysin antibodies and subsequently confirmed by the results of Western blot analysis using recombinant amphiphysin protein. Controls consisted of 40 patients with various nonparaneoplastic neurological diseases; 101 patients with cancer but without paraneoplastic neurological syndrome; 9 patients with small cell lung cancer, anti-Hu antibodies, and paraneoplastic neurological syndrome; 3 patients with M2-type antimitochondrial antibodies but no neurological disorder; and 30 normal subjects. RESULTS: Of the 5 patients with antiamphiphysin antibodies, patient 1 had sensory neuronopathy, encephalomyelitis, and breast cancer; patient 2 had limbic encephalitis, and small cell lung cancer was detected in the mediastinum after 24 months of follow-up; patient 3 had encephalomyelitis and ovarian carcinoma; and patients 4 and 5 had Lambert-Eaton myasthenic syndrome and small cell lung cancer (patient 4 subsequently developed cerebellar degeneration). None of the 5 had stiffness. Two patients (Nos. 2 and 4) had antimitochondrial antibodies. The two patients (Nos. 4 and 5) with Lambert-Eaton myasthenic syndrome had antibodies directed against the voltage-gated calcium channel, and patient 2 subsequently developed anti-Hu antibodies. In the controls, antiamphiphysin antibodies were detected by Western blot analysis in 3 of 8 patients with anti-Hu antibodies, but in none of the other groups. CONCLUSIONS: These data indicate that antiamphiphysin antibodies are not specific for one type of tumor or one neurological syndrome and can be associated with other neural and nonneural antibodies. The simultaneous association of several antibodies in some patients suggests multimodal autoantibody production.     

Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer

The serum and cerebrospinal fluid (CSF) of 8 women with ataxia, 6 of whom also had eye movement abnormalities believed to be opsoclonus, were found to contain a highly specific antineuronal antibody we call anti-Ri. Seven of the 8 women also had or developed cancer: carcinoma of the breast in 5, adenocarcinoma in an axillary lymph node in 1, and carcinoma of the fallopian tube in 1. Four patients presented with the neurological disorder; the cancer was diagnosed first in the other 4. Immunohistochemical studies using serum or CSF from all 8 patients revealed a highly specific antibody interaction with central nervous system neuronal nuclei but not with glial or other cells; the titer ranged from 1:5,000 to 1:320,000 in serum and from 1:2,000 to 1:16,000 in CSF. Biotinylated IgG from the patients' serum reacted with the tumors of 3 of 4 patients with anti-Ri antibody but not with breast cancers from patients without anti-Ri antibody. Immunoblots against cerebral cortex neuronal extracts identified protein antigens of 55-kd and 80-kd relative molecular mass. Serum titers by immunoblot ranged from 1:500 to more than 1:40,000 and CSF titers, from 1:10 to 1:2,000. The relative amount of anti-Ri was always higher in CSF than in serum. The antibody was not present in sera from normal individuals; patients with breast cancer without opsoclonus; other patients with opsoclonus; or patients with other paraneoplastic syndromes related to breast, ovarian, or small-cell lung cancer. We conclude that the presence of anti-Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.     

Paraneoplastic cerebellar degeneration associated with ovarian cancer: anti-Yo immunoreactivity in autoptic cerebellum and ovarian carcinoma

Paraneoplastic cerebellar degeneration is a rare disorder caused likely by autoimmune mechanisms in malignant oncologic diseases, and the most common tumors are ovarian, breast, lung cancer, and m. Hodgkin. An immune reaction is supposed to be directed against identical antigens of cerebellum and tumor, and paraneoplastic antibodies called anti-Yo, anti-Hu, anti-Ri, or anti-Tr are often detected in blood and cerebrospinal fluid. The course of paraneoplastic cerebellar degeneration as a complication of ovarian cancer is described. The relationship between the malignancy and pathologic changes in cerebellum was confirmed by positive immunohistochemical and immunofluorescence reaction between a patient's anti-Yo-positive serum and her own Purkinje's and ovarian cancer cells.     

Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia

Various paraneoplastic autoantibodies have been linked to discrete neurologic syndromes and tumors in adults, but little is known about their incidence in children. We report a cross-sectional study of known paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86% of whom were moderately or severely symptomatic, and 68% of whom had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection), six of whom had never been treated with immunosuppressants. All were seronegative for anti-Hu, anti-Ri, and anti-Yo, the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. These data contrast with reports of anti-Hu-positive sera in children with high-stage tumors and suggest that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia. They underscore the need to search for unique autoantibodies, as well as cellular mechanisms of pediatric paraneoplastic disease.     

Paraneoplastic movement disorders

Paraneoplastic movement disorders are rare autoimmune nonmetastatic complications of cancer. Common paraneoplastic movement disorders include cerebellar syndrome, opsoclonus myoclonus, basal ganglia disorders, stiff person syndrome, and neuromyotonia. Syndromes usually present before cancer diagnosis and are commonly associated with one or more serum antibodies. Increasing numbers of antibodies have been identified (Hu, Yo, Ri, CV2, amphiphysin, Ma, Ta, Tr, NMDA, mGluR1, PCA2, ANNA‐3, VGCCA). Antibodies are highly correlated with the likelihood of an underlying cancer and are closely associated with certain tumors. Clinical clues to paraneoplastic aetiology include speed of onset, severity, speed of progression, resistance to treatment, and more widespread neurological signs than one would expect from nonparaneoplastic aetiologies. Cancer should be sought in those with classical presentations and those with possible presentations who have paraneoplastic antibodies. If no tumor is found on initial investigation, interval screening is advisable. The most common associated cancers found are small cell lung cancer, breast, gynaecological, testicular, lymphoma, and thymoma. Early identification and treatment sometimes leads to neurological improvement and may improve cancer prognosis. Prognosis is dependent on the tumor type and its likely response to treatment. © 2009 Movement Disorder Society     

Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients

In recent years several authors have described a close correlation between circulating antineuronal antibodies of different types and the occurrence of paraneoplastic neurological syndromes. Because this has not been widely accepted, we screened 300 serum samples from 181 ovarian cancer patients for the presence of circulating antineuronal antibodies by immunofluorescence. The findings were confirmed by immunoblotting. In 11 patients circulating antineuronal antibodies were detected. In 4 patients they were classified as anti-Yo and in 7 as anti-Ri, titres ranging from 1 : 400 to 1 :  204 800. All the patients underwent thorough neurological and neurophysiological investigations, with special regard to paraneoplastic syndrome. None of them had symptoms pointing to a paraneoplastic neurological syndrome, although patients were followed up to 2 years after the first examination. Thus the frequency of circulating antineuronal antibodies in ovarian cancer patients is higher than the frequency of paraneoplastic syndromes, and antibody positivity does not necessarily lead to the appearance of a neurological paraneoplastic syndrome. Received: 16 August 1995 Received in revised form: 1 June 1996 Accepted: 6 September 1996     

Paraneoplastic syndromes of the peripheral nerves

PURPOSE OF REVIEW: To describe the paraneoplastic disorders of the motor and sensory nerves and neurons, and their immunologic associations. RECENT FINDINGS: Recently proposed diagnostic criteria for paraneoplastic disorders may assist in determining the likelihood a given neuropathy or neuronopathy is related to an underlying malignancy. Of this group of disorders, paraneoplastic sensory neuronopathies are the most frequent; many of these patients have anti-Hu antibodies and small-cell lung cancer. There is often motor, autonomic, or central nervous system involvement, and electrophysiological studies may demonstrate not only sensory changes, but also motor abnormalities. While cancer has been found more frequently than expected in patients with Guillain-Barré syndrome, this association is extremely rare. A limited number of reports have described chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy with conduction block, vasculitic neuropathies, and motor neuron disease as paraneoplastic disorders. Anti-CV2 antibodies are frequently associated with a paraneoplastic sensorimotor axonal neuropathy and small-cell lung cancer. Peripheral nerve hyperexcitability may occur with or without a cancer association, and in both instances patients often have antibodies to voltage-gated potassium channels; thymoma and small-cell lung cancer are the most common underlying tumors. Plasma cell proliferative disorders are frequently associated with neuropathies, particularly demyelinating ones. SUMMARY: There is increasing recognition of an extensive variety of paraneoplastic disorders of the peripheral nerves. In many of these disorders onconeuronal antibodies are absent. Whole body fluorodeoxyglucose positron emission tomography scanning helps uncover the associated tumor, and recently proposed criteria may assist in the diagnosis. In many instances, prompt treatment of the tumor and immunotherapy result in symptom stabilization or neurologic improvement.     

Neuro-ophthalmology and paraneoplastic syndromes

PURPOSE OF REVIEW: To describe the neuro-ophthalmological manifestations of paraneoplastic syndromes and their immunological associations. RECENT FINDINGS: Neuro-ophthalmological signs and symptoms are usually present in paraneoplastic syndromes of the central nervous system. Unlike opsoclonus, less characteristic eye movement abnormalities are difficult to recognize as presenting symptoms of paraneoplastic syndromes. In this setting, the detection of several antibodies, including anti-Hu, Yo, Ma2, Ri, Tr, CV2/CRMP5 or voltage-gated calcium channel antibodies may help to establish that the neuro-ophthalmological disorder is paraneoplastic. Among the recently characterized antibodies, those against the Ma proteins often associate with brainstem encephalitis and vertical gaze paralysis. A small subset of patients with opsoclonus and ataxia harbor anti-Ri antibodies. In other patients, there is preliminary evidence that the autoantigens of opsoclonus reside in the postsynaptic density, but no dominant antibody marker has been identified. Uveitis and optic neuritis are rare accompaniments of paraneoplastic encephalomyelitis; some of these patients harbor anti-CV2/CRMP5 in association with other antibodies. Studies on paraneoplastic retinopathy indicate that immunity to retinal proteins other than recoverin can result in a similar syndrome to that associated with recoverin antibodies, and that melanoma-associated retinopathy may associate with several retinal antibodies. SUMMARY: There is increasing recognition of an extensive variety of neuro-ophthalmological abnormalities as manifestations of paraneoplastic syndromes and of several antineuronal antibodies as clinical markers of these disorders. Basic immunological studies support the pathogenic role of some of these antibodies, and are elucidating the pathogenic mechanisms that underlie these and other antibody-associated paraneoplastic syndromes.     

Qualitative evidence of Ri specific IgG-synthesis in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes

The presence of Ri-specific oligoclonal IgG bands in the CSF was investigated in five patients with paraneoplastic anti-Ri associated neurological syndromes (PNS) and six controls. In 4/5 CSF samples reactivity of IgG bands with recombinant Ri antigen was found using isoelectrofocusing combined with affinity blotting; in one patient with absence of oligoclonal bands of total IgG in CSF Ri-specific oligoclonal bands were detected with the same sample, indicating a higher sensitivity of Ri-specific affinity blotting as compared to affinity blotting with anti-human IgG antibodies. Our results confirm previous studies demonstrating IgG synthesis against onconeuronal antigens by intrathecal B-cell clones in PNS and extend this observation to patients with anti-Ri syndrome. The pathogenic relevance of these antibodies, however, is further challenged by the finding that specific intrathecal IgG synthesis might not be a prerequisite of CNS involvement, because it was missed in one of our patients.     

Chemotherapy treatment for anti-Hu paraneoplastic syndrome without active malignancy

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.     

Association of anti-Yo (type I) antibody with paraneoplastic cerebellar degeneration in the setting of transitional cell carcinoma of the bladder: detection of Yo antigen in tumor tissue and fall in antibody titers following tumor removal.

Anti-Yo (type I) autoantibodies reactive with Purkinje cell cytoplasmic antigens of 34 and 62 kd are found in the serum and cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration associated with cancer of the ovary, uterus, adnexa, or breast. Anti-Yo antibody response is rarely associated with other tumors. Here, we present a patient who developed paraneoplastic cerebellar degeneration and anti-Yo antibody response in association with transitional cell carcinoma of the bladder. The presence of anti-Yo antibodies was confirmed by immunofluorescence assay and by Western blot analysis against both Purkinje cell lysates and the CDR62 fusion protein. Yo antigen was demonstrated in sections of the patient's tumor. Antibody titers fell after tumor removal. Transitional cell carcinoma should be considered in patients presenting with subacute cerebellar degeneration and anti-Yo antibody response in whom ovarian, adnexal, uterine, or breast cancer cannot be detected.     

Anti-Yo antibodies and cerebellar degeneration in a man with adenocarcinoma of the esophagus

Serum antibodies to the Yo antigen are usually associated with paraneoplastic cerebellar degeneration arising in female patients with gynecological or breast malignancy and are rarely associated with other tumors. We report a male patient who presented with paraneoplastic cerebellar degeneration and anti-Yo antibodies following removal of an esophageal adenocarcinoma. This is only the third report of anti-Yo antibodies occurring in a male patient. The Yo antigen was expressed by the esophageal tumor but not in a frontal lobe cerebral metastasis identified at postmortem. Interestingly, CD8+ T-cell infiltration was also found in the tumor, but not in the metastasis, consistent with down-regulation of Yo expression by the tumor cells leading to evasion from immune-mediated tumor surveillance.     

A novel antineuronal antibody in a motor neuron syndrome associated with breast cancer.

A 72-year-old woman developed a lower motor neuron syndrome (MNS) 4 months before the appearance of breast cancer. Monoparesis progressed to quadriparesis despite high-dose IV immunoglobulins, plasma exchange, and azathioprine, and high-dose IV methylprednisolone. The patient improved only after the removal of the tumor. MRI demonstrated hyperintensities in the cervical spinal cord. The patient had antibodies that reacted with axonal initial segments and nodes of Ranvier. The findings suggest that in this patient lower MNS may be a paraneoplastic condition associated with breast cancer.     

Antibody types and IgG subclasses in paraneoplastic neurological syndromes

Three major patterns of antineuronal antibody response have been identified in patients with paraneoplastic neurological syndromes: Type I ('Anti-Yo'), associated with cerebellar degeneration in the setting of breast or gynecological cancer, Type IIa ('anti-Hu') associated with encephalomyeloneuritis in patients with small cell carcinoma of the lung, and Type IIb ('anti-Ri') associated with breast cancer. We have employed immunofluorescence methods to determine the antibody classes and the IgG subclasses which react with neurons in each of these patterns of paraneoplastic antibody response. In this study, IgG was the only antibody class identified; IgM and IgA antibodies were not found. IgG1 was the major subclass represented and was found in 9/9 patients with Type I antibody response, 26/27 patients with Type IIa antibody response, and 3/3 patients with Type IIb antibody response. Many patients also exhibited positive staining for IgG2 and IgG3. Trace amounts of IgG4 antineuronal antibodies were detected in a single patient with Type I antibody response; IgG4 antibodies were not found in other patients. Patients with paraneoplastic neurological syndromes exhibit an antibody response which is overwhelmingly IgG and is comprised predominantly of IgG subclasses capable of fixing complement. The role of these antibodies in the pathogenesis of paraneoplastic neurological disease remains uncertain.     

Anti-neuronal antibodies and central nervous system diseases: contribution to diagnosis and pathophysiology

Antibodies against antigens found in the central nervous system have been evidenced in several neurological diseases. The most well-known are associated with paraneoplastic neurological diseases (Anti-Hu, Yo, Ri amphiphysin, Tr, CV2 and Ta antibodies). Some of these antibodies are specific for certain types of cancer or neurological syndromes and are highly useful diagnostic tools for the clinician. They have contributed to the hypothesis that these paraneoplastic neurological syndromes involve autoimmune cross reactions between tumoral and nervous system antigens. They are however most unlikely pathogenic on their own. Anti voltage-dependent calcium channel antibodies associated with Lambert-Eaton syndrome which is paraneoplastic in only 60 p. 100 of the cases are also observed in cases of paraneoplastic cerebellar atrophy. Anti-GAD antibodies are seen in non-paraneoplastic stiff man syndrome and in certain progressive cerebellar atrophies. Antibodies reacting with different glutamate receptors are detected in different neurological diseases including Rasmussen's encephalitis. Finally, antibodies are described in diverse conditions such as amyotrophic lateral sclerosis, Sydeham chorea or Gilles de la Tourette syndrome. The significance of the antibodies observed outside the context of paraneoplastic syndromes is not well understood, but the anti-GAD antibodies associated with progressive cerebellar disorders and autoimmune polyendocrinopathies could be an expression of the autoimmune nature of certain neurological degenerative processes affecting the central nervous system.     

Paraneoplastic cerebellar degeneration: clinical-immunological correlations

Four different antineuronal autoantibodies have been identified in 23 of 47 patients with paraneoplastic cerebellar degeneration (PCD). The most common, an antibody against 34- to 38-kDa and 62- to 64-kDa protein antigens in the cytoplasm of Purkinje cells, was found in 18 patients. It is a highly specific marker for a severe stereotypical subacute pancerebellar syndrome of truncal and appendicular ataxia, dysarthria, and nystagmus in women with cancer (usually ovarian or breast carcinoma). Different anti-Purkinje cell antibodies (APCA) were found in 2 other patients with PCD. With two possible exceptions, an APCA was not found in patients with other neurological diseases, with cancer not associated with neurological symptoms, or in normal subjects. Antibodies reactive with neuronal nucleoproteins were identified in 3 other patients with PCD: an antibody that recognized 35- to 40-kDa neuronal antigens was found in 2 women with small-cell lung carcinoma, while an antibody in a woman with breast carcinoma identified 53- to 61-kDa and 79- to 84-kDa antigens. Detection of an antineuronal antibody in a patient without known cancer should prompt a careful search for a tumor at a site appropriate to the antibody type.     

Chorea-athetosis in the anti-Hu syndrome

INTRODUCTION: Paraneoplastic choreo-athetoses are rare. We report a case of anti-Hu syndrome with choreo-athetosis. CASE REPORT: A 48-year-old woman developed a small-cell lung carcinoma revealed by an anti-Hu syndrome. The neurological features included choreo-athetosis predominating in the upper limbs, chronic sensorimotor axonal polyneuropathy, and opsoclonus. The cerebrospinal fluid was acellular and contained several oligoclonal IgG bands, not found in the corresponding serum. Magnetic resonance imaging revealed bilateral high-intensity lesions on T2/FLAIR sequence in the corona radiata. Moderate transitory improvement of the paraneoplastic neurological syndrome was observed after several carboplatin-etoposid cycles. CONCLUSION: A paraneoplastic origin must be considered in all cases of unexplained choreo-athetosis. Paraneoplastic choreo-athetosis is most often associated with other neurological symptoms. The most frequent associated tumor is a small-cell lung carcinoma with anti-CRMP5 and/or anti-Hu antibodies. Our patient developed paraneoplastic choreo-athetosis related to an anti-Hu syndrome in the absence of anti-CRMP5/CV2 antibodies. Paraneoplastic choreo-athetosis might result from a central lesion, and/or from proprioceptive deafferentation subsequent to peripheral neuropathy.