Anti-Ri antibody-mediated paraneoplastic cerebellar degeneration: A rare, treatable yet poorly recognized entity
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.190257
Source of Support: None, Conflict of Interest: None
Paraneoplastic cerebellar degeneration (PCD) is a well-characterized and easily recognized paraneoplastic neurological syndrome (PNS). Till date, more than 10 different nuclear, cytoplasmic, and ion channel antibodies have been associated with PCD, with each of these having a characteristic clinical picture. Anti-Ri antibody-mediated PCD is characterized clinically by the presence of cerebellar ataxia, myoclonus, and opsoclonus. We report the case of a 76-year-old woman with breast carcinoma and anti-Ri antibody-mediated PCD along with ataxia, opsoclonus, torsional nystagmus, and eyelid myokymia, who improved after tumor resection and immunotherapy.
A 76-year old previously healthy woman presented to us with a history of 3 month duration of gradually progressive unsteadiness of gait and involuntary movements of the eyes and eyelids. She also complained of blurring of vision, which she attributed to frequent involuntary movement of eyes. There was no history of headache, seizures, myoclonus, vertigo, diplopia, bulbar symptoms, and incoordination in upper or lower limbs. She did not complain of any systemic symptoms or loss of weight or appetite. Personal, family, and previous histories were noncontributory, and there was no history of drug or toxin exposure. She was significantly disabled and required the support of one person for her activities of daily living. General physical and systemic examination including breast palpation was normal. On neurological examination, she was found to have torsional nystagmus, opsoclonus (especially on looking to either side), eyelid myokymia, and increased blink rate (60/min) [Video 1]. Gait was broad based and ataxic, and she needed support to walk. Rest of the neurological examination including cranial nerves, muscle tone and power, and deep tendon and superficial reflexes and sensations was normal. There was mild incoordination in both upper and lower limbs. Based on the clinical picture, the possibility of a brainstem lesion was thought of. The etiologies considered were as follows: Neoplastic disease, demyelinating disease, noninfectious or infectious granulomatous disease, or a paraneoplastic brainstem involvement. Detailed hematological and biochemical parameters (hemoglobin, total and differential leukocyte counts, platelet counts, renal and liver function tests, serum calcium and phosphorus, serum electrolytes, blood sugar, serum human immunodeficiency virus (HIV) and Treponema pallidum hemagglutination assay (TPHA), serum antinuclear and antineutrophilic cytoplasmic antibodies, and serum angiotensin-converting enzyme levels) were normal. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain was normal. Sonomammography showed an oval, 9 × 5-mm, well-defined lesion in the right breast, with irregular borders and calcification having brain imaging reporting and data system (BIRADS) grade 4a. It showed avid fluorodeoxyglucose (FDG) uptake on FDG-PET (positron emission tomography). Contrast-enhanced computed tomography (CT) scan of the chest and the abdomen and cerebrospinal fluid (CSF) examination were normal. Core biopsy of the breast nodule showed markedly pleomorphic cells with reversed nuclear: cytoplasmic ratio, suggestive of infiltrating ductal carcinoma grade III. Serum paraneoplastic antibody panel was strongly positive for anti-Ri antibodies. A diagnosis of anti-Ri antibody-mediated PCD was made, and she underwent a total mastectomy of the right breast along with axillary clearance followed by radiotherapy. On immunohistochemistry, the tumor was estrogen receptor (ER) positive and progesterone receptor (PR) and Herceptin (Her2)/Neu negative. She also received monthly intravenous pulse methylprednisolone (1 g daily for 3 days). At a 6 month follow-up, her eye movements and ataxia had improved, though anti-Ri antibody was still positive in serum. She is currently independent in performing the activities of daily living.
Despite recent advances in medicine, PNS continue to be a diagnostic dilemma. It occurs in <0.1% of all patients with cancer. PCD accounts for 50% of subacute cerebellar ataxia in patients >50 years of age., Thus, PCD should be considered in all patients with acute or subacute cerebellar ataxia without other risk factors such as stroke, alcoholism, primary or metastatic neoplasms in the cerebellum, drugs, etc. The likelihood of PCD is increased by the presence of constitutional symptoms (e.g., weight loss) and multiaxial neurological involvement (e.g., peripheral neuropathy, muscle or neuromuscular disease, ocular manifestations such as opsoclonus and myoclonus, and cognitive and behavioral disturbances). The most common neoplasms associated with PCD include gynecological carcinomas, breast cancer, small-cell lung carcinoma, and Hodgkin's lymphoma.
The typical clinical features include subacute (weeks to few months) cerebellar ataxia, though rarely, the course can be acute or insidious., Gait and truncal ataxia occurs early and is more severe than limb ataxia. Dysarthria is common and often severe enough to impair effective communication. Patients often complain of severe vertigo and nausea early in the disease, which may resolve once the disease stabilizes. Ocular findings include vertical and torsional nystagmus and opsoclonus. Mood disturbances are common, while dementia occurs occasionally. Usually the symptoms progress rapidly, leaving the patient severely disabled within 6 months. In general, disability is more marked in patients with anti-Hu and anti-Yo antibodies than in those with anti-Ri antibodies.
There are no specific laboratory or neuroimaging features for PCD, and the diagnosis rests on a high index of clinical suspicion and a thorough search for underlying malignancy. Neuroimaging is typically normal except in advanced cases, where mild cerebellar atrophy may be seen. Erythrocyte sedimentation rate and C-reactive protein may be mildly elevated. CSF may show mild lymphocytic pleocytosis (typically <20 cells), elevated protein (usually <100 mg/dL), increased IgG index, and oligoclonal bands. As PCD may precede the detection of cancer, paraneoplastic autoantibodies [Table 1] should be looked for in all suspected patients. If present, these provide specific evidence of cancer-related autoimmunity and warrant a thorough and repeated search for the underlying occult malignancy.,,
Our patient presented with subacute cerebellar ataxia, torsional nystagmus, opsoclonus, and eyelid myokymia. Imaging and CSF studies were normal. Coexistence of opsoclonus and eyelid myokymia along with ataxia and normal imaging findings pointed strongly toward a paraneoplastic etiology. Anti-Ri antibodies were positive in our patient, and a detailed evaluation revealed an underlying breast carcinoma.
Testing for antineuronal antibodies ( first demonstrated in 1976 and 1983) has become a routine practice in patients with subacute cerebellar ataxia.,, The most common autoantibodies associated with PCD include anti-Yo (38%), anti-Hu (32%), anti-Tr (14%), and anti-Ri (12%) followed by others [Table 1].
Type 2 antineuronal nuclear autoantibody (ANNA-2, anti-Ri) was first identified in 1988 and fully characterized in 1991. It binds to two highly conserved neuron-specific RNA-binding protein antigens (55 and 80 kDa, respectively) encoded by Nova-1 and Nova-2 genes respectively and are widely distributed in the nervous system., The classic clinical syndrome associated with anti-Ri antibody includes truncal ataxia and opsoclonus, though there are reports of peripheral neuropathy, myelopathy, brainstem dysfunction, axial rigidity, and spasms.,, Approximately 80% of patients have underlying cancer of the breast or lung (50% each). The clinical picture in our patient was correlating with the existing knowledge of its development except that we noted frequent eye blinking and eyelid myokymia.
The treatment of PCD continues to be controversial. The options include aggressive treatment of the underlying neoplasm with or without concomitant immunosuppression with intravenous immunoglobulin, plasma exchange, corticosteroids, and cytotoxic agents., The choice of various options should be individualized according to the needs of the patient. In our case, the patient underwent radical tumor excision and received monthly pulses of intravenous methylprednisolone (1 g daily for 3 days). At a 6 month follow-up, she was independently performing the activities of daily living without any evidence of residual tumor on whole-body FDG-PET scan, though she needed to be on pulse methylprednisolone treatment for continued improvement.
To sum up, we report a rare case of anti-Ri antibody-associated PCD for the first time from northern India with unique clinical features like eyelid myokymia and frequent blinking. We also stress on the need for long-term immunomodulation in our patient for maintaining improvement.
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