Paraneoplastic brainstem encephalitis and anti-Ri antibodies.

Abstract

Sirs: Anti-Ri antibodies were first identified in a patient with paraneoplastic opsoclonus arising as a complication of breast cancer. The terms most frequently used to describe the syndrome associated with anti-Ri antibodies are paraneoplastic opsoclonus-myoclonus ataxia (POMA) and opsoclonusmyoclonus syndrome (OMS) [11]. However, this report emphasizes that the brainstem is the major target of autoimmune dysfunction in patients with anti-Ri antibodies and as a result a wide spectrum of ocular motor disorders can be observed in this patient group. A 68-year-old female with a 50 pack-year smoking history was referred for neurological assessment following a subacute onset of dysequilibrium, nausea, vomiting, and visual disturbance. Ophthalmological examination revealed a paroxysmal alternating tilt reaction with torsional eye movements in the direction of the hypotropic eye. Primary position upbeat nystagmus was present and the amplitude of upgaze was reduced, but larger vertical excursions were elicited by the vestibulo-ocular reflexes indicating a supranuclear gaze palsy. Saccadic velocities were reduced in all directions. Neurological examination also revealed dysmetria of all limbs and an irregular jaw tremor. A gadolinium enhanced brain MRI was normal. The cerebrospinal fluid (CSF) contained 9 lymphocytes/mm3, protein 0.65 g/L, glucose 3.7 mmol/L. Cytology was negative. Oligoclonal bands were detected in the CSF despite a normal IgG/albumin ratio of 28 % [0–30]. Immunohistochemistry and western blot revealed that the patient’s serum contained anti-Ri antibodies [11]. Seven years previously the patient had undergone a right radical nephrectomy/ureterectomy to remove a transitional cell carcinoma of the right renal pelvis. Repeat abdominal/pelvic CT identified a right para-aortic mass and a fine needle aspiration and core biopsy of the right para-aortic mass identified a recurrence of the transitional cell carcinoma. The original nephrectomy specimen and core biopsy were examined for Ri expression using previously described methods [11]. The original tumour showed reactivity with biotinylated anti-Ri antibodies, but this reactivity was not detected against the core biopsy of recurrent tumour. A course of three two-litre plasma exchanges were performed without a detectable clinical improvement and although there was prompt resolution of the jaw tremor following the first of four cycles of cisplatin, methotrexate and vinblastine chemotherapy, the complex ophthalmoplegia persisted. The patient went on to develop progressive gait ataxia, but neither opsoclonus nor myoclonus was observed in the 18 months following presentation. Anti-Ri antibodies are a serological marker of paraneoplastic neurological dysfunction and are found in association with a broad spectrum of malignancies (Table 1). Although the terms POMA and OMS are often used to describe the neurological syndrome associated with anti-Ri antibodies,analysis of the 22 reported cases with anti-Ri antibodies [1–6, 8–13, this report] reveals that opsoclonus was a feature in only 11/22 cases and myoclonus was reported in 5/22 cases.However, even in the absence of opsoclonus, ocular motor dysfunction is usually prominent in patients with anti-Ri antibodies and the description of a paroxysmal alternating tilt reaction and reduced saccadic velocities in this report extends the broad range of ocular motor abnormalities associated with anti-Ri antibodies (Table 1). Probing cDNA libraries with anti-Ri sera has defined two antigens, Nova–1 and Nova–2, as the target of autoimmune dysfunction in the anti-Ri syndrome [15]. Nova–1 and Nova–2 are widely expressed within the central nervous system and post mortem studies on three patients with anti-Ri antibodies revealed widespread perivascular and interstitial lymphocytic infiltrates within the CNS in each case [7, 8, 14]. However, although cognitive abnormalities [10, 11, 14] myelopathy [5, 8, 11] and basal ganglia dysfunction [10, 11, 14] can occur in association with anti-Ri antibodies, clinical assessment reveals that brainstem structures are parLETTER TO THE EDITORS