During the course of an intercontinental flight in August 2009, a 65-year-old woman developed “dizziness” and an “inability to sense myself in space.” Her feelings of imbalance intensified to the point that she had difficulty standing and was unable to walk off the plane on arrival. Fully upright, she felt as though “there is a sensation of backwards motion, with someone trying to push me off my heels.” She also had a two-month history of impairment of short-term memory, intermittent blurring of vision (“eyes bobbing up and down”), and a twenty-pound weight loss. Vestibular neuritis was diagnosed, and prednisone was prescribed. Her symptoms progressed and she was admitted to the Massachusetts General Hospital. She smoked one to two packs per day for years, but quit four years previously. She drank two glasses, or more, of wine per night. On examination she was alert and appropriately interactive, but depressed and cognitively impaired. She showed normal registration of three items, but could recall none at five minutes. She was unable to name the month or her current location. She followed simple and complex commands and could spell “world” backwards without error. The cranial nerves were normal, apart from abnormal eye movements. During attempted fixation of a far target, she had prominent upbeat nystagmus, accompanied by lid nystagmus and saccadic intrusions. The upbeat nystagmus suppressed during near viewing. Horizontal and vertical saccades were dysmetric, and pursuit was saccadic in all directions. Prominent upbeat nystagmus made evaluation of vertical optokinetic and vestibular responses difficult; horizontally, her optokinetic responses were impaired, but her vestibulo-ocular reflex (VOR) appeared preserved. While sitting, she had a pronounced tendency to fall backwards. Her nystagmus showed marked dependency on head position. When evaluated, six months later, her nystagmus was upbeat when erect, absent when supine, reduced when prone, and beating away from the ground (apogeotropic) when lying on either side. Her gait was broad-based and unsteady, and she was unable to walk in tandem. Sensory examination showed mild impairment of joint position and vibration sense in the toes. Muscle strength was normal with symmetrical tendon reflexes and mild ataxia of the lower limbs. Investigations were directed towards detecting an occult malignancy. Brain MRI showed signal changes consistent with small vessel ischemic change, but normal brainstem and cerebellum; cerebrospinal fluid (CSF) showed protein of 69 mg/dl, sugar of 60 mg/dl, 7 WBC/mm3 (97% lymphocytes, 3% monocytes), IgG of 22.5 mg/dl (elevated), and albumin of 33.2 mg/dl (normal). CSF tested negative for malignant cells, oligoclonal bands, and viral titers. An abdominal CT revealed a solid 3.8 × 2.9 × 3.5 cm well-defined, heterogeneous mass in the tail of the pancreas (). A CT-guided core biopsy revealed a pancreatic endocrine neoplasm.
CT of abdomen and pelvis with intravenous contrast: solid appearing 3.8 × 2.9 × 3.5 cm well-defined heterogenous mass arising from the tail of the pancreas.
Paraneoplastic antibody testing, including anti-Ri, Anti-Yo, anti-Hu, anti-Ma1 and Ma2, anti-ZiC4, and anti-CV2, was positive only for anti-Hu antibodies at a titer of 1/15,360. The tumor showed strong reactivity with a monoclonal antibody against Hu, confirming the expression of this antigen. (). Analysis of patient’s serum and CSF for antibodies against the neuropil of brain, brainstem, and cerebellum (typically indicating a cell membrane or cell surface autoantigen) showed both samples had reactivity with the nuclei of neurons (Hu antigen) as well as with an unknown antigen expressed in the neuropil of the brain. In further studies, cultures of live, non-permeabilized rat hippocampal neurons confirmed the presence of an antibody reacting against a neuronal cell surface antigen (). Although analyses for the identity of the antigen were conducted, using a cell-based assay with cells expressing NMDAR, AMPAR, GABA(B) receptor, GlyR, LGI1, and Caspr2, all were negative, suggesting a novel autoantigen. A spleen-sparing distal pancreatectomy on the eighth day of the patient’s admission produced a well-circumscribed tan-red tumor diagnosed as a well-differentiated endocrine carcinoma with metastasis to one of 23 regional lymph nodes.
The patient was treated with cyclophosphamide, one dose intravenously 1100 mg (600 mg/m2) followed by oral 75 mg daily (1 mg/kg/day), and a course of intravenous immunoglobulin (0.5 g/kg/day for five days). During the initial two months in hospital, she showed progressive decline in cognitive function and memory, increasing gait ataxia and inability to converse intelligibly. However, six weeks post-surgery, she started to improve cognitively, becoming more attentive, conversational, and oriented. Her upbeat nystagmus persisted; at this point, her eye movements were recorded. Subsequently, she received a four-month therapeutic trial of Memantine 10 mg. b.i.d. for her upbeat nystagmus, starting in December 2009, and she tolerated it well with no side effects. Unfortunately, as she had no improvement in her visual acuity in primary gaze and no suppression of the nystagmus, the drug was stopped in March 2010.
In 2011, the patient rapidly deteriorated with marked ataxia, dysarthria, and declining cognitive function, and she is now confined to a wheelchair. She was readmitted on two occasions, most recently in March 2011, when she started on a trial of Rituximab. She initially received IV Ig 0.4 g/kg for five days, (subsequently monthly) and then Rituximab 375 mg/m2 weekly for four weeks. Her oncologist reports that she is currently stable on this regime.