Case Presentation: A 63-year-old man with a history of hypertension presented with gait instability, progressive over one month, as well as positional hand tremors and nausea. On initial evaluation, he was afebrile with blood pressure of 169/98. Abnormalities on neurological examination included ocular flutter, left upper extremity dysmetria and wide-based cautious gait with bilateral leg tremor. Initial laboratory testing was only notable for CK of 44 IU/L (normal 47-322 IU/L). MRI brain and spine were unremarkable. Lumbar puncture revealed a nucleated cell count of 29 (93% lymphocytes) with normal protein and glucose. CSF autoimmune encephalopathy panel as well as infectious studies including EBV, VZV, and HSV PCR and fungal, acid fast and bacterial cultures were negative. Three days of methylprednisolone 1g IV was trialed for possible myelitis with minimal recovery. Abdominal imaging subsequently identified a 4.3cm mass abutting the duodenum and pancreas. Biopsy of a portocaval lymph node was pursued, and while awaiting results, five days of IVIG was attempted without improvement. Pathology ultimately revealed neuroendocrine small cell carcinoma (SCC) of likely gallbladder origin. Given new SCC and CSF lymphocytic pleocytosis, his ataxia was determined to be paraneoplastic in nature for which cisplatin and etoposide were initiated. His dysmetria improved, but with ongoing ataxia, he was discharged to a rehabilitation center with oncology follow-up.
Discussion: Paraneoplastic syndromes of the nervous system (PNS) are a heterogenous spectrum of diseases that develop due to immune cross-reactivity between malignant antigens and nervous system cells, resulting in autoantibodies against either intracellular or cell surface proteins. The differentiation is important because those targeting intracellular receptors cause cell death indirectly via T-cells, leading to irreversible damage. In contrast, cell surface autoantibodies cause dysfunction more responsive to immunomodulatory therapy. Cerebellar degeneration, as in this patient, is a feature of several PNS’ associated with anti-Yo, anti-Hu, anti-Tr, and other antibodies. Identification of these antibodies can be useful in making the diagnosis and narrowing the differential of the underlying malignancy; however, results may be delayed due to limited testing availability and antibodies are not found in 40% with clinically likely PNS. In antibody negative PNS, the presence of CSF pleocytosis and response to immunomodulating therapy can be suggestive. Neurologic symptoms precede the diagnosis of malignancy in 80% of PNS. Commonly identified malignancies include small cell lung carcinomas, thymomas, lymphomas, ovarian and breast cancers. Extrapulmonary small cell carcinomas (EPSCC) are rare, accounting for only about 1000 cases per year in the US. Like lung SCCs, early identification of EPSCC is critical, as they are aggressive with poor outcomes. Treatment of PNS entails managing the underlying neoplasm and immunomodulatory therapy to halt and potentially reverse nervous system damage. Improvement is variable, but early intervention portends the best outcome.
Conclusions: Hospitalists are often the first physicians to encounter undiagnosed PNS. Maintenance of a high index of suspicion in patients with unexplained neurologic symptoms facilitates diagnosis of PNS and associated neoplasms. This can expedite initiation of immunomodulating therapy and treatment of the underlying tumor, optimizing neurologic and oncologic outcomes.