A 55 year-old male with a history of anxiety presented with bilateral limb tremor associated with transient loss-of-consciousness. The seizure was attributed to benzodiazepine withdrawal and he was discharged on levetiracetam. He subsequently developed speech impairment, sleep disturbance, agitation and hallucinations which prompted re-admission. CSF analysis showed a monocytic pleocytosis. EEG revealed epileptiform abnormalities in bilateral temporal lobes. Brain MRI was unremarkable. CT chest showed hilar lymphadenopathy. Mediastinoscopy and lymph node biopsy were performed. The patient was transferred to UCSD Medical Center.
On admission he was afebrile with normal vital signs. Neurologic exam was notable for disorientation, dysarthria and global aphasia. Hepatitis serology, EBV, CMV and HIV testing were negative. Rheumatologic evaluation was notable for a normal C4, C3, and negative DS-DNA, RF, SCL 70, anti-smith ab, SSA and SSB ab, ANA, and ANCA. A CSF paraneoplastic panel was notable for GABA-B-R positivity with a 1:256 titer (normal <1:2). Mediastinal lymph node pathology was consistent with thymic small cell carcinoma.
Over the course of several months he was treated with IVIG, plasma exchange, Cisplatin/Etoposide and Rituximab. The behavioral disturbance continued, prompting intermittent restraints, bedside sitter, and psychiatric consultation. Uncontrolled agitation precluded radiation therapy. Ultimately, he developed medication-refractory status epilepticus and was transitioned to comfort care.
Discussion:
Limbic encephalitis (LE) is characterized by memory loss, confusion, seizures, behavioral disturbance and personality changes. Paraneoplastic limbic encephalitis (PLE) is caused by autoantibodies and precedes the diagnosis of cancer in about 60% of patients. Malignancies that have been associated with PLE include lung cancer, testicular germ cell tumors, breast cancer, Hodgkin’s disease, teratoma of ovary, and thymoma. This is the first case report of a patient with thymic small cell cancer presenting with PLE.
GABA-B-R antibody associated encephalitis was first described in 2010 and treatment refractory seizures are a signature feature. Up to one half of the patients reported with GABABR mediated PLE were diagnosed with small cell lung cancer (SCLC).
Work-up includes evaluation for infection, primary autoimmune disorders and toxic-metabolic causes. CSF analysis is often normal but can show a pleocytosis. Brain MRI may show increased T2 signal in the medial temporal lobe. EEG can be used to diagnose subclinical seizures and exclude other causes of encephalitis. Paraneoplastic autoantibody testing can help establish the diagnosis. If immune-mediated LE is suspected, evaluation for associated cancer is recommended.
First line therapy includes IVIG, plasmapheresis, and steroids. Rituximab and cyclophosphamide are second-line options. Therapy for LE is usually initiated prior to confirmation of the underlying etiology and should be coordinated with cancer-directed regimens. Prompt initiation and subsequent escalation of treatment is associated with better clinical outcomes.
Conclusions:
Altered mental status is a common reason for admission to Hospital Medicine and has an extensive differential diagnosis. The presence of seizure, cognitive changes and behavioral disturbance should prompt work-up for LE and associated etiologies. Full recovery can hinge on the diagnosis and treatment of an associated malignancy.