Autoimmune Encephalitis Secondary to Melanoma

Abstract

Background: The receptor for -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) is a glutamate receptor that mediates synaptic transmission in the central nervous system. Antibodies against the AMPA receptor are found in encephalitis associated with lung, breast, and thymus tumors (1). To our knowledge, paraneoplastic autoimmune encephalitis with antiAMPA receptor antibodies has not been reported with melanoma. Objective: To describe a patient with encephalitis, antiAMPA receptor antibodies, and metastatic melanoma. Case Report: A 61-year-old woman noted difficulty with goal-directed tasks and planning, which progressed over a few days to short-term memory loss and confusion. She was admitted to the hospital, where the initial examination found inattention, short-term memory problems, and mild dysmetria. The laboratory work-up was unremarkable, except for mild hyponatremia (sodium level, 134 mmol/L) and thrombocytosis (platelet count, 457109 cells/L). She had elevations in erythrocyte sedimentation rate (29.8 mm/h) and C-reactive protein level (228.6 nmol/L). Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis (total nucleated cell count, 0.071109 cells/L; 75% lymphocytes), a slightly elevated protein level (0.63 g/L), and a normal glucose level (4.0 mmol/L [72 mg/dL]). Tests of her serum and CSF for infection, including bacterial infection, fungal infection, herpes simplex virus, varicella-zoster virus, cytomegalovirus, and EpsteinBarr virus, were unremarkable. A T2 and fluid-attenuated inversion recovery magnetic resonance imaging scan of her brain showed evolving, bilateral, striatal hyperintensities (Figure 1). An electroencephalogram showed diffuse slowing with no evidence of epileptiform discharges. Fine-needle aspiration biopsy on her left supraclavicular and axillary lymphadenopathy revealed abundant, epithelioid, moderate to large malignant cells. Her physicians started her on a high-dose steroid regimen, followed by intravenous immunoglobulin for presumed immune-mediated encephalitis. An aspiration event led to acute respiratory failure and intubation. After 3 weeks of progressive neurologic decline, she was transferred to the neurologic intensive care unit at our institution for further management. Figure 1. Fluid-attenuated inversion recovery magnetic resonance imaging sequences. Left. Baseline scan. Right. Follow-up (3-month) scan showing generalized volume loss (prominence of Sylvian fissures). When the patient arrived, we found that she opened her eyes to noxious stimuli, revealing roving eye movements. However, she had no blink to threat and no evidence of consciousness on repeated examinations. Her CSF studies found antiAMPA receptor antibodies. We administered another course of steroids and followed it with plasma exchange and rituximab. A positron emission tomographycomputed tomography (PET-CT) scan confirmed active lymph nodes in her left cervical and axillary regions. An excisional biopsy of the left supraclavicular lymph node showed a metastatic tumor that was positive for S-100 and negative for Melan-A by immunohistochemistry. She had no skin lesions suggestive of melanoma, and the origin of this tumor was unclear. The tissue was tested for BRAF-V600E by immunohistochemistry and showed 80% positivity, which confirmed the diagnosis of melanoma. Because her mental status was not improving, we decided to treat her with a BRAF inhibitor (vemurafenib) and an MEK inhibitor (cobimetinib). She did not improve after 2 weeks, so we discharged her to home and her family arranged for hospice care. Two weeks after discharge, she woke up and asked for water. She was discharged from hospice care, and we resumed treatment with vemurafenib and cobimetinib. We also started her on a weekly regimen of methylprednisolone and intravenous immunoglobulin, which was later tapered to monthly. After 3 months, a PET-CT scan found no recurrence of melanoma (Figure 2), and a neurologic evaluation revealed excellent clinical recovery, except for difficulty with short-term memory. At her 9-month follow-up, her recovery persisted and she remained cancer-free. Figure 2. 18 F-FDG positron emission tomographycomputed tomography axial scans. 18 F-FDG= 18 F-labeled fluoro-2-deoxyglucose. Left. Baseline scan showing increased uptake in left axillary lymph node. Right. Follow-up (3-month) scan showing complete remission of FDG-avid lymph node after targeted chemotherapy. Discussion: Two aspects of this case are highly unusual. First, although antiAMPA receptor encephalitis is associated with underlying tumors in two thirds of cases (2), to our knowledge, this is the first reported case of malignant melanoma presenting as antiAMPA receptor encephalitis. Second, other cases of tumor-associated antiAMPA receptor encephalitis have not responded readily to treatment, especially in the long term (1, 3). Our patient seemed to be having a similar course while she was in the hospital. We know that combined BRAF and MEK inhibition in BRAF-V600Emetastatic melanoma significantly improves survival (4). We believe that this improvement was not apparent in our patient until she had been at home in hospice care for 2 weeks. On the basis of this experience, we encourage clinicians to consider melanoma as a possible diagnosis for patients with antiAMPA receptor encephalitis because some patients with this disease can respond exceedingly well to appropriate therapy.