Autoimmune-Associated Epilepsy

Clinical History & Presentation

Approximately 2.5 years ago, Mr R, then age 22 years, developed left-sided groin pain that worsened over the course of months, although he was otherwise healthy. He eventually sought medical evaluation, and imaging and laboratory workup revealed a tumor in his left testes. Mr R had a left orchidectomy approximately 6 months after the pain began. His postoperative imaging studies were concerning for tumor metastases. As a result, Mr R underwent a laparotomy for lymph node removal 3 months after his orchidectomy surgery. During his second surgery, an appendiceal tumor was seen incidentally and subsequently also removed. He underwent 2 rounds of chemotherapy at 3 months after the second procedure (1 year after symptoms began); his chemotherapy regimen included carboplatin and etoposide. Tumor pathology showed a neuroendocrine tumor was fully excised.

After another 3 months, Mr R’s cancer was deemed in remission, and he was cleared to return to work as a nurse. He started working night shifts at the hospital and initially felt he performed well and was returning to his baseline. After another 2 months, however, toward the end of his shift, while charting, he reportedly told the other nurses that he was feeling “off” and that his leg was bothering him. Mr R then became unresponsive and developed generalized convulsions. A code was called, and he was transported to a hospital emergency department. Mr R was administered multiple antiseizure medications (ASMs), including 6 mg lorazepam, 3 g levetiracetam, and fosphenytoin load, despite which he continued to seize. He was then intubated for refractory status epilepticus and started on a midazolam drip. Head CT revealed no acute findings, and initial cerebrospinal fluid (CSF) studies did not suggest viral or bacterial infection. Mr R was admitted to the medical intensive care unit for further management.

Diagnostic Studies

Mr R was assessed for toxic and metabolic causes of status epilepticus, and all test results were found to be unremarkable. His EEG demonstrated diffuse slowing with concern for left focal dysfunction without evidence of further seizures. Brain MRI demonstrated bilateral mesial temporal lobe T2 signal hyperintensities with minimal contrast enhancement (Figure 1A and D) concerning for autoimmune encephalitis. A second lumbar puncture was performed to obtain further CSF studies, and Mr R was started on a 5-day course of intravenous (IV) methylprednisolone. A sample of serum and an aliquot of CSF were sent for autoimmune encephalitis antibody panel testing (Mayo Clinic, Rochester, MN). The paraneoplastic encephalopathy panel result was positive for antiMa2 antibodies, confirming suspicion for a paraneoplastic process. CSF analysis also demonstrated normal protein and elevated oligoclonal bands.

Differential Diagnosis

Mr R’s clinical presentation, along with the presence of antiMa2 antibodies in his CSF, was consistent with paraneoplastic limbic encephalitis. Considering the presumed diagnosis of limbic encephalitis, Mr R’s new-onset refractory status epilepticus (NORSE) was thought to fit the clinical picture of acute symptomatic seizure secondary to autoimmune encephalitis (ASSAE), a common presentation of limbic encephalitis. Other causes of symptomatic seizures, including intracranial infections, also had to be considered.

Treatment and Follow-up

Mr R completed the 5-day course of IV methylprednisolone as an inpatient and was discharged home with levetiracetam treatment and a close outpatient neurology follow-up scheduled. At a follow-up outpatient visit 3 months later, Mr R reported that he had enjoyed a totally seizure-free interval. He was troubled, however, to report worsening cognitive issues. He had developed insidious worsening of anterograde amnesia with an inability to retain new information that severely limited his ability to perform daily living activities. Repeat brain MRI revealed mild progression of paraneoplastic limbic encephalitis with evidence of progressive T2 abnormality in the hippocampi, bilaterally, along with new bilateral hippocampal contrast enhancement (Figure 1B and E).

Because of concern for a relapse of limbic encephalitis, Mr R was directly admitted from the clinic for more aggressive immunotherapy. On day 1 of rehospitalization, plasma exchange (PLEX) therapy was initiated, followed immediately by 5 days of IV methylprednisolone. Mr R was then discharged with maintenance immunotherapy consisting of daily oral prednisone and mycophenolate.

Neuropsychiatric testing done 5 months after the second hospitalization for limbic encephalitis showed significant improvement in Mr R’s amnesia and return of his short-term memory. A repeat brain MRI at that time revealed near-complete resolution of bilateral hippocampal contrast enhancement and significant improvement of mesial temporal lobe T2 signal abnormality (Figure 1C and F). Mr R gradually progressed to have complete resolution of symptoms, including absence of breakthrough seizures; he successfully regained licensure as a nurse. Therefore, a decision was made to taper daily steroids in favor of a maintenance regimen consisting of mycophenolate and levetiracetam.

Steroid treatment was eventually discontinued, but 3 months after discontinuation, Mr R began having increasingly frequent but brief episodes. During these, he would first experience a “weird” taste that would then progress to a feeling of déjà vu and then a burning sensation of his face. He maintained awareness throughout these episodes, which lasted for a few seconds. Follow-up brain MRI showed progressive atrophy and effacement of internal architecture consistent with bilateral hippocampal sclerosis (Figure 2). Ambulatory EEG at that time captured more than 100 brief focal aware seizures in 48 hours, and interictal EEG showed frequent left temporal spikes and sharp waves (Figure 3). Monthly infusion of rituximab and IV immunoglobulin (IVIG) were added to Mr R’s treatment regimen. At his most recent follow-up (22 months since his initial presentation with seizures), he continued to have multiple focal-aware seizures despite polytherapy that included ASMs cenobamate, levetiracetam, oxcarbazepine, and clobazam along with continued immunotherapy with rituximab, IVIG, and prednisolone.