Contributed by Jessica Dwyer, MD and Bruce Rabin, MD, PhD
A 25 year old African American female with no significant past medical history presented to the hospital with complaints of a severe headache and agitation for approximately one week. While in the emergency department, she became extremely agitated and violent, requiring physical restraints and benzodiazepine sedation. Her initial workup was unremarkable with the exception of a qualitative urine toxicology screen that was positive for cannabinoids. The patient was admitted to the inpatient psychiatry service for presumed acute psychosis. Within a few hours, she developed generalized seizures and required intubation for airway protection. A CT scan of her head, a brain MRI, and an EEG were negative for any acute intracranial pathology. Despite sedation and anti-epileptic medication, the patient continued to have persistent seizures and agitation. She was immediately transferred to the ICU where her sedation was increased and she was maintained on mechanical ventilation. She remained afebrile, had stable vital signs, and had an unremarkable physical exam. However, any time sedation was held she developed generalized tonic clonic seizure activity and had to be re-sedated. A work-up for acute status epilepticus was initiated, and the results of relevant laboratory tests are provided in Table 1.
Table 1. The results of relevant laboratory tests are as follows:
In addition to the listed results, a CT angiogram of the head was negative for acute intracranial abnormalities, including venous thrombosis. A pan-CT scan of the chest, abdomen, and pelvis was negative. A repeat EEG demonstrated findings consistent with a marked post-ictal or encephalopathic state, but with some additional possible ictal activity. Based on these results, it was thought that the seizures and altered mental status were likely due to encephalitis of either an infectious or autoimmune etiology. She was started on empiric anti-viral and antibiotic therapies, but did not demonstrate clinical improvement. In addition, the results of all the tests for bacterial, fungal, and viral organisms were negative. Due to the suspicion of an autoimmune etiology, she was started on an empiric regimen of intravenous methylprednisolone for five days with five rounds of plasmapheresis, but again she did not demonstrate clinical improvement. She was screened for multiple autoantibodies including anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-Ro, anti-La, anti-neutrophil cytoplasmic antibodies (ANCA), anti-thyroglobulin antibodies, and anti-thyroid peroxidase antibodies. These were all negative. The clinicians then requested a panel of autoantibodies associated with various neurologic syndromes and paraneoplastic diseases to be performed. This panel was performed at an outside reference laboratory, and included assays to detect anti-neuronal nuclear antibodies, anti-glial nuclear antibodies, anti-Purkinje cell antibodies, amphiphysin antibodies, CRMP-5 IgG antibodies, anti-glutamate decarboxylase antibodies, anti-voltage gated calcium channel antibodies, anti-voltage gated potassium channel antibodies, and anti-NMDA receptor antibodies. Eventually, the final diagnosis was made when the patient's CSF returned POSITIVE for anti-NMDA receptor antibodies.
Once the diagnosis was made, she was started on more aggressive immunotherapy with cyclophosphamide and rituximab since she did not demonstrate initial improvement with steroids and plasmapheresis. Given the high association of this disease with ovarian malignancies, the patient was evaluated by Gynecology-Oncology. A CA-125 level was noted to be mildly elevated at 36.9 U/mL (normal <35 U/mL). All other ovarian tumor markers, including β-HCG, testosterone, and α-fetoprotein, were negative. A pelvis MRI did not demonstrate any evidence of an ovarian neoplasm, but there were multiple bilateral peripherally located ovarian follicles which were thought to be consistent with the diagnosis of polycystic ovarian syndrome. It was eventually decided that since the patient did not demonstrate any clinical improvement with medical therapy, a prophylactic bilateral salpingo-oophorectomy should be performed. On gross examination of the specimen, one ovary contained a 1.5 cm cyst filled with a scant amount of sebaceous material admixed with brown hair. Histology confirmed the presence of a mature cystic teratoma.
During her hospitalization, multiple attempts were made to wean the patient off of mechanical ventilation, but all attempts were unsuccessful due to persistent seizure activity. It also became increasingly difficult to adequately manage the patient's seizure activity, and at one point she required a combination of up to six anti-epileptic and sedative medications. She remained in the ICU in an induced coma. In total, she was hospitalized for 53 days with no improvement in her cognitive status or seizure management despite multiple interventions, including removal of the disease-inciting teratoma. In addition, her hospital course was complicated by feeding difficulties requiring the insertion of a feeding tube, ileus, ventilator-associated Klebsiella pneumoniae pneumonia, hypotension requiring vasopressor therapy, anemia requiring two blood transfusions, a deep venous thrombosis in the left common femoral vein requiring the placement of an IVC filter, and adrenal insufficiency. A second round of plasmapheresis was performed, but her clinical status remained unchanged. An MRI of the brain demonstrated diffuse parenchymal atrophy secondary to persistent seizure activity. A family meeting was held and the patient was placed on comfort measures only. She died shortly after being removed from mechanical ventilation. The family denied the request for an autopsy.