Mammele S, Thompson KS, Abe KK. A rapidly fatal case of anti-NMDA receptor encephalitis due to acute brain edema and herniation. Neurology. 2019 May 21;92(21):1014-1016.
A 12-year-old previously healthy boy of white, Asian, and Pacific Islander descent presented with acute onset of headache, fatigue, emesis, confusion, agitation, and brief generalized tonic-clonic seizures after previously recovering from a brief diarrheal illness 1 week prior. In the emergency department, he opened his eyes only to verbal prompting, was speaking confused words, and obeyed commands for motor response. Head CT without contrast was unremarkable. CSF was significant for lymphocytic pleocytosis (white blood cells 73 cells/[mu]L, 86% lymphocytes) and elevated protein (151 mg/dL) and he was started on ceftriaxone and acyclovir. EEG was consistent with encephalopathy and MRI with contrast was normal. Shortly after procedural sedation, he had another brief tonic-clonic seizure. He was given fosphenytoin and subsequently, he had equal and reactive pupils and localized to stimuli. Within a few hours, he developed fevers to 41[degrees]C and despite aggressive cooling, adequate oxygenation, and hemodynamics, he abruptly became unresponsive to noxious stimuli, with dilated and unreactive pupils. He was intubated and started on mannitol, 3% saline, IV immunoglobulins, and a methylprednisolone pulse. Repeat CT and MRI about 26 hours after the previously normal brain imaging studies were consistent with diffuse acute infarction and cerebral herniation. Neurosurgery believed the patient would not benefit from surgical intervention and brain death was diagnosed on hospital day 3.
Brain autopsy showed larger than expected brain weight, edematous gyri, bilateral tonsillar and uncal herniation, midbrain compression, and obstruction of the 3rd and 4th ventricles. Brain development and architecture were normal. There was evidence of early neuronal cell death and degenerative changes as well as diffuse lymphocytic and plasma cell perivascular cuffing and perivascular microglia prominence. CSF NMDA receptor antibodies from admission returned positive postmortem. Viral and bacterial cultures and other tests including herpes simplex virus 1/2, lymphocytic choriomeningitis virus, measles, mumps, varicella-zoster, enterovirus, mycoplasma, cytomegalovirus, and Epstein-Barr virus were negative for acute infection. These findings were consistent with NMDARE [anti-NMDA receptor encephalitis].
Mortality due to NMDARE has been reported to be 12% in adults compared with 4% in children. Deaths have been attributed to multiorgan dysfunction, refractory status epilepticus, pneumonia, hypovolemic shock, as well as suicide. We are not aware of a report of death due to cerebral edema and herniation, particularly with such hyperacute onset and progression. Time from symptom onset to death has been reported to range from 6 weeks to 5 months. In this case, there was unusually early onset of cerebral edema and rapid progression to diffuse infarction, herniation, and brain death within 3 days of presentation.
Identified risk factors for poor outcome include CSF pleocytosis, a Glasgow Coma Scale score below 8, intubation, and intensive care unit admission, which were all present in this patient.4,5 Other risk factors that were not present in this patient include status epilepticus, multiorgan dysfunction, hyponatremia, hypoalbuminemia, and oligoclonal bands.
This patient had psychiatric manifestations such as agitation and confusion, which are often seen in NMDARE. He was not found to have a tumor; however, NMDARE is rarely associated with malignancy in children,2 and associated malignancy does not appear to affect mortality rates.
In addition to their role in synaptic plasticity and learning, NMDA receptors are also known to mediate neuronal cell death as a result of overactivation. Superoxide produced in response to NMDA receptor stimulation generated primarily by NOX2 activation may result in excitotoxic cell death. The precise role of synaptic and extrasynaptic NMDA receptors in cell death remains to be determined. Neuronal cell damage is associated with cerebral edema.
This reported case of NMDARE is unusual for the rapid onset of cerebral edema and rapid progression to herniation and brain death occurring only 3 days after symptom onset. While this may be a rare complication of NMDARE, clinicians should be vigilant for acutely increased intracranial pressure in patients with clinical findings of encephalitis in general.