A 17-year-old black African female initially presented to a local clinic with 2 weeks of gradual-onset bi-frontal headache, insomnia, and subjective fevers. She was treated for non-specific infection - despite no documented fever or microbial isolates - with empiric antibiotics for 10 days during which she also developed restlessness and third-person auditory hallucinations. She was then referred to a psychiatrist who diagnosed her with an acute schizoaffective disorder given the additional history of underlying psychological stressors (it was the death anniversary of her mother, and her final high-school national examinations were imminent). She was admitted and treated with psychotropic medication, but after five days she developed documented fevers, orofacial dyskinesias with tongue-biting, and agitation, and she was additionally treated for neuroleptic malignant syndrome (NMS). She then became comatose and was thus transferred to our tertiary referral hospital.
On our initial assessment, she had a temperature of 39 C and tachycardia; neurologically her Glasgow Coma Scale (GCS) was 7/15, she had grimacing, tongue biting, bruxism, hyper-salivation and abnormal arm movements which were difficult to classify (Figure 1, Supplementary Video S1). She was intubated, mechanically ventilated and admitted to the intensive care unit (ICU).
We immediately ran investigations comprehensive blood and/or urine tests for infection, auto-immune disease (including vasculitis) and toxic causes (including porphyria), also comprising polymerase chain reaction (PCR) for tropical fever pathogens (human immunodeficiency virus, Treponema pallidum, malaria, Leptospira, rickettsia, dengue, West Nile, chikungunya and rabies viruses - with additional testing in saliva and neck hairline skin biopsies for the latter), contrast-enhanced computed tomography scan of the head, chest and abdomen which were all normal/negative.
Examination of her cerebrospinal fluid (CSF) revealed elevated pressures, and white cell count of 115/mm3, 98% lymphocytes, with negative PCR for bacterial, tuberculosis and herpes (simplex and varicella zoster) meningo-encephalitis pathogens (including on repeat CSF on day 2). Contrast-enhanced MRI brain scan demonstrated leptomeningeal enhancement (Figure 2A) with corresponding sulcal hyperintensities (Figure 2B) and serial electroencephalography (EEG) showed non-specific diffuse slowing with no epileptiform discharges.
She was initially treated for viral encephalitis, but this was stopped after two negative PCRs in CSF. After two further independent neurology opinions in addition to the primary neurologist (author DSS), we diagnosed the patient with probable NMDARE as defined by international criteria and commenced immunosuppression with high-dose intravenous methylprednisolone (IVMP) 1 gram/day for five days and concurrent intravenous immunoglobulins. The orofacial and upper limb movement disorders were controlled with a combination of oral levetiracetam and tetrabenazine, midazolam and propofol infusions, and maxillo-mandibular fixation. On day 7 both serum and CSF autoimmune encephalitis panels returned positive for antibodies against the NMDA receptor, giving a definite diagnosis of NMDARE. MRI pelvis did not show any ovarian or extra-gonadal teratoma.
At day 15 repeat MRI brain scan showed almost complete resolution of the meningeal enhancement (Figure 2C) and sulcal hyperintensities (Figure 2D) but her GCS remained persistently low at 8/15 and her unrelenting dyskinesias required higher sedation requirements. We repeated the IVMP course now with concurrent plasma exchange and weekly rituximab dosed at 375mg/m2 body surface area. Her ICU stay was complicated by right brachial deep vein thrombosis treated with low-molecular weight heparin, and tongue maceration that required surgical debridement. She had both tracheostomy and percutaneous endoscopic gastrostomy tubes fixed due to the prolonged ICU admission.
During the fourth week, she developed high-grade fevers due to multi-drug resistant Pseudomonas aeruginosa and Klebsiella pneumoniae, isolated from tracheal aspirates and the tracheostomy site. Despite timely initiation of appropriate intravenous antibiotics including carbapenems and continued debridement of the tracheostomy site, the patient went into septic shock leading to multi-organ dysfunction and succumbed 30 days into her hospital stay.