For 1 week, a 34-year-old woman complained of headache, feeling feverish, and being unsure of herself. She attributed these symptoms to stress and anxiety and took two of her husband’s alprazolam pills one afternoon. The following day, she was found confused and was brought to the emergency room. Upon arrival she had generalized convulsions that were treated with lorazepam 4 mg intravenously and phenytoin 1,000 mg intravenously, and she was intubated for airway protection. Her temperature was 38.7°C; other vital signs, general examination, routine blood studies, and urine toxicology screening were normal. A head CT scan was unremarkable; cerebrospinal fluid (CSF) analysis showed a white blood cell count of 18 cells/ml (98% lymphocytes), red blood cell count of 26 cells/ml, glucose 4.27 mmol/l (77 mg/dl), and protein 0.55 g/l. Aciclovir 10 mg/kg body weight every 8 hours was started for possible herpes simplex virus (HSV) encephalitis. MRI fluid-attenuated inversion recovery (FLAIR) showed bilateral medial temporal lobe hyperintensity, predominantly involving the left hippocampus (). An electroencephalogram (EEG) showed 8–12 Hz mixed polymorphic alpha activity, without focal slowing, spikes or sharp waves. HSV polymerase chain reaction (PCR) was negative and aciclovir was discontinued. The patient’s mental status improved, and she was discharged home on levetiracetam 500 mg twice daily.
Figure 1 MRI scan of the patient at symptom presentation and follow-up. (A) MRI fluid-attenuated inversion recovery (FLAIR) obtained at symptom presentation demonstrates bilateral medial temporal lobe hyperintense signal, predominantly involving the left hippocampus (more ...)
The following evening the patient awoke after having visions that she would stab and kill her 3-year-old son, and asked to be taken back to the hospital. On arrival, vital signs and neurologic examination were normal. She was tearful with pressured speech, and denied hearing voices or having suicidal ideations. She was diagnosed with acute psychosis and readmitted.
The patient’s medical history was notable for obesity and hyperglycemia, both attributed to a polycystic ovarian syndrome. She did not smoke, drink alcohol, or use illegal drugs. One sister had scleroderma and another had systemic lupus erythematosus.
Levetiracetam was discontinued and valproic acid loaded at 1,500 mg intravenously and then continued at 500 mg three times daily. CSF analyses were similar to those previously obtained; bacterial and fungal studies, cytology and flow cytometry were unrevealing. Tests for Lyme disease, Epstein–Barr virus, and arboviruses were negative. Aciclovir was restarted at the same dosage as previously, although a repeat HSV PCR was negative. The patient was given lorazepam 1–2 mg intravenously every 2 hours as needed and olanzapine 5 mg daily for aggressive agitation. Over the next few days she became less communicative, stopped following commands, and developed catatonic features. MRI showed persistent FLAIR hyperintensity in the hippocampi and mild increased meningeal enhancement. An EEG demonstrated 2–6 Hz polymorphic delta and theta activity, without epileptic activity. She developed episodes of hypoventilation, hypotension (around 80/30 mmHg), and bradycardia (30 beats per minute) with periods of asystole lasting up to 15 seconds. A transthoracic echocardiogram was normal, and the patient was transferred to the neurointensive care unit of another institution.
On arrival, the patient’s temperature was 39.4°C; she was intubated and sedated. Her sedation was immediately discontinued. Several hours later, she remained unresponsive; her eyes would open without tracking or blinking to threat. The patient’s pupils were reactive and her oculocephalic and gag reflexes were intact. Muscle tone was increased, with rigidity and normal reflexes. She had frequent facial grimacing, rhythmic abdominal contractions, kicking motions of the legs, and intermittent dystonic postures of the right arm. An EEG showed no epileptiform correlate to the motor activity, but because of concern for an occult epileptic focus, topiramate 100 mg twice daily was added. Testing for HIV, rapid plasma reagin, and a comprehensive panel for autoimmunity (including among others anti-double-stranded DNA, thyroid peroxidase, and antineutrophil cytoplasmic antibodies) were negative. CSF analy sis showed a white blood cell count of 30 cells/ml (97% lymphocytes), red blood cell count of 12 cells/ml, glucose 5.00 mmol/l (90 mg/dl), protein 0.58 g/l, IgG index 1.72 (normal 0.28–0.66), and three oligoclonal bands not present in serum. Repeat cytology and HSV PCR were negative, and aciclovir was discontinued.
A CT scan and pelvic ultrasound revealed a calcified hypodense lesion in the left adnexa (6.0 × 6.1 × 7.9 cm). Serum tumor markers were negative. Tests for paraneoplastic and voltage-gated potassium channel antibodies were negative, but antibodies to N-methyl-D-aspartate receptors (NMDARs) were identified in serum and CSF (). Given the rapid deterioration of the patient’s condition, a left salpingo-oophorectomy was performed, revealing an immature teratoma of the ovary ().
Figure 2 Demonstration of N-methyl-D-aspartate receptor antibodies in the patient’s cerebrospinal fluid. (A,B) Sagittal section of rat hippocampus incubated with the patient’s cerebrospinal fluid (CSF; diluted 1:20). The anti-N-methyl-D-aspartate (more ...)
Figure 3 Histopathological studies of the patient’s teratoma. (A–C) Areas of the tumor containing adipose tissue (a), epithelial tissue (e), and nervous tissue (n), all in the same section (panel A). Other areas contained choroid plexus (panel (more ...)
The patient underwent tracheostomy and gastrostomy tube placement, and was started on intravenous methylprednisolone 1 g/day for 10 days and plasma exchange (5 exchanges in 10 days), followed by intravenous immunoglobulin (IVIg) 0.4 g/kg body weight/day for 5 days. As no improvement was noted, a bolus of cyclophosphamide was given (750 mg/m2). The patient continued on a slow steroid taper. One week later, the abnormal movements subsided and the cardiac arrhythmia resolved. She gradually became more alert and was weaned off the ventilator. She was severely deconditioned with minimal antigravity strength in all extremities. Language, cranial nerves and sensory function were intact. She did not remember the preceding 2 months, but could form new memories. Two months after discharge, follow-up MRI revealed considerable improvement of the FLAIR hyper-intensity in the hippocampi (). Her cognitive functions, memory, and psychiatric evaluation were normal. The neurological examination showed only mild generalized weakness; she could walk without assistance and had started chemotherapy.