COG Puzzler: What's Gyn got to do with it?

In cooperation with NASPAG

Submitted by Lissa Yu, MD

Dr. Yu is a resident in the Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale-New Haven Hospital, New Haven, Connecticut.

Presentation

A 14-year-old G0 presented to the emergency department (ED) with 3 days of altered mental status. According to her family, she had been frightened by a magic show 3 nights earlier. Since then, she had not slept much, occasionally smacked her lips, and had headaches that were relieved by ibuprofen. The patient reported being afraid to fall asleep for fear she “might die in her sleep and never wake up.”

Before coming to the hospital, the patient had begun stuttering and became shaky, was lowered to the floor, couldn’t breathe, turned blue for 2 seconds, and then recovered spontaneously. There was no tongue biting, loss of urine, or neck stiffness witnessed at the time.

Medical, family, and social history

The patient and her family reported no fevers, although the entire family had recently had an upper respiratory infection. She had no recent travel or tick bites and denied playing in the woods. The patient’s medical history was significant only for eczema and neither she nor her family had a neurologic, psychiatric, or endocrine history. One cousin, however, had “light triggered” epilepsy. The patient had never been sexually active and had not seen a gynecologist. She was homeschooled and active in dance classes, where she had many friends. She denied smoking, drinking, and drug use.

Examination

At her presentation to the ED, the patient was febrile to 101.1ºF, and her heart rate ranged from the 90s to the 140s. All other vital signs were normal, including oxygen saturation. Her exam was significant for inappropriate answers to many questions and inability to follow commands, but without gaze deviation or asymmetry. Her heart, lung, and abdominal exam were within normal limits except for intermittent regular tachycardia, 1 café-au-lait lesion on her abdomen, eczema in her antecubital fossa, and mild hidradenitis in her axillae.

Tests and treatments

While in the ED, the patient was witnessed to have a 2-minute tonic-clonic seizure, with desaturation into the 80s, which resolved with repeated administration of intravenous lorazepam. A computed tomography (CT) scan of the head did not reveal any acute processes. The patient’s white blood cell count was 12,600 with 70% neutrophils. Her metabolic panel was within normal limits. Her thyroid-stimulating hormone level was 0.8. Urine toxicology and serum toxicology were negative as were a urine pregnancy test, ammonia level, and alcohol panel. Her direct fluorescent antibody test was negative.

The patient was admitted to the pediatric ICU, where a lumbar puncture showed 22 red blood cells and 26 WBCs with lymphocytic predominance (92% lymphocytes). Cerebrospinal fluid cultures were negative. The patient was treated with fosphenytoin, acyclovir, ceftriaxone, and vancomycin. An initial electroencephalogram was negative for epiletiform discharges or seizures and magnetic resonance imaging (MRI) of the head showed no acute process. Tests (PCR) for herpes simplex virus, enterovirus, and parechovirus returned negative. Blood cultures were persistently negative. Electrocardiograms repeatedly confirmed sinus rhythm.

Subsequent studies

A CT of the patient’s chest/abdomen/pelvis suggested a calcification in her left ovary, and a follow-up MRI described a targetoid 2.3-cm mass that demonstrated a hyperintense focus with a hypointense rim, suggesting an involuting corpus luteum, but not excluding a lipid-deficient teratoma/dermoid. An additional lab study was ordered.
 

What's your diagnosis?

• Psychotic break

• Central nervous system mass

• Infectious or autoimmune meningitis

• Thyrotoxicosis

• Encephalitis with ovarian teratoma

• Tick-borne illness

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Differential diagnoses

Differential diagnoses included ingestion, thyrotoxicosis, infectious or autoimmune meningitis or encephalitis, tick-borne illness, acute disseminated encephalomyelitis, electrolyte abnormality, psychotic break, sleep deprivation, and central nervous system mass.

Final diagnosis

After a lab test demonstrated anti-N-methyl D-aspartate (NMDA) receptor antibodies, the diagnosis was made: anti-N-methyl D-aspartate (NMDA) receptor encephalitis with mature ovarian teratoma.

The patient was initially treated with steroids, IVIG, and plasmapheresis, as well as anti-epileptic medications for seizure suppression. The patient subsequently underwent an uncomplicated left ovarian cystectomy, with pathology confirming mature teratoma with areas of mature neural tissue. Unfortunately, her symptoms continued to worsen and titers continued to increase. After thorough multidisciplinary discussion, 3 weeks later the patient underwent a left oophorectomy; pathology confirmed ovary with corpus luteum, cystic follicles, focal surface adhesions, and no residual teratoma. She slowly improved clinically and was discharged from the hospital after a 6-month stay. She continued with rehabilitation, initially at an inpatient facility and then at home, and with rituximab and cyclophosphamide treatment.

Next: Discussion >>

Discussion

Anti-NMDA receptor encephalitis is associated with symptoms including psychiatric changes, insomnia, changes in memory and decreased consciousness/stupor, seizures, and autonomic instability. Many patients initially present with headache, fevers, or other flu-like symptoms before development of these neuropsychiatric findings.^1-3 Diagnosis is made with confirmation of IgG antibodies to the NR1 subunit of the NMDA receptor, either from serum or CSF; IgM and IgA antibodies have shown minimal clinical value. CSF titers appear to have more clinical correlation but may be difficult to practically obtain and trend.⁴ Initial findings may also include CSF positive for lymphocytic pleocytosis or oligoclonal bands, EEG with frequent slow disorganized activity and infrequent epileptic activity, and brain MRI showing abnormalities in cortical or subcortical regions; however, these studies may also be normal.²

A case study of 100 patients with anti-NMDA receptor encephalitis revealed that 59% had associated neoplasms, most commonly ovarian teratomas; in this series, all teratomas contained nervous tissue and all that were examined for expression of NMDA receptor tested positive.¹ In the same series, 21 patients were women and girls younger than 19 years, of whom 12 had ovarian teratoma and 9 had no known tumor.¹ In a series of children and adolescents, ovarian teratomas were found in 56% of women aged >18 years with anti-NMDA receptor encephalitis, 31% in girls aged ≤18 years, and 9% in girls aged ≤14 years.³

Pelvic masses may be found on pelvic imaging, including MRI, CT, or ultrasound. Rarely, this encephalitis may be associated with other tumors such as testicular germ cell tumors, lymphomas, or carcinomas.² When tumors are found, resection is indicated. Standard treatment also includes glucocorticoids, intravenous immune globulin, and plasma exchange. In settings where these interventions fail to show improvement, rituximab or cyclophosphamide may be used. Supportive care may include mechanical ventilation and prolonged ICU stay as well as physical rehabilitation and psychiatric treatment.⁴ Outcomes are variable and though progressive or persistent neurologic deterioration is common, spontaneous recovery has also been reported.^2-4

References

1. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091–1098.

2. Dalmau J, Rosenfeld MR. Paraneoplastic and autoimmune encephalitis. In: UpToDate.com, UpToDate, Waltham, MA.

3. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009;66(1):11.

4. Rosenfeld MR, Dalmau J. Anti-NMDA-receptor encephalitis and other synaptic autoimmune disorders. Curr Treat Options Neurol. 2011;13(3):324–332.