ANTI- NMDA RECEPTOR ENCEPHALITIS
Anti-NMDA (N-Methyl-D-Aspartate) receptor encephalitis is considered a rare autoimmune disorder. In the space of 5 months, I see 2 cases. I am sharing as each case is a teaching lesson and a reminder to always be prepared to think outside the box.
A Hispanic female in her late thirties underwent a right oophorectomy for a markedly large cyst uneventfully. Final path report revealed a teratoma. Over the next two weeks, patient has made several ER visits for abnormal behavior and telepsych consult pinned diagnosis of psychosis and patient was started on Seroquel. Since she wasn’t getting better and started hallucinating in crescendo pattern, both visual and auditory, she came to our institution. Patient didn’t have any focal deficit but exhibited short term memory deficit, did have visual hallucination. MRI of brain was neg. A consulting neurologist evaluated patient and was puzzled because oophorectomy is the definitive treatment for this rare type of encephalitis associated with teratoma and she already had the procedure done. She wondered if some of the fluid had spilled and was still immunogenic. An LP was performed and it revealed a lymphocytic pleocytosis (total WBC of 76 with 88% lymph). CSF is neg for meningitis/ viral encephalitis titers. Paraneoplasm titer was also negative. With a high suspicion of the above condition and without the result of the Anti-NMA receptor titer, a regimen of Solu-Medrol 500mg IV Q12hrs plus 5 gm of IVIG were started. A pelvic MRI revealed loculated fluid but no mass. Anti-NMDA CSF titer came back positive at 1:40. Gyn consultant evaluated patient and recommended contralateral oophorectomy. In his note, he mentioned there was a partial tear and spilling of the cystic fluid during the previous oophorectomy. Patient underwent a left oophorectomy and pathology came back positive for teratoma. Despite the second oophorectomy, no drastic improvement could be noticed. Patient at times would make some hard to describe vocal sounds, would respond inappropriately to questions and or develop sexual obsession, etc. For a time, the possibility of steroids-induced psychosis was entertained, and the Solu-Medrol was stopped. However, it was resumed since the psychosis didn’t improve. But slowly improvement did take place. She received the full course of high dose steroids and gamma globulin. Patient lasted about 12 days in the hospital and toward the end begged to go home. A caretaker who was always at the bedside vouched to continue to supervise her and since she was getting close to her baseline, she was then discharged. Unfortunately, she returned to the hospital a few days later for worsening psychosis. Neurologist started plasmapheresis and patient was transferred to a tertiary center, Mayo Clinic. She returned about 1 week later. While there, she basically received a 5-day course of plasmapheresis. The recommendation was to use Rituxan next if no improvement took place. Over the following week, patient gradually improved. Prophylactic Vimpat and Seroquel 100mg daily as well as PRN Haldol were used throughout each hospital stay. Patient was finally discharged and in follow-up with her PCP and neurologist, is finally off the Seroquel after an appropriate tapering and the Vimpat.
This is ongoing. Another Hispanic female in her early twenties with a past history of thyroidectomy for thyroid cancer developed new onset of visual and auditory hallucination, loss of short-term memory and seizure. She uses no illicit drugs, doesn’t drink or smoke. She came to ER after the seizure. Head CT was negative. Her behavior was very erratic, ranging from crying fits to aggressiveness intermingled with hallucinations on and off. Same neurologist evaluated patient and recommended a pelvic CT and indeed it revealed a teratoma. Patient has LP and same titers as above were requested. Again, a lymphocytic pleocytosis is noted (94% lymphocytes). CSF Anti-NMDA receptor antibody titer was requested and 1gm of Solu-Medrol x 5 days as well as IVIG at 400mg/kg/day x5 were started. Gyn consultant evaluated patient and proceeded to do an oophorectomy. Path report revealed teratoma. Vimpat was started. Despite oophorectomy, patient’s condition kept deteriorating. Agitation became more frequent and patient was transferred to ICU. She ran from one complication to another. The antipsychotic meds caused dystonia and as such, they had to be stopped. Patient was treated with plasmapheresis and then Rituximab due to failure of response to plasmapheresis. Then patient developed respiratory insufficiency and had to be intubated. A transvaginal ultrasound didn’t reveal any teratoma in the right ovary. MRI of pelvis is not performed because of patient’s agitation at first but now due to intubation. Effort to transfer patient to a tertiary center is initiated. CSF anti-NMDA receptor antibody titer was sent and is still pending.
In both cases, a woman younger that 40 presents with acute onset of psychosis and presence of a teratoma. In the first case, the patient had bilateral teratomas. This condition was first described in 2005 as a neuropsychiatric entity. It’s a newbie and we are still accumulating data about the whole spectrum. So far what is accepted is that it occurs predominantly in young women with female to male ratio of 8:2; up to 37% of cases occur in patients younger than 18. A teratoma may be seen in half of the cases in women. Herpes simplex can also provoke an attack. This autoimmune disorder may also take time to resolve despite treatment with immunotherapy. It is supposed to be a rare condition, but the following fact does make us wonder about the true prevalence. Teratomas seem to be found more commonly in African Americans. The obvious question that needs to be asked is if the diagnosis is missed too often in this group. Young African Americans without a family history of mental illness and with no exposure to illicit drugs who present with psychotic behavior should probably be screened for it. The idea is that immunotherapy can help whereas missing the diagnosis will condemn the patient to long term neuroleptic meds that probably won’t work and will create a vicious cycle. Enough of such patients who deserve proper psychiatric treatment don’t get it. We don’t need to add to that list people who are misdiagnosed. This becomes a multidisciplinary approach involving primary care providers (Peds, IM and Gyn) as well as psychiatrist. The gold standard for the diagnosis remains the CSF anti-NMDA receptor antibody titer. The presence of teratoma in a young female supports it, but its absence doesn’t rule it out either.
Reynald Altéma, MD.
- Dalmau J, Armangué T, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019 Nov;18(11):1045-1057. doi: 10.1016/S1474-4422(19)30244-3. Epub 2019 Jul 17. PMID: 31326280.
- Titulaer MJ, McCracken L, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65.
- Guasp M, Dalmau J. Encephalitis associated with antibodies against the NMDA receptor. Med Clin (Barc). 2018 Jul 23;151(2):71-79. English, Spanish.
- Liu H, Jian M, Liang F, Yue H, Han R. Anti-N-methyl-D-aspartate receptor encephalitis associated with an ovarian teratoma: two cases report and anesthesia considerations. BMC Anesthesiol. 2015 Oct 16;15:150.