| Author | Affiliation |
|---|---|
| Jessa Baker, BA | University of California, Irvine School of Medicine, Irvine, California |
| Chris Jeziorkowski, MD | Advocate Christ Medical Center, Department of Emergency Medicine, Oak Lawn, Illinois |
| Cory Siebe, MD | Denver Health Medical Center, Department of Emergency Medicine, Denver, Colorado |
| Megan Boysen Osborn, MD, MHPE | University of California, Irvine School of Medicine, Department of Emergency Medicine, Irvine, California |
Introduction
Case reports
Discussion
INTRODUCTION
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalitis with prominent neuropsychiatric features. Patients present with acute psychosis, memory impairment, dyskinesias, seizures, and/or speech disorders. The clinical course is often complicated by respiratory failure, requiring intubation. Approximately half of patients are found to have an associated ovarian tumor, which expresses NMDAR. Recognition of anti-NMDAR encephalitis by emergency physicians is essential in order to initiate early treatment and avoid psychiatric misdiagnosis. The disease is highly treatable with tumor removal and immunosuppression, and most patients demonstrate a full recovery. In this case series, we report two cases of anti-NMDAR encephalitis in adult women in the United States and provide a review of the literature.
CASE REPORTS
Case #1
Chief complaint: “Acting drunk”
A 27-year-old Japanese-American female presented to the emergency department (ED) in August for altered mental status. She had been seen in the ED one and a half weeks prior for fever, diarrhea and vomiting and was discharged home on promethazine. At the time of her second ED visit, her husband described four days of increasing altered mental status and stated that the patient was “acting drunk.” She also had short-term memory deficits, insomnia, hallucinations, falls, and episodes of stiffening and jerking movements. Her past medical, surgical, social, and family histories were negative. She had no recent trauma or zoonotic exposures.
On exam, her vital signs were significant only for a temperature of 38 degrees Celsius rectally and heart rate of 110. She appeared agitated and confused. She had no cervical adenopathy or meningismus. Her pupil exam was normal. Her cardiopulmonary, abdominal, and skin examinations were unremarkable. Despite her confusion, she was alert and moving all extremities. She was uncooperative with the majority of the neurologic exam. Her reflexes, including Babinski’s, were normal. Her speech was clear, but she appeared to be having visual and auditory hallucinations.
Her basic metabolic panel, blood alcohol, urine toxicology screen, thyroid stimulating hormone (TSH), human immunodeficiency virus antibody, acetaminophen and salicylate levels were all within normal limits. Her complete blood count was significant for a white blood cell (WBC) count of 17 x 109 cells/L. Her cerebrospinal fluid (CSF) was significant for 33 white blood cells/μL with 95% lymphocytes, 0 red blood cells/μL, and normal protein and glucose (37 mg/dL, 87 mg/dL, respectively). Her CSF gram stain was negative. A non-contrast head computed tomography (CT) and magnetic resonance imaging (MRI) scan were both normal. A chest x-ray was normal.
The patient was admitted to the hospital for further workup and treatment. She developed intractable seizures and hypoventilation, requiring intubation and sedation. The patient’s CSF was found to be positive for anti-NMDA receptor antibody IgG. Subsequently, a transvaginal ultrasound was performed, which showed a 4 cm ovarian dermoid cyst.
The patient was diagnosed with anti-NMDA receptor encephalitis and improved with immunosuppression and removal of the dermoid cyst.
Case #2
Chief complaint: “Changes in speech”
A 28-year-old African-American female presented to the ED with changes in speech. She stated that her speech had been “slow” for the past two weeks, associated with an intermittent occipital headache. She denied visual disturbances or focal deficits. Her family members stated that she was having changes in her personality (increased anxiety and tearfulness) and insomnia. Two weeks prior to her current presentation, she had been seen at an outside ED for a “flu-like” illness. Her past medical, surgical, social, and family histories were unremarkable.
On exam, her vital signs were unremarkable. Her head and neck, cardiopulmonary, abdominal, and skin examinations were unremarkable. On neurologic exam, she was alert, oriented, with normal motor and sensation throughout her extremities. Cerebellar exam was within normal limits, including a normal gait. Her speech was slurred with episodes of aphasia. She appeared anxious and was tearful.
Her basic metabolic panel, TSH, and urine toxicology screen were normal. Complete blood count was significant for WBC count of 12.5 × 109 cells/L. Head CT was normal. The patient was admitted and over the next 24 hours, she developed worsening anxiety, mania, paranoia, agitation, auditory and visual hallucinations, left facial droop, and ataxia of the right upper extremity. The admitting team performed a lumbar puncture 36 hours after her initial ED presentation. The patient’s CSF was significant for 320 WBC/μL with 92% lymphocytes, 10 red blood cells/μL, glucose of 50 mg/dL, and protein of 70 mg/dL.
Serum NMDAR antibody IgG was positive. A pelvic ultrasound and pelvic MRI were both negative. The patient was treated with intravenous immunoglobulin (IVIG) and methylprednisolone for three days and had a complete recovery.
DISCUSSION
Between 1997 and 2007, several authors reported cases of patients with paraneoplastic encephalitis associated with an ovarian teratoma;1-10 however, the exact etiology of the disease was unknown. In 2007, Dalmau and colleagues discovered anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibodies in the serum and CSF of patients with these distinct neuropsychiatric symptoms.11 The disease is now called anti-NMDAR encephalitis and has been widely described. In fact, the California Encephalitis Project found that anti-NMDAR encephalitis was more common than any individual viral etiology of encephalitis in patients younger than 30 years old, exceeding enterovirus, herpes simplex virus, varicella zoster virus, and West Nile virus.12
Anti-NMDA receptor encephalitis typically starts with a viral-like prodrome and patients may have headache, fever, nausea, vomiting, diarrhea, anorexia, insomnia, or upper respiratory tract symptoms11-18 (Table). A few days to weeks later, patients develop psychiatric symptoms (hallucinations, insomnia, fear, catatonia, delusions, mania, paranoia, anxiety, and agitation), short-term memory loss, abnormal movements (orofacial dyskinesias, choreoathetoid movements, muscle rigidity, dystonic postures, oculogyric crisis), seizures, and/or changes in speech (mutism, dysarthria, aphasia, incomprehensible speech).11,12,14-18 Other neurologic symptoms such as hemiparesis and ataxia occur less frequently.11 On presentation, patients may have a fever.11,13 As the disease progresses, patients may develop central hypoventilation, requiring intubation, and autonomic instability (hyperthermia, tachycardia, bradycardia, hypertension, hypotension).13,19
| Study and year | Median age and range (years) | Number of patients (Percent female) | Viral prodromea | Psychiatric symptomsb | Memory deficits | Changes in speechc | Seizures | Movement disordersd | Central hypoventilation and/or intubation |
|---|---|---|---|---|---|---|---|---|---|
| Dalmau (2007)e | 27 (14–44) | 12(100% F) | 10 (83%) | 10 (83%) | 6 (50%) | 6 (50%) | 11 (92%) | 7 (58%) | 10 (83%) |
| Iizuka (2008) | 26.5(17–33) | 4(100% F) | 4 (100%) | 4 (100%) | NR | 4 (100%) | 3 (75%) | 4 (100%) | 3 (75%) |
| Dalmau (2008) | 23(5–76) | 100(91% F) | 72 (of 84 pts,86%)f | 77 (77%) | 23 (23%) | NRg | 76(76%) | 86 (86%) | 66 (66%) |
| Florance (2009) | 14(2–48) | 81h(85% F) | 15 (of 31,48%) | 19 (of 32,59%) | NR | 17 (of 32,53%) | 23 (of 30,77%) | 26 (of 31,84%) | 7 (of 31,23%) |
| Gable (2012) | 12.5 (2–28) | 32(75% F) | NRj | ≥24j (75%) | NR | 23 (72%) | 22 (69%) | 20 (63%) | 13 (41%) |
| Lin (2014) | 18(7–28) | 12(83.3% F) | 7 (58.3%) | 11 (91.6%) | NR | 7 (58.3%) | 11 (91.6%) | 12 (100%) | 8 (66.7%) |
| Wang (2015) | 21.6(9–39) | 51(63% F) | 31(61%) | 46 (90%) | 16 (31%) | 23 (45%) | 43 (84%) | 29 (57%) | 14 (28%) |
F, female; GI, gastrointestinal; URI, upper respiratory tract infection; R, range; NR, not reported aViral prodrome includes symptoms such as fever, cough, rhinorrhea, vomiting, diarrhea, headaches. bPsychiatric symptoms include hallucinations, insomnia, fear, catatonia, delusions, mania, paranoia, anxiety, and agitation. cChanges in speech include mutism, dysarthria, aphasia, and incomprehensible speech. dMovement disorders include orofacial dyskinesias, choreoathetoid movements, muscle rigidity, dystonic postures, and oculogyric crisis. eDalmau and colleagues include previously reported cases in their case series. fInformation was only available for 84 patients gChanges in speech described, but exact number was not reported. hThere were 81 patients in the study, but the characteristics of the pediatric patients are those reported. jThe exact number of prodromal symptoms and psychiatric symptoms is not reported. However, 56% of patients had a fever, 28% had GI symptoms, 19% had URI symptoms, and 38% had headache. Hallucinations (66%), psychosis (59%), and irritability (75%) were reported separately, but there was no description of the overall number of patients with psychiatric symptoms.
Emergency physicians may be unfamiliar with the clinical presentation of anti-NMDAR encephalitis, since it was not fully characterized in the literature until recently. The diagnosis is often delayed as patients undergo extensive testing (MRI, electroencephalogram, lumbar puncture) and evaluation by neurology and/or psychiatry services to rule out infection or other neurologic or psychiatric cause.15,19 Many patients get admitted to a psychiatric unit prior to definitive diagnosis.11 Head CT is usually normal, but MRI may be abnormal in 25–55% of cases.20 Cerebrospinal fluid will be abnormal in 79–100% of cases with elevated WBCs showing a lymphocytic predominance, normal glucose, and normal or elevated protein, with or without oligoclonal bands.11,14,16,21 The definitive diagnosis is made through the detection of antibodies to NR1, NR2A and/or NR2B subunits of the NMDA receptor in the CSF or serum.13,14,15,22
Approximately one half of patients with anti-NMDAR encephalitis have an associated tumor14,15,16,19, most commonly an ovarian teratoma, which, along with the autoimmune nature of the disease, may explain the female predilection for the disorder.15,16 The frequency of teratomas varies with age, with female patients in the third decade of life having the highest frequency of teratomas.15,16 These teratomas have been shown to contain both mature and immature neuronal tissue, which expresses NMDA receptor subunits NR1, NR2A and/or NR2B on the surface,22 which is thought to be the basis of the antibody response.11 Several other tumors have rarely been reported (i.e. testicular teratoma15, small-cell lung cancer15, neuroblastoma19, Hodgkin’s lymphoma19), but the majority of patients without an ovarian teratoma have no tumor at all.14,15,16,19
Consideration of anti-NMDAR encephalitis by emergency physicians is essential so that early treatment can be initiated. Clinicians should consider the diagnosis in new-onset psychosis or even recurrent psychosis, especially in female patients. The majority of patients will recover with first-line treatment, including tumor removal and immunotherapy (corticosteroids, IVIG, and/or plasmapheresis).11,12 Dalmau et. al. reported full recovery of eight out of nine patients following tumor resection and immunotherapy.11 Refractory cases may respond to rituximab and/or cyclophosphamide.21
In conclusion, emergency physicians should suspect anti-NMDAR encephalitis in any young female who presents with new onset seizures, psychiatric symptoms, memory loss, dyskinesias, and/or changes in speech. Patients should be tested for anti-NMDAR subunits in the CSF and serum and should undergo imaging to exclude an ovarian teratoma (ultrasound or MRI). Anti-NMDAR encephalitis is highly treatable with tumor removal and immunosuppression.
Footnotes
Section Editor: Rick A. McPheeters, DO
Full text available through open access at http://escholarship.org/uc/uciem_westjem
Address for Correspondence: Megan B. Osborn, MD, MHPE, University of California, Irvine School of Medicine, Department of Emergency Medicine, 333 City Boulevard West, Suite 640, Orange, CA 92868. Email: mbo@uci.edu. 9 / 2016; 17:623 – 626
Submission history: Revision received April 13, 2016; Submitted April 24, 2016; Accepted June 13, 2016
Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.
REFERENCES
1. Nokura K, Yamamoto H, Okawara Y, et al. Reversible limbic encephalitis caused by ovarian teratoma. Acta Neurol Scand. 1997;95(6):367-73.
2. Okamura H, Oomori N, Uchitomi Y. An acutely confused 15-year-old girl. Lancet. 1997;350:488.
3. Aydiner A, Gürvit H, Baral I. Paraneoplastic limbic encephalitis with immature ovarian teratoma–a case report. J Neurooncol. 1998;37(1):63-6.
4. Taylor RB, Mason W, Kong K, et al. Reversible paraneoplastic encephalomyelitis associated with a benign ovarian teratoma. Can J Neurol Sci. 1999;26(4):317-20.
5. Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123(Pt 7):1481-94.
6. Lee AC, Ou Y, Lee WK, et al. Paraneoplastic limbic encephalitis masquerading as chronic behavioural disturbance in an adolescent girl. Acta Paediatr. 2003;92(4):506-9.
7. Muni RH, Wennberg R, Mikulis DJ, et al. Bilateral horizontal gaze palsy in presumed paraneoplastic brainstem encephalitis associated with a benign ovarian teratoma. J Neuroophthalmol. 2004;24(2):114-8.
8. Stein-Wexler R, Wootton-Gorges SL, Greco CM, et al. Paraneoplastic limbic encephalitis in a teenage girl with an immature ovarian teratoma. Pediatr Radiol. 2005;35(7):694-7.
9. Vitaliani R, Mason W, Ances B, et al. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol. 2005;58(4):594-604.
10. Yang YW, Tsai CH, Chang FC, et al. Reversible paraneoplastic limbic encephalitis caused by a benign ovarian teratoma: report of a case and review of literatures. J Neurooncol. 2006;80(3):309-12.
11. Dalmau J, Tuzun E, Wu H, et al. Paraneoplastic Anti-N-methyl-D-aspartate Receptor Encephalitis Associated with Ovarian Teratoma. Ann Neurol. 2007;61(1):25-36.
12. Gable MS, Sheriff H, Dalmau J, et al. The Frequency of Autoimmune N-Methyl-D-Aspartate Receptor Encephalitis Surpasses That of Individual Viral Etiologies in Young Individuals Enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7):899-904.
13. Sansing L, Tuzun E, Ko MW, et al. A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol. 2007;2(5):291-6.
14. Iizuka T, Sakai F, Ide T, et al. Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal. Neurology. 2008;70(7):504-11.
15. 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(12):1091-8.
16. 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):11-8.
17. Lin JJ, Lin KL, Hsia SH, et al. Anti-N-methyl-D-aspartate receptor encephalitis in Taiwan–a comparison between children and adults. ; Children with Encephalitis and/or Encephalopathy Related Status Epilepticus and Epilepsy (CHEESE) Study Group. Pediatr Neurol. 2014;50(6):574-80.
18. Wang W, Li JM, Hu FY, et al. Anti-NMDA receptor encephalitis: clinical characteristics, predictors of outcome and the knowledge gap in southwest China. Eur J Neurol. 2016;23(3):621-9.
19. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63-74.
20. Rosenfeld MR, Dalmau J. Anti–NMDA-Receptor Encephalitis and Other Synaptic Autoimmune Disorders. Curr Treat Options Neurol. 2011;13(3):324-32.
21. Titulaer M. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-65.
22. Tüzün E, Zhou L, Baehring JM, et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 2009;118(6):737-43.
