Anti-NMDA Receptor Encephalitis in Children and Adolescents

We have discussed many causes of encephalitis and encephalopathy previously (ex, Eastern Equine Encephalitis, Posterior Reversible Encephalopathy, FIRES, Reye’s Syndrome) and have highlighted the fact that they can be challenging to diagnose early. An irritated brain can lead to such a wide array of symptoms. It is even more challenging when the initial symptoms seem to align with what we perceive as psychiatric concerns. While it is important for us to maintain a safe work environment for our patients and our team, managing the agitated patient requires more of us than administering Droperidol or Ketamine. Let’s digest a morsel on an important cause of altered behavior in patients that we should consider – Anti-NMDA Receptor Encephalitis:

Anti-NMDA Receptor Encephalitis: Basics

• Is an autoimmune disorder is characterized by identifying IgG antibodies against a specific subunit of the NMDA receptors in the CNS.
• It is commonly missed during the first few ED visits.
  • Often initially misdiagnosed as a psychiatric illness.
  • Treatment delays can lead to long-term deficits and psychological stressors to both the patient and their family.
• It is Rare, but….
  • Anti-NMDA receptor encephalitis is now recognized as the most common cause of encephalitis in children and young adults
  • Surpassed viral etiologies.  
• Male to female ratio of diagnosis is 1:4
• The most commonly affected patients are young adult females between 25-35 years old, however there are many confirmed cases of children age less than 12 and adults greater than 85.

Anti-NMDA Receptor Encephalitis: Clinical Features

The symptoms progress over weeks to months, and tend to occur in stages. Patient’s usually present in the psychotic stage and are often misdiagnosed at multiple visits.

1. Prodromal state: typically presents with viral-like symptoms (fever, headache, etc) that resolve over 1-2 weeks.
2. Psychotic phase
   • Adults and adolescents present with acute or subacute behavioral changes and/or psychiatric manifestations
   • Anxiety, hallucinations, delusions, psychosis, which can occur alone or together
   • Sleep disorders
   • Seizures that may be resistant to AEDs
3. Younger children are more likely to present with movement disorders or seizures
4. Akinetic (or unresponsive) phase: Mutism, decreased motor activity, catatonia
5. Hyperkinetic phase with autonomic instability and prominent movement disorders (automatisms, dyskinesia, dystonia, choreoathestosis, etc)

Anti-NMDA Receptor Encephalitis: Differential Diagnosis

• Primary psychiatric disorders (ex, schizophrenia, acute psychosis)
• Infectious encephalitis
• Neuroleptic malignant syndrome
  • Rare, life-threatening reaction to anti-psychotic medications
• Ingestion
  • Always ask what medications your patient’s are taking and what they may have access to in the home…
  • the benadryl might have seemed like a good idea to help with insomnia… but, its anticholingeric effects have made us become as mad as a hatter…

Anti-NMDA Receptor Encephalitis: Evaluation 

• Routine laboratory workup is generally non-specific. 
• Serum and CSF anti-NMDAr IgG antibodies 
  • One retrospective study found that CSF sensitivity was 100%, with serum sensitivity 85.6%.
  • Higher titers in both CSF and serum were associated with poor outcomes.
• HSV serum and CSF PCR
  • HSV is one of the most common etiologies of encephalitis and is devastating.
  • It is best to assume the worst and cover for this possibility.
• Brain MRI
  • Can be normal!
  • May see non-specific white and gray matter changes.
• Pelvic and abdominal imaging to assess for tumor (see below)

Anti-NMDA Receptor Encephalitis: Treatment

• Remember your ABCs!
• Treat the seizures, but….
  • Keep in mind that seizure management can be difficult and the patient may not respond to AEDs.
• Manage severe behavioral symptoms, but…
  • Neuroleptic malignant syndrome has occurred in this patient population with use of antipsychotic agents, so be careful.
• Empiric antimicrobial coverage with…
  • Ceftriaxone & vancomycin if concerned for bacterial meningoencephalitis.
  • IV acyclovir for HSV coverage while awaiting PCR results.
• First line therapies for anti-NMBDA receptor encephalitis consists of…
  • High dose steroids,
  • IVIG, and
  • PLEX – Therapeutic plasma exchange
  • Only 50% of patient’s respond, and will require second line therapies such as Rituximab. 
• Make sure to consult your friendly neighborhood pediatric neurologist and/or rheumatologist!

Anti-NMDA Receptor Encephalitis and Adolescent Females

There is an association between anti-NMDAr encephalitis and ovarian teratomas. 

• The prevalence ranges from 12.5%-61% in females of reproductive age, with approximately 45% of females older than 18 years old with teratoma.
  • Prevalence decreases with decreasing age.
• Risk of teratoma is higher in African American and Asian women. 
• These females should have imaging with either MRI or CT as well as abdominal or transvaginal ultrasound to assess for ovarian teratoma.

Moral of the Morsel

• It’s NOT always psych! Keep a high index of suspicion for anti-NMDAr encephalitis in children and adolescents who have had multiple ED visits for new and worsening psych/behavioral concerns, seizures, and/or movement disorders over several months. Earlier diagnosis leads to better outcomes.
• Serum AND CSF antibody titers! While CSF is more sensitive, serum tends to result sooner.
• Don’t forget about HSV… Empirically treat with acyclovir while awaiting lab results. 
• Female patient? Make sure to obtain imaging to rule out ovarian teratoma! 

Resources: 

Yeshokumar A, Gordon-Lipkin E, Arenivas A, Rosenfeld M, Patterson K, Blum R, Banwell B, Venkatesan A, Lancaster E, Panzer J, Probasco J. Younger Age at Onset Is Associated With Worse Long-term Behavioral Outcomes in Anti-NMDA Receptor Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2022 Jul 6;9(5):e200013. doi: 10.1212/NXI.0000000000200013. PMID: 35794025; PMCID: PMC9258981.

Samanta D, Lui F. Anti-NMDAR Encephalitis. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 31869136. 

Peery HE, Day GS, Doja A, Xia C, Fritzler MJ, Foster WG. Anti-NMDA receptor encephalitis in children: the disorder, its diagnosis, and treatment. Handb Clin Neurol. 2013;112:1229-33. doi: 10.1016/B978-0-444-52910-7.00045-3. PMID: 23622333.

Dalmau, Josep, and Myrna Rosenfeld. “Autoimmune (Including Paraneoplastic) Encephalitis: Clinical Features and Diagnosis.” UpToDate, June 2023, www.uptodate.com/contents/autoimmune-including-paraneoplastic-encephalitis-clinical-features-and-diagnosis?search=anti+nmda+receptor+encephalitis&source=search_result&selectedTitle=1~29&usage_type=default&display_rank=1#H2973236366. 

Wu CY, Wu JD, Chen CC. The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review. Int J Mol Sci. 2021 Oct 9;22(20):10911. doi: 10.3390/ijms222010911. PMID: 34681570; PMCID: PMC8535897.

Zhang L, Lu Y, Xu L, Liu L, Wu X, Zhang Y, Zhu G, Hong Z. Anti-N-methyl-D-aspartate receptor encephalitis with accompanying ovarian teratoma in female patients from East China: Clinical features, treatment, and prognostic outcomes. Seizure. 2020 Feb;75:55-62. doi: 10.1016/j.seizure.2019.12.016. Epub 2019 Dec 19. PMID: 31874360.

Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, Gleichman AJ, Balice-Gordon R, Rosenfeld MR, Lynch D, Graus F, Dalmau J. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014 Feb;13(2):167-77. doi: 10.1016/S1474-4422(13)70282-5. Epub 2013 Dec 18. Erratum in: Lancet Neurol. 2014 Feb;13(2):135. PMID: 24360484; PMCID: PMC4006368.