What is anti-NMDA receptor encephalitis?

Anti-NMDA receptor encephalitis is a neuroimmunologic disorder mediated by intrathecal autoantibodies against the GluN1 subunit of the NMDAr. It manifests with a range of neuropsychiatric symptoms, sometimes preceded by a viral-like prodromal syndrome.1 The disorder frequently affects young adults, with a female predominance (4:1), though it has been described in patients of all ages including children and the elderly.2

How common is anti-NMDAr encephalitis?

Anti-NMDAr encephalitis is one of the most frequently identified neuronal autoantibodies in autoimmune encephalitis with an estimated annual incidence of ~1.5 cases per million persons. A contemporary study in Rochester, MN (USA) illustrated that the incidence and prevalence of autoimmune encephalitis (including cases of anti-NMDAr) are comparable to infectious encephalitis and the detection of these disorders has increased over time.3, 4

What potential triggers or risk factors are associated with anti-NMDAr encephalitis?

Two triggers for anti-NMDAr encephalitis have been identified: tumors (most commonly ovarian/extraovarian teratomas) and herpes simplex encephalitis (HSE). In female patients aged 12 to 45 years old, the most commonly identified tumor is an ovarian teratoma which is best identified with a pelvic MRI or CT, or transvaginal ultrasound.5 In patients older than 45 years, there has been evidence that carcinomas are more common.6 This requires a different workup as FDG-PET/CT may better detect carcinomas, whereas this is less sensitive to detect teratomas.7

With regards to herpes infections, a case series of patients with HSE demonstrated that 27% of patients with HSE develop autoimmune encephalitis within 2-16 weeks post-infection with 64% of those cases being anti-NMDAr encephalitis.7 Therefore, for patients with new neuropsychiatric symptoms following HSE, screening for the NMDAr autoantibody is recommended.7

How do patients with anti-NMDAr encephalitis present?

Patients with anti-NMDAr encephalitis often experience a viral-like prodromal syndrome with systemic symptoms suggestive of a viral infection (low-grade fever, malaise, anorexia, and/or headache). Patients will subsequently experience progressive behavioral and psychiatric symptoms that are later accompanied by neurological symptoms. These psychiatric and behavioral symptoms are typically what leads patients to seek medical evaluation8, 9 Psychosis and acute behavioral changes are the most frequently reported psychiatric symptoms.8 The most common psychiatric symptoms are summarized in the table below8, 10, 11

The onset of neurologic symptoms typically occurs within days to weeks following psychiatric symptoms and commonly involves hyperkinetic movement disorders, seizures, and cognitive dysfunction. Cognitive dysfunction typically occurs simultaneously with psychiatric symptoms and is the main contributor to long-term disability.12 In the days to weeks following neurologic symptoms, some patients may exhibit impaired consciousness, autonomic dysfunction, and hypoventilation requiring care in the intensive care unit.5 A detailed clinical history and comprehensive examination will usually identify concurrent neurological signs or symptoms that initially may be subtle.13

It is rare to have isolated psychiatric symptoms in anti-NMDAr encephalitis [13]. A retrospective study identified neurological symptoms in 94% of patients with anti-NMDAr encephalitis [13]. Therefore, alternative disorders should be considered in patients with isolated psychiatric symptoms.

What is the best test to detect NMDAr antibodies?

In patients with suspected anti-NMDAr encephalitis, we recommend screening serum and CSF with a comprehensive autoantibody panel as clinical syndromes associated with different autoantibodies may overlap.14 CSF testing for the NMDAr antibody is both more sensitive and specific than serum testing. It is also recommended that testing is done with a cell-based assay combined with immunohistochemistry (for both serum and CSF testing).15 We send samples to the Mayo Clinic Laboratories Encephalopathy Panels (Test IDs ENS2 and ENC2: https://www.mayocliniclabs.com/test-catalog/overview/92116 & https://www.mayocliniclabs.com/test-catalog/overview/92117).

Who should be tested for anti-NMDAr encephalitis?

Patients who present with signs and symptoms typical for anti-NMDAr encephalitis should undergo serum and CSF autoimmune antibody testing. As mentioned above, anti-NMDAr encephalitis manifests with a wide range of psychiatric and neurological symptoms, often preceded by a viral-like prodrome. It is rare to have isolated psychiatric symptoms in anti-NMDAr encephalitis13 and therefore alternative disorders should be considered in patients with psychiatric symptoms without neurological symptoms.

What other diagnostic testing can support the diagnosis of anti-NMDAr encephalitis?

Other features supportive of the diagnosis of anti-NMDAr encephalitis include the presence of a mild CSF pleocytosis (usually <50 cells/uL) and/or the presence of intrathecal antibody production detected as CSF-specific oligoclonal bands. EEG testing can be helpful and may demonstrate the following features: extreme delta brush (~30% of patients)16 focal or diffuse slow and disorganized activity, and/or epileptiform activity. MRI abnormalities occur in 40-50% of patients with anti-NMDAr encephalitis although the findings are variable and often nonspecific.3 Whole body or brain FDG-PET can be considered when there is a high suspicion for autoimmune encephalitis to assess for evidence of systemic malignancy and/or abnormal brain metabolism suggestive of autoimmune encephalitis. Retrospective studies suggest that a relative hypometabolism in the parietal-occipital lobes in conjunction with hypermetabolism in the frontal and basal ganglia can be seen in acute phase of anti-NMDAr encephalitis, although this finding is nonspecific.17, 18

What are the criteria for a diagnosis of anti-NMDAr encephalitis?

Early diagnosis and treatment is associated with a better long-term outcome in anti-NMDAr encephalitis.19 Given that serological and CSF autoantibody testing can take days to weeks to result, formal diagnostic criteria for probable anti-NMDAr encephalitis does not include autoantibody testing in order to expedite treatment.20 We recommend initiating treatment for patients with probable anti-NMDAr encephalitis while autoantibody testing is pending. A definitive diagnosis of anti-NMDAr encephalitis can then be made when autoantibody testing returns.

The diagnosis of probable anti-NMDAr encephalitis can be made when all the following three criteria have been met:

1. Rapid onset (less than 3 months) of at least four of the six following major groups of symptoms:

  • Abnormal (psychiatric behavior) or cognitive dysfunction
  • Speech dysfunction (pressured speech, verbal reduction, mutism)
  • Seizures
  • Movement disorders, dyskinesias, or rigidity/abnormal postures
  • Decreased level of consciousness
  • Autonomic dysfunction or central hypoventilation

2. At least one of the following laboratory study results:

  • Abnormal EEG (focal or diffuse slow or disorganized activity; epileptic activity, or extreme delta brush)
  • CSF with pleocytosis or oligoclonal bands

3. Reasonable exclusion of other disorders*

  • The diagnosis of probable anti-NMDAr encephalitis can also be made in the presence of three of the above group of symptoms and identification of a teratoma
  • The diagnosis of definite anti-NMDAr encephalitis can be made in the presence of three of the above group of symptoms and IgG anti-GluN1 NMDA receptor antibodies after reasonable exclusion of other disorders

From Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15: 391-404. 2016/02/26. DOI: 10.1016/S1474-4422(15)00401-9
* A full discussion of the differential diagnosis of anti-NMDAr encephalitis is beyond the scope of this document.

How is anti-NMDAr encephalitis treated?

For patients with an underlying malignancy, definitive therapy involves the prompt removal of the tumor and adjuvant systemic therapy, if necessary from an oncological perspective. Additionally, acute treatment consists of rapid initiation of immunotherapy. Consensus on the optimal immunotherapy regimen is lacking. The most commonly used acute therapies include high-dose corticosteroids, IVIG, and plasmapheresis. We typically use a combination of high dose IV methylprednisolone 1000 mg x 5 days followed by plasmapheresis (~5 sessions over 7-10 days).  IVIG and corticosteroids are reasonable alternatives.3 Acute treatment should be initiated before autoantibody testing returns when the diagnosis of probable anti-NMDAr encephalitis has been made (see above). Retrospective data suggests that early initiation of chronic therapies such as rituximab or cyclophosphamide may improve long term outcomes.21 We typically initiate chronic treatment with rituximab after treatment with high dose IV methylprednisolone and plasmapheresis as there is retrospective evidence to suggest that patients treated with rituximab are more likely to return to independent living and experience a reduced relapse rate.19, 22 There are several ongoing, international clinical trials that will help better inform this discussion over the coming years. We recommend an inpatient neuroimmunology or neurology consult for all possible anti-NMDAr encephalitis patients to assist with acute workup and management and referral to a neuroimmunologist on discharge for long-term monitoring and treatment.

How are the psychiatric symptoms associated with anti-NMDAr encephalitis treated?

Treatment of the underlying malignancy combined with immunotherapy leads to improvement in the psychiatric symptoms in anti-NMDAr encephalitis over the long term.23 However, patients often require acute symptomatic management of these symptoms. There is no broad consensus on the optimal therapeutic regimen. Highly sedating medications, such as anticholinergics, benzodiazepines and valproic acid and antipsychotics associated with higher levels of sedation, like quetiapine or chlorpromazine, have been shown to be helpful.24 Trazodone or clonidine can be useful in managing sleep symptoms. Control of psychiatric symptoms needs to be balanced against control of the neurological symptoms as high doses of antipsychotic medications can cause excessive dopaminergic blockade and exacerbate dyskinetic and dystonic movements. Patients with unstable or elevated mood symptoms have been shown to improve with mood stabilizers like valproic acid, which has the added benefit of seizure prophylaxis and an intravenous formulation.25 A trial off psychiatric medication can be performed in stable patients after definitive treatment for anti-NMDAr encephalitis has been completed and their acute symptoms have resolved.

How are seizures associated with anti-NMDAr encephalitis treated?

The most common seizure types in anti-NMDAr encephalitis are focal seizures with or without loss of awareness, epilepsia partialis continua, and generalized tonic clonic seizures. Immunosuppressive therapy is the definitive treatment for these seizures and most patients exhibit improvement in seizures following immunotherapy. However, most patients are also treated with anti-seizure medication as adjuvant therapy in addition to immunotherapy. Limited retrospective data suggests that sodium channel blocking medications may have a higher association with seizure freedom in anti-NMDAr encephalitis.25 We typically avoid the use of levetiracetam to avoid exacerbating neuropsychiatric symptoms. Cohort studies evaluating outcomes have found that the majority of properly treated patients are seizure-free 2-3 years after initial presentation.3, 26  A trial off anti-epileptic medications can be performed in seizure-free patients after this time period.

How is cognitive dysfunction managed in anti-NMDAr encephalitis?

Studies have demonstrated that all patients with anti-NMDAr encephalitis will develop some amount of cognitive dysfunction during the course of their illness that often persists for years.21 Cognitive dysfunction is the main contributor to long-term morbidity in anti-NMDAr encephalitis patients.12 Delayed treatment initiation has been associated with poorer cognitive outcomes highlighting the importance of early treatment initiation.12 Given the high prevalence and morbidity of cognitive dysfunction in anti-NMDAr encephalitis, all patients should receive dedicated neuropsychological testing after initial treatment and disease stabilization. Patients should then receive long-term cognitive rehabilitation tailored to their specific deficits. This will help reduce the long term detrimental educational and occupational effects that commonly occur in anti-NMDAr encephalitis.

Can patients with anti-NMDAr encephalitis experience a relapse?

Relapse can occur in anti-NMDAr encephalitis patients, sometimes occurring several years after their initial episode.27 Relapse may occur in the absence of a tumor or in association with an occult or recurrent malignancy. We recommend treating relapses like an initial presentation of anti-NMDAr encephalitis and re-evaluating patients for malignancy.28

What is the expected course and prognosis of anti-NMDAr encephalitis?

The onset of neuropsychiatric symptoms may occur over a period of weeks to months and prolonged deficits may persist for months to years. Five variables have been found to be independent predictors of poor functional status 1 year after symptom onset (defined as modified Rankin Scale score ≥3). Together, these variables form the anti-NMDAr encephalitis One-Year Functional Status (NEOS) score. These factors include:

  1. Admission to intensive care unit
  2. Treatment delay >4 weeks following onset of symptoms
  3. Lack of improvement within 4 weeks of treatment initiation
  4. Presence of MRI abnormality
  5. CSF pleocytosis with ≥20 white blood cells per µL

The NEOS score has been found to be more useful for predicting the rate of recovery than the ultimate extent of recovery.29

Anti-NMDAr encephalitis patients commonly experience long term complications from their illness and as mentioned above, a minority of patients experience a relapse. Patients typically improve in their cognitive functioning following immunotherapy, though the recovery process can be time dependent. Improvement is primarily seen early, after the acute phase; however, patients can continue to see improvements several years after disease onset.26 Delayed treatment initiation has been associated with poorer cognitive outcomes.12 A prospective cohort study found that moderate to severe cognitive deficits (measured by neuropsychologic testing) persisted in two thirds of patients at 4.9 years following the onset of symptoms. Additionally, 30% of patients reported ongoing psychosocial issues and were unable to return to work or school. Over the long term, a significant number of anti-NMDAr encephalitis patients experience moderate to severe anxiety and depression.30 Predictive factors associated with a poor outcome include younger age of onset and persistent neuropsychiatric symptoms following the initial treatment of the disorder.30 There is currently no standardized assessment for objective monitoring of the cognitive and psychosocial sequalae of anti-NMDAr encephalitis. To establish a baseline of cognitive abilities following disease stabilization, and to track response to treatment, formal neuropsychological testing should be performed in patients with anti-NMDAr encephalitis. We recommend longitudinal follow up in a neuroimmunology center and ongoing comprehensive care with physical therapy, occupational therapy, and psychology.31

References

  1. Dalmau J, Geis C and Graus F. Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System. Physiol Rev 2017; 97: 839-887. DOI: 10.1152/physrev.00010.2016.
  2. Guasp M and Dalmau J. Encephalitis associated with antibodies against the NMDA receptor. Med Clin (Barc) 2018; 151: 71-79. 2017/12/01. DOI: 10.1016/j.medcli.2017.10.015.
  3. Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 2019; 18: 1045-1057. 2019/07/22. DOI: 10.1016/S1474-4422(19)30244-3.
  4. Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018; 83: 166-177. 2018/01/03. DOI: 10.1002/ana.25131.
  5. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12: 157-165. 2013/01/08. DOI: 10.1016/S1474-4422(12)70310-1.
  6. Bost C, Chanson E, Picard G, et al. Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies. Journal of Neurology 2018; 265: 2190-2200.
  7. Armangue T, Leypoldt F, Malaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 2014; 75: 317-323. 20140225. DOI: 10.1002/ana.24083.
  8. Herken J and Prüss H. Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients. Frontiers in psychiatry 2017; 8: 25.
  9. Kuppuswamy PS, Takala CR and Sola CL. Management of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions. General hospital psychiatry 2014; 36: 388-391.
  10. Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Annals of neurology 2014; 75: 317-323.
  11. Barry H, Hardiman O, Healy DG, et al. Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. The British Journal of Psychiatry 2011; 199: 508-509.
  12. Finke C, Kopp UA, Prüss H, et al. Cognitive deficits following anti-NMDA receptor encephalitis. Journal of Neurology, Neurosurgery & Psychiatry 2012; 83: 195-198.
  13. Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 2013; 70: 1133-1139. DOI: 10.1001/jamaneurol.2013.3216.
  14. Kim AE, Kang P, Bucelli RC, et al. Autoimmune Encephalitis With Multiple Autoantibodies: A Diagnostic and Therapeutic Challenge. Neurologist 2018; 23: 55-59. 2018/03/02. DOI: 10.1097/NRL.0000000000000171.
  15. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13: 167-177. 2013/12/24. DOI: 10.1016/S1474-4422(13)70282-5.
  16. Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012; 79: 1094-1100.
  17. Probasco JC, Solnes L, Nalluri A, et al. Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 2017; 4: e352. 2017/06/02. DOI: 10.1212/NXI.0000000000000352.
  18. Yuan J, Guan H, Zhou X, et al. Changing Brain Metabolism Patterns in Patients With ANMDARE: Serial 18F-FDG PET/CT Findings. Clin Nucl Med 2016; 41: 366-370. 2016/02/26. DOI: 10.1097/RLU.0000000000001164.
  19. Thaler FS, Zimmermann L, Kammermeier S, et al. Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis: Real-world Evidence From the GENERATE Registry. Neurol Neuroimmunol Neuroinflamm 2021; 8 20211001. DOI: 10.1212/NXI.0000000000001088.
  20. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15: 391-404. 2016/02/26. DOI: 10.1016/S1474-4422(15)00401-9.
  21. Heine J, Kopp UA, Klag J, et al. Long‐term cognitive outcome in anti–N‐Methyl‐D‐Aspartate receptor encephalitis. Annals of neurology 2021; 90: 949-961.
  22. Nosadini M, Eyre M, Molteni E, et al. Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis. JAMA Neurol 2021; 78: 1333-1344. DOI: 10.1001/jamaneurol.2021.3188.
  23. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. The Lancet Neurology 2013; 12: 157-165.
  24. Chapman MR and Vause HE. Anti-NMDA receptor encephalitis: diagnosis, psychiatric presentation, and treatment. American Journal of Psychiatry 2011; 168: 245-251.
  25. de Bruijn MA, Van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019; 92: e2185-e2196.
  26. Feyissa AM, Lopez Chiriboga AS and Britton JW. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm 2017; 4: e353. 2017/07/07. DOI: 10.1212/NXI.0000000000000353.
  27. Gabilondo I, Saiz A, Galan L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology 2011; 77: 996-999. 20110824. DOI: 10.1212/WNL.0b013e31822cfc6b.
  28. Gabilondo I, Saiz A, Galán L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology 2011; 77: 996-999.
  29. Balu R, McCracken L, Lancaster E, et al. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology 2019; 92: e244-e252. 2018/12/24. DOI: 10.1212/WNL.0000000000006783.
  30. Annalisa Morgan YL, Nicolas R. Thompson , Alex Milinovich,, Justin R. Abbatemarco JAC, Stephen Hantus, Daniel Ontaneda, and Vineet Punia AR-G, Rachel Galioto , Amy Kunchok. Longitudinal clinical outcomes, cognitive impairment, and mood
  31. Symptoms in anti-NMDA receptor encephalitis. [IN PRESS]
  32. Blum RA, Tomlinson AR, Jette N, et al. Assessment of long-term psychosocial outcomes in anti-NMDA receptor encephalitis. Epilepsy Behav 2020; 108: 107088. 2020/05/07. DOI: 10.1016/j.yebeh.2020.107088.