ANTI-N-METHYL-D-ASPARTATE RECEPTOR PHASES OF THE ILLNESS

 PRODROMAL PHASE – fever, headache, nausea, vomiting and

ENCEPHALITIS URTI-like symptoms
 PSYCHOTIC PHASE – 2 weeks after the initial phase, psychiatric
 Caused by immunoreactivity against NMDA receptor (NR1) subunit of the
symptoms occur, which are highly variable
NMDA receptor
 UNRESPONSIVE PHASE – mutism and akinesia
 Once of the most common autoimmune encephalitides
 HYPERKINETIC PHASE – autonomic instability, hypo or
hypertension, hypo or hyperthermia, cardiac arrythmia,
hypoventilation
 GRADUAL RECOVERY PHASE

PATHOGENESIS
 IgG antibodies against glutamate N1 subunit of the NMDA receptor
 NMDAR is an excitatory glutamate receptor when activation allows
influx of Na and Ca ions through the channel
o Foung in the forebrain, hippocampus, limbic system
 Activation removes the magnesium plug leading to glutamate and
glycine binding to their respective sites
 Misregulation of these receptors by glutamate, leads to apoptotic
signaling
 Excitotoxic damage by glutamate at the NMDAR is implicated in
neurodegenerative disorders (Parkinson’s, Huntington, epilepsy and
dementia

EPIDEMIOLOGY
 Predominantly affect young individuals younger than 45 years old
 Female predominance (less evident in children younger than 122
years and adults over 45 years)
DIAGNOSIS
 Confirmation requires positive serum or CSF sample screening
for antibodies for antibodies for NMDA receptor subunit
(Recommendation by Dalmau: test of both serum and CSF)
 Clinical symptoms of this disorders correlate well with antibody
titers
 CSF abnormalities:
o Mild lymphocytic pleocytosis
o Normally or mildly increased protein concentration
o CSF specific oligoclonal bands
 MRI: hyperintensities in a variety of regions (hippocampi,
cerebellar and cerebral cortex, basal ganglia, frontobasal and
insular regions)
 EEGs: nonspecific slowing or slow continuous rhythmic activity
during the catatonic phase of illness
o Very helpful in distinguishing between encephalitis and
primary psychiatric disorder (90% of patients with this
illness have evidence of non-specific slowing at some
stage of this illness)
 PET: not at present likely to support clinical practice but shows
variable findings with evidence of cortical hypometabolism

CLINICAL PRESENTATION DIAGNOSTIC CRITERIA FOR ANTI-NMDA RECEPTOR ENCEPHALITIS

 Non-specific prodrome: headache, low grade fever or viral like
illness (headache, respiratory or GI symptoms) – weeks prior to
acute presentation
 Psychiatric symptoms: agitation, bizarre, disinhibited behavior,
delusions auditory and visual hallucinations
 Cognitive dysfunction: short-term memory, concentration
difficulties
 Motor dysfunction: epileptic seizures, dyskinetic movements,
orofacial dyskinesias (grimacing/lip smacking)
 Autonomic instability: autonomic instability and hypoventilation,
cardiac dysrhythmias
 Association with known pathology: ovarian teratomas
 DIFFERENTIAL DIAGNOSIS
1. Neurological – viral encephalitis (CMV, EBV, HSV, VZV, HIV, HHV6,
HHV7M, arbovirus, rabies virus), cerebral vasculitis, other forms of
autoimmune encephalitis and encephalitis lethargica
2. Psychiatric – primary initial differential in the initial phase of the
illness
3. Other autoimmune causes – limbic encephalitis, antiphospholipid
syndromes, SLE, Sjogren’s syndrome, Grave’s, Hashimoto’s)
4. Toxic/Metabolic disorders – drug ingestion, porphyria,
mitochondrial disorders
TREATMENT OPTIONS
 First line of treatment: immunotherapy, IVIg, plasma exchange
 Second line treatment: rituximab or cyclophosphamide
 Treatment thought to be more effective for those who have an
underlying tumour removed
Sources:
 Ford, B., McDonald, A., & Srinivasan, S. (2019). Anti-NMDA receptor encephalitis: A
case study and Illness Overview. Drugs in Context, 8, 1–8.
https://doi.org/10.7573/dic.212589
 Nosadini, M., Thomas, T., Eyre, M., Anlar, B., Armangue, T., Benseler, S. M.,
Cellucci, T., Deiva, K., Gallentine, W., Gombolay, G., Gorman, M. P., Hacohen, Y.,
Jiang, Y., Lim, B. C., Muscal, E., Ndondo, A., Neuteboom, R., Rostásy, K., Sakuma, H.,
… Dale, R. C. (2021). International consensus recommendations for the treatment
of pediatric NMDAR antibody encephalitis. Neurology - Neuroimmunology
Neuroinflammation, 8(5). https://doi.org/10.1212/nxi.0000000000001052
 Barry, H., Byrne, S., Barrett, E., Murphy, K. C., & Cotter, D. R. (2015). Anti-N-methyl-
d-aspartate receptor encephalitis: Review of clinical presentation, diagnosis and
treatment. BJPsych Bulletin, 39(1), 19–23.
https://doi.org/10.1192/pb.bp.113.045518
 Agarwal R, Gupta V. Anti-NMDA Receptor Encephalitis In Children. [Updated 2021
Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022
Jan-.

PROGNOSIS
 75% of patients with NMDA receptor antibodies recover or have
mild sequelae
 25% have severe deficits or die
 12-24% risk of relapse
 The NEOS (anti-NMDAR Encephalitis One-Year Functional Status)
score includes 5 independent risk factors for poor prognosis
o need for ICU admission,
o no treatment within 4 weeks of symptom onset
o lack of clinical improvement in 4 weeks after starting
therapy
o abnormal brain MRI
o CSF white blood cell (WBC) count higher than 20 cells/L
The score ranges from 0 to 5, with 1 point assigned to each of
these factors
A higher score is associated with higher modified Rankin scale
score at 1 year.