Mechanism – autoantibodies alter the NMDAR-related synaptic transmission creating complex neuropsychiatric syndrome; there is presence of CSF autoantibodies against the GluN1 subunit of NMDAR
- ?similar mechanism as hypofunction of NMDAR in schizophrenia
- ?overlap of anti-NMDAR encephalitis with demyelinating disorders
Two-stage mechanism –
First stage (3 mo or longer):
- severe psychosis symptoms, movement disorders, coma
- transient MRI abnormalities
- brain biopsy/autopsy findings are B cell, plasma cell, CD4 T cells and less frequently CD8 T cells and deposits of IgG
- of note, these findings are different from CD8 cytotoxic T cell-mediated encephalitis which has extensive neuronal loss
Second stage (duration of 6 mo or longer):
- resolution of the first stage symptoms, but still alterations in behavior, memory, cognition, and executive functions
- MRI changes c/w inflammation are minimal at this second stage
Prevalence – more prevalent in women with female/male ratio of 8:2
Triggers – teratoma (i.e. ovarian teratomas) and HSV are known triggers for NMDAR autoimmunity
Presentation – difficult to separate from a primary psychiatric disorder
Prognosis – 80% improved or recovered after immunotherapy or tumor removal
Definite diagnostic criteria –
IgG GluN1 antibodies (should attempt to get CSF in addition to serum)
Exclusion of HSV encephalitis or Japanese B encephalitis (these could have relapsing immune-mediated neuro symptoms)
*and, 1 or more of the 6 sx listed in the probably diagnostic criteria (below)
Probable diagnostic criteria –
Rapid onset (within </= 3 mo) of at least 4 or the following 6:
- abnormal psychiatric/cognitive behavior
- speech dysfunction
- seizures
- movement disorders/dyskinesias/rigidity/abnormal postures
- decreased consciousness
- autonomic dysfunction or central hypoventilation
At least 1 of the following labs:
- abnormal EEG
- CSF with pleocytosis or oligoclonal bands
Or, 3 of the above groups of symptoms and systemic teratoma
And, exclusion of HSV encephalitis or Japanese B encephalitis (these could have relapsing immune-mediated neuro symptoms)
Poor specificity of NMDAR antibodies – IgM, IgA, and less frequently IgG are present in the sera of many pts with wide ranges of disease
Seizures and risk of epilepsy with anti-NMDAR encephalitis – 70% of pts will develop seizures with variable manifestations; of note, 91% of those developing seizures survived the disease with all of them seizure-free at 31 month follow up
- more often (47% of the time), the seizure-free status was due to immunotherapy
- less often (16% of the time), the seizure-free status was due to AEDs
- for the balance of the cohort, the seizure-free status was from unclear combination of immunotherapy/AEDs/spontaneous
Challenge in ICU –
- differentiating true seizure from dyskinesias and differentiating fever from hyperthermia of primary disease or nosocomial infection
- dysautonomic cardiac arrests (7% of a cohort studied in ICU)
Transplacental transfer of NMDAR antibodies –
Potential for neurological deficits in neonates
Systematic review of 13 pregnant patients found that 9 of the mothers recovered; 1 died. 7 of the babies were healthy but 3 had neuro deficits.
Treatment –
First line
- steroids
- IVIG
- PLEX
Second line
- rituximab
- cyclophosphamide (Cytoxan)
Refractory/third line
- bortezumib (data is driven by case reports)
- tocilizumab
No study has investigated the upfront use of rituximab
References
Dalmau Lancet Neurology 2019 – An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models