Anti-NMDA Receptor Encephalitis

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:

1. abnormal psychiatric/cognitive behavior
2. speech dysfunction
3. seizures
4. movement disorders/dyskinesias/rigidity/abnormal postures
5. decreased consciousness
6. autonomic dysfunction or central hypoventilation

At least 1 of the following labs:

1. abnormal EEG
2. 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