Anti-NMDA receptor antibody encephalitis

History
In 1997, Nokura et al. reported on a case of a 19 year old woman who developed memory loss, followed by psychosis, coma, and seizures, associated with an ovarian teratoma, with significant improvement in symptoms after the teratoma was resected. Several similar cases were later published, but the ultimate etiology remained unclear until 2007 when Dalmau et al. reported on 12 patients with these symptoms in whom they found antibodies to the NMDA receptor, in most cases with intrathecal synthesis of antibody.

Epidemiology

 * Incidence
 * All-comers estimated 1.5 cases per million population per year.
 * Patients with encephalitis of unknown origin: 1-4% of cases.
 * Patients with schizophrenia: 19% of 48 patients with a diagnosis of schizophrenia had NMDAR antibodies, without signs of encephalitis . However, most other studies have found much lower rates of anti-NMDAR antibody positivity in non-encephalitic psychosis (2-3%), and most did not examine the CSF, so this association remains uncertain (details beyond the scope of this site, but reviewed by Dalmau et al. 2019)
 * Healthy controls: 3% of people in one study
 * Sex: 8:2 female:male ratio
 * Females: more commonly age 12-45 and with associated tumors
 * Age:
 * Median 21 years (range 8 months to 85 years)
 * 0-18 years: 37% of cases
 * 19-44 years: 58% of cases
 * 45+ years: 5% of cases
 * Subtypes
 * Paraneoplastic (associated tumor): 38% of cases, of whom 97% were female
 * 94%: ovarian teratoma
 * 4%: extraovarian teratoma
 * 2%: lung tumor, breast tumor, testicular tumor, ovarian carcinoma, thymic carcinoma, or pancreatic cancer
 * Autoimmune: 52% of cases

Teratoma-associated
Antibodies are produced, often in patients with an associated teratoma, to the GluN1 subunit of the NMDA receptor. In patients with teratomas, those with anti-NMDAR encephalitis are more likely to have neuroglial components as well as inflammatory infiltrates with B-cells, plsma cells, and dendritic cells. Tumor infiltrating B-cells synthesize NMDAR antibodies in vitro. Therefore it appears that the body produces antibodies in response to these glial components, that then cross-react with normal nervous system NMDA receptors.

Herpes simplex virus associated
From 2012-2017 several retrospective reports suggested that NMDAR antibodies occurred in patients with herpes simplex virus (HSV) encephalitis, especially in those who had a relapse of disease. These reports were confirmed in 2018, with the publication of a series of 51 patients with HSV encephalitis prospectively followed showed that 14 of them (27%) developed autoimmune encephalitis 2-16 weeks after the initial HSV encephalitis. None of them had neuronal antibodies initially, but all of them had neuronal antibodies after, NMDAR Ab in nine (64%), and other antibodies in the remaining five (36%). Another 11 patients developed antineuronal antibodies without developing autoimmune encephalitis, three of whom had anti-NMDAR Ab, but none of these three still had antibodies at one year.

Other viruses
There is one case report of a patient who presented with symptoms of anti-NMDAR encephalitis who had positive serum measles IgG and IgM with positive CSF IgG but negative IgM, with lower serum antibody titers over time. NMDAR antibodies were negative. A year later she developed worsened epilepsy, and NMDAR antibody was then positive in both serum and CSF. The authors hypothesize that measles virus may have triggered antu-NMDAR encephalitis in this case. Varicella zoster virus (VZV) has also been detected in the CSF of a patient with anti-NMDAR encephalitis. In 2016 authors detected evidence of a previously undescribed densovirus in CSF from a patient with anti-NMDAR encephalitis.

Other infectious agents
There is one case report of a 51 year old Chinese male who had concurrent Angiostrongylus cantonensis infection along with NMDAR antibodies in CSF and serum, but MRI appeared less consistent with NMDAR antibodies. There is a Japanese report of a patient with neurosyphilis who had concurrent NMDAR antibodies and MRI changes consistent with limbic encephalitis. There are reports of four patients with Japanese encephalitis and NMDAR antibodies in both CSF and serum. There is also one recent report of a patient with both EBV and anti-NMDAR encephalitis concurrently.

Vaccination
One case report describes a two year old girl who developed anti-NMDAR encephalitis two weeks after receiving a second dose of vaccination for Japanese encephalitis, and another describes a 15 year old with anti-NMDAR encephalitis after TdaP.

Final common pathway
Antibodies appear to alter the organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor, leading to internaliztion of the receptor.However, there may be more than one antibody type, as only antibodies obtained from patients with symptoms seemed to have these effects.

Dalmau and colleagues hypothesize that these decrease the activity of the NMDA-receptor leading to the following:
 * Effect on dopaminergic, noradrenergic, and cholinergic systems → autonomic instability
 * Inactivation of GABAergic neurons →
 * Disinhibition of excitatory pathways → psychosis, rigidity, dystonia, seizures
 * Effect on brainstem central pattern generator → movements in bulbar, limb, an dtrunk muscles
 * Effect on brainstem respiratory system (nuclei of Kölliker-Fuse) → hypoventilation

Prodrome (common): occurs in ~60-70% of patients

 * Headache, fever, nausea/vomiting, diarrhea, URI symptoms.
 * Lasts for several days to two weeks prior to psychiatric symptoms

Early phase (1-2 weeks)

 * Behavioral symptoms (hallucinations, delusions, disorganized thinking, depression, mania, catatonia, insomnia, disorganized thinking, social withdrawal): more common in adults
 * May initially lead to admission to psychiatric facility, which occurred in 41% of patients in one series. However, about half (53%) of these patients admitted to psychiatry had neurological symptoms (usually headaches, confusion, anterograde amnesia, seizures, abnormal movements, aphasia, or cognitive impairment), and most of the remainder (another 38%) developed neurological signs/symptoms within several days
 * Seizures: more common in children, occur in ~70% of patients overall.
 * Seizure types include tonic-clonic seizures (79%), focal seizures without impaired awareness (55%), focal seizures with impaired awareness (42%)
 * Status epilepticus occurs in 25-35% of patients and refractory status epilepticus in 15-21% of patients
 * Aphasia: more common in children
 * Memory deficits: more common in adults
 * Abnormal movements: often presenting symptom in children, occur in ~75% of adults and ~95% of children
 * Oro-lingual-facial dyskinesias: most common
 * Other movements: choreoathetosis, oculogyric crisis, dystonia, rigidity, opisthotonic posturing
 * Antipsychotic intolerance: in one series, 47% of patients were transferred to a medical unit for hyperthermia, muscle rigidity, mental status changes, or rhabdomyolysis that suggested neuroleptic malignant syndrome, although similar symptoms can occur in patients even without neuroleptics.

Later phase (weeks to months)

 * Decreased level of consciousness
 * Abnormal movements (as above)
 * Dysautonomia: hyperthermia, tachycardia or bradycardia, hypertension or hypotension, urinary incontinence, erectile dysfunction
 * Seizures
 * Central hypoventilation
 * Focal deficits: rare, more common in children

Clues to diagnosing anti-NMDAR encephalitis in patients with new-onset psychiatric symptoms.
Can use the SEARCH For NMDAR-A mnemonic.
 * Sleep dysfunction: usually insomnia
 * Excitement, disinhibition, or manic behavior alternating with depressive behavior
 * Agitation/aggression
 * Rapid onset: symptoms usually develop within days of weeks
 * Children and young adult prominence
 * History of psychiatric disease is absent
 * Fluctuating catatonia
 * Negative and positive symptoms at presentation. In schizophrenia, positive symptoms are usually more frequent than negative symptoms at disease onset.
 * Memory deficit
 * Decrease of verbal output or mutism
 * Antipsychotic intolerance
 * Rule out neuroleptic malignant syndrome
 * Antibodies and additional paraclinical tests (EEG, MRI, or CSF)

Antibody testing

 * Testing in the CSF may be 100% sensitive, but serum testing is only 85-90% sensitive

Blood biomarkers

 * Neurofilament light chains are elevated in 8% of patients with NMDA receptor antibody encephalitis with psychosis, and only in 4% of patients with primary psychiatric psychosis. As such, these may be useful for differentiating these two disorders.  A cutoff sNfL of ≥15 pg/mL was 85% sensitive and 96% speciic for anti-NMDAR encephalitis.

MRI

 * 50-66% of cases are normal
 * 33-50% of cases have abnormalities
 * T2/FLAIR hyperintensity: medial temporal lobes most commonly (22%), cerebral cortex (17%), cerebellar cortex (6%), brainstem (6%), basal ganglia 5%, and other places(corpus callosum, periventricular white matter, hypothalamus) more rarely
 * Can have contrast enhancement in the affected areas or meninges in 14% of cases
 * Can have cerebral or cerebellar atrophy that is possibly reversible. In one small series (n = 15), cerebral atrophy occurred in 5 patients (33%), and cerebellar atrophy in 2 patients.  Cerebellar atrophy was associated with worsened outcome, but most atrophy was at least partially reversible, showing improvement or resolution on follow-up imaging several years later.

CSF (general)

 * 20% of cases are initially normal
 * 80% abnormal
 * Moderate lymphocytic pleocytosis
 * Normal or mildly elevated protein
 * Oligoclonal bands in 60%

EEG

 * Nonspecific, slow, disorganized activity
 * Electrographic seizures and status epilepticus
 * Delta-theta rhythmic activity

Brain biopsy

 * Nonspecific, with perivascular B-cell lymphocytic cuffing, sparse parenchymal t-cell infiltrates, or microglial activation

For ovarian teratoma

 * Studies to evaluate for ovarian teratoma: MRI, CT scan, or pelvic/transvaginal ultrasound

Diagnostic criteria
Graus et al. proposed criteria for the diagnosis of anti-NMDAR encephalitis in 2016, and they have been validated. The criteria are as follows:

Probable anti-NMDA receptor encephalitis
Must meet all three of the following criteria:
 * 1) Onset in less than three months of at least four of the following major groups of symptoms
 * 2) * Abnormal behavior or cognitive dysfunction
 * 3) * Speech dysfunction (pressured speech, verbal reduction, or mutism)
 * 4) * Seizures
 * 5) * Movement disorder, dyskinesia, rigidity, or abnormal postures
 * 6) * Decreased level of consciousness
 * 7) * Autonomic dysfunction or central hypoventilation
 * 8) At least one of the following test results
 * 9) Abnormal EEG (focal or diffuse slowing, disorganization, epileptic activity, or extreme delta brush)
 * 10) CSF with pleocytosis or oligoclonal bands
 * 11) Reasonable exclusion of other disorders



Definite anti-NMDA receptor encephalitis
Must have at least one of the major groups of symptoms listed above and anti-GluN1 IgG antibodies.

Disease-modifying treatment
Look for any tumors (especially ovarian teratoma), take them out if they are found, and treat early with immunotherapy.
 * Removal of teratoma (if present)
 * First-line immunotherapy
 * Steroids (Methylprednisolone 1g IV daily x5 days, PLUS EITHER IVIG (0.4 g/kg/day x5 days) OR plasmapheresis
 * Second-line immunotherapy (initiate if no response to first-line therapy after 10 days). This was required in nearly 50% of patients who did not improve after first-line therapy in a large series.
 * Rituximab (375 mg/m2 every week for 4 weeks) AND/OR cyclophosphamide (750 mg/m2 given with the first dose of rituximab, followed by monthly cycles)
 * Continue second-line immunotherapy until patients have substantial clinical recovery, usually with a decrease in CSF and serum antibody concentrations. Because relapses are common, consider mycophenolate mofetil or azathioprine for at least one year after initial immunotherapies are discontinued.
 * Third-line immunotherapy. This was required in ~10% of patients who did not improve after first and second-line therapies. Can consider the following:
 * Tocilizumab (an IL-6 receptor antagonist): 8 mg/kg administer for ≥2 cycles in regular 1-month intervals (standard regimen for rheumatoid arthritis or neuromyelitis optica). In one retrospective study, patients with autoimmune encephalitis (multiple types) who had shown no improvement 4 weeks after rituximab, those given tocilizumab had better outcomes at 24 months than those given additional rituximab or those only observed.  Approximately 29% of patients in this study had anti-NMDAR antibodies (n = 26). A small series (n = 3) of pediatric patients showed improvement with tocilizumab as well.  This medication has been used in conjunction with bortezomib in one case.
 * Bortezomib (a proteosome inhibitor): 4-5 cycles of 1.3 mg/m2 subcutaneous. This medication has been reported to be effective to varying degrees in several case reports and small series. However the total published experience here includes only 16 patients as of  November 2019, so experience is very limited and the risk for publication bias is very high.    Importantly, in one of the two largest series (n = 5), patients showed some improvement but not compared with historical controls, and all remained severely disabled (mRS 5) despite treatment. These patients had been given tocilizumab as well.
 * Methotrexate
 * Intrathecal: Oldest patient reported who received this is 23 years old. In one case series (n = 4) of patients aged 16-23 who did not response to first-line therapies, three had improvement in titers and exam.  In another series (n = 3) of three pediatric patients who did not respond to first-line therapies or rituximab, all had improvements in titers but only two had clinical improvement.
 * Oral: One series (article in Spanish) of five pediatric patients, all of whom improved.
 * Immunoadsorption: In one series, 7 patients with NMDA-R Ab showed improvement after immunoadsorption. However, in one series of autoimmune encephalitis (n = 21, 5/21 with NMDAR-Ab) given either plasmapheresis or immunoadsorption, there was no notable difference between those given plasmapheresis or immunoadsorption.
 * Annual tumor surveillance, especially in women age 12 years and older

Early treatment is associated with improved outcomes.

If a tumor was present, 80% of patients who had the tumor removed and underwent first-line immunotherapy showed substantial improvement. However, only 48% of those without an associated tumor had a similar degree of improvement after first-line immunotherapy. In the patients who did not improve after first-line immunotherapy, most (13/16 in one series) showed substantial improvement after second-line immunotherapy. If they did not respond to first-line immunotherapy and were not administered second-line immunotherapy, nobody showed substantial improvement.

Symptomatic treatment

 * Abnormal movements: can use tetrabenazine or botulinum toxin
 * Seizures: can use any AEDs

Demyelinating disorders
Anti-NMDAR encephalitis can be associated with demyelination in up to 3% of cases, with the greatest overlap being in anti-aquaporin-4 and anti-myelin oligodendrocye glycoprotein disease (neuromyelitis optic and related syndromes). In 2010, Kruer et al. reported a case of a 15 year old female who had longitudinally extensive transverse myelitis, optic neuritis, multifocal lesions, along with anti-NMDAR antibodies and a syndrome consistent with anti-NMDAR encephalitis. Aquaporin-4 antibodies were negative, but biopsy was consisitent with possible seronegative neuromyelitis optic (NMO). Subsequently, additional cases were described of patients with transverse myelitis and optic neuritis in the absence of anti-AQP4 antibodies who had clinical syndromes and antibodies of anti-NMDAR encephalitis. Others published cases of anti-NMDAR encephalitis who developed NMO associated with aquaporin-4 antibodies. Then in 2014, Cobo-Calvo et al. described a patient with anti-NMDAR encephalitis who developed optic neuritis and tested positive for antibodies to myelin oligodendrocye glycoprotein (MOG), and this was followed by several other case reports of this overlap syndrome. Overlap with MOG-antibody disease may be more common than overlap with aquaporin-4 positive NMO. These anti-AQP4 and anti-MOG-associated disorders (along with a few antibody-negative cases of demyelination) were described in 3.3% of patients with anti-NMDAR encephalitis in one large series of 691 patients. White matter involvement may be more common in pediatric patients. Case reports also exist of relapsing-remitting multiple-sclerosis like disorders concurrent with or following anti-NMDAR encephalitis  but NMDAR antibodies are rare in patients with demyelinating disorders who do not have symptoms of anti-NMDAR encephalitis.

Cardiac
Patients can have tachycardia or bradycardia, and can have dysautonomic cardiac arrest (7% in one series). Vasopressors were required in 33% of cases.

Pulmonary
78% of patients in one series required mechanical ventilation, and for an average of 47 days. 51% of all patients required a tracheostomy.

Infectious
Fever is very common, and difficult to differentiate from nosocomial infection vs due to the primary disease. Nosocomial infections occurred in 71% of cases in one series, including ventilator-assocaited pneumonia in 54%, urinary tract infection in 30%, and central line associated infection in 16% of patients.

Renal
In one series, 8% of patients required renal replacement therapy.

Functional outcome and mortality
Most patients do well overall, but mortality is ~4-10%. In a large series, at 24 months approximately 80% of patients were independent (half of these back to normal), while 10% died.

Many patients require hospitalization for 3-4 months in the acute phase of the disease.

Estimated mortality is 4%, with median time from disease onset to death being 3.5 months (range 1-8 months). Causes of death include sepsis, sudden cardiac arrest, acute respiratory failure, refractory status epilepticus, and tumor progression.

Neuropsychological outcomes are variable. In a systematic review of 10 studies looking at cognitive function, most reported that after 12 months there were frequently disturbances in memory, executive function, attention and processing speed. There were no longstanding deficits in language or visuospatial abilities. For pediatric patients, one study showed that 64% returned to their previous school level. At 1-3 years after onset, many had persistent problems in sustained attention and fatigue, including word-finding difficulty in 24%, attention deficits in 18%, impulsiveness in 18%, anxiety in 18%, indecisiveness in 12%, and dyslexia in 12%.

Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) Score
This score was developed in 2019 and is not yet validated in a separate cohort. Importantly, of those with poor functional status (mRS 3-5) at 1 year, 35% of them regained independence at 2 years.

Biomarkers

 * CSF CXCL13: a retrospective study suggested that higher CSF levels of CXCL13 (a B-cell chemoattractant) correlated with poor response to treatment. Clinical utility is not yet known.
 * CSF YKL-40: Changes in CSF levels of this protein (that is expressed by microglia during inflammation) were shown to correlate with changed in mRS. This has not yet been validated and clinical utility is not yet known.
 * CSF Fas/FasL: Higher concentrations at onset correlated with worsened functional outcomes at 6 months as measured by mRS. This has not yet been validated and clinical utility is not yet known.

Relapses
Relapses of disease occur in 12-25% of patients.

Seizures and epilepsy
Long-term, seizures usually go away when the disease is appropriately treated. In one series of 39 patients who survived the disease, all were seizure free after a median follow-up time of 31 months, with only three patients (8%) continuing to be on AEDs. In another series, 80% of patients had no further seizures within 6 months of onset, and all were seizure free within 2 years of disease onset. Duration of AED therapy had no impact on seizure freedom.

Risks in pregnancy
An animal study suggested that these antibodies may possibly transfer to the fetus and can lead to perinatal mortality and neurodevelopmental problems. Indeed, there are reports of transient anti-NMDAR encephalitis in neonates born to women with the disorder, some of whom developed normally while others had developmental delay and abnormalities such as cortical dysplasias. In a review of 13 cases of pregnant patients with anti-NMDAR encephalitis, most patients recovered quite well (11 of 13), while one continued to have dystonia and hand spasticity, and one died. Of the babies, 8 of 13 were normal, but two were miscarried, one was aborted, and two had neurological problems (developmental delay and seizures in one, torticollis and strabismus in the other).