Anti-NMDAR Encephalitis

Etiology

Anti-NMDA receptor encephalitis develops through the formation of IgG antibodies, particularly IgG1 and IgG3 subclasses, that bind to the NR1 subunit. This antibody interaction causes internalization of NMDA (glutamate) receptors, resulting in reduced neuronal Ca2+ influx and decreased receptor-dependent synaptic currents.[4] These pathogenic antibody-mediated effects contribute to the neurological dysfunction characteristic of this autoimmune encephalitis.

In some patients, antibody production occurs in association with an underlying ovarian teratoma and, less commonly, other tumors. Viral encephalitis, particularly herpes simplex virus (HSV) encephalitis, may also contribute to NMDAR antibody development, with antibody production occurring over the subsequent 3 weeks and followed by the emergence of autoimmune encephalitis.[5] In most cases, the specific trigger responsible for antibody formation remains unknown. Regardless of the initiating factor, the disease process ultimately involves excessive production of autoantibodies by intrathecal plasma cells, contributing to ongoing immune-mediated neuronal dysfunction.

Epidemiology

Although anti-NMDAR encephalitis remains a rare disorder, the estimated incidence reaches approximately 1.5 cases per million population.[6] Anti-NMDAR encephalitis represents the best-known and likely the most common form of autoimmune encephalitis.[7] Data from the California Encephalitis Project demonstrated that the incidence of anti-NMDAR encephalitis exceeded the incidence of any individual viral encephalitis.[8]

Reported cases have occurred across a broad age range, including infants as young as 2 months and adults up to 85 years of age. Females develop anti-NMDAR encephalitis approximately 4 times more frequently than males. Young adult females between 25 and 35 years of age represent the population most commonly affected.

Pathophysiology

Autoimmune encephalitis was previously classified as paraneoplastic or nonparaneoplastic, depending on whether tumor-associated antibodies were present. These paraneoplastic antibodies include anti-neuronal nuclear antibody type 1 (anti-Hu), anti-Ri, or anti-Yo. With a better understanding of the pathophysiology of different autoimmune encephalitis, a more nuanced, pathophysiologically based classification is used.

The modern-day classification of immune encephalitis is based on the targets of the antibodies. The classical paraneoplastic encephalitis, as noted above, is mediated predominantly by T cells, with cytotoxic T cells demonstrated in pathological specimens. These immune responses result from molecular mimicry between neuronal tissue antigens and tumor antigens. The antibodies themselves are not pathogenic. These antibodies direct their activity towards intracellular constituents.

The other class of autoimmune encephalitis consists of antibodies directed against synaptic or cell-surface antigens, eg, anti-NMDAR, anti-GAD, and anti-VGKC antibody-mediated encephalitides. These are real antibody- or B-cell-mediated autoimmune encephalitis with real pathogenic antibodies.[9] Anti-NMDAR antibody-mediated encephalitis is a B-cell-mediated autoimmune encephalitis with an actual pathogenic antibody that can be removed by plasma exchange, resulting in improvement of the underlying pathology. The anti-NMDR antibody binds to the NR1 subunit, leading to internalization of NMDA (glutamate) receptors, reduced neuronal Ca2+ influx, and decreased receptor-dependent synaptic currents.[4] 

History and Physical

The clinical presentation of anti-NMDAR encephalitis has been categorized into 5 distinct phases: the prodromal phase, psychotic phase, unresponsive phase, hyperkinetic phase, and recovery phase.[10]

Prodromal  and Psychotic Phases

The disease typically begins with a prodromal phase resembling a common viral infection. Within weeks to a few months, usually less than 3 months, patients rapidly develop complex neuropsychiatric manifestations during the psychotic phase. Clinical presentations vary between children and adults. Adults more commonly present with psychiatric symptoms, whereas children frequently exhibit movement disorders or seizures as initial manifestations. Acute or subacute behavioral changes represent the most common presenting features among adult patients. No specific psychiatric phenotype defines anti-NMDAR encephalitis; however, patients without a prior psychiatric diagnosis may rapidly develop a range of positive and negative psychiatric symptoms, including visual or auditory hallucinations, acute schizoaffective episodes, depression, mania, addictive behaviors, and eating disorders (see Image. Clinical Features of Psychotic Phase Anti-NMDAR Encephalitis).

The rapid onset of symptoms contrasts with the slower progression typically observed in primary psychiatric disorders. Anti-NMDAR antibodies have been identified in 3% to 4% of patients initially diagnosed with schizophrenia.[11] Many patients require psychiatric inpatient admission because of severe behavioral symptoms and may receive symptomatic treatment for weeks before the diagnosis is recognized. Although some patients demonstrate neurological features at initial presentation, others develop these manifestations within several weeks. Importantly, some individuals exhibit intolerance to neuroleptic medications and may develop hyperthermia, muscle rigidity, rhabdomyolysis, or coma following neuroleptic exposure.

Unlike schizophrenia, which more commonly presents with predominant positive symptoms, patients with anti-NMDAR encephalitis frequently exhibit both positive and negative symptoms. The neuropsychiatric spectrum includes apathy, anxiety, fluctuating sensorium, bizarre behaviors, hypersexuality, wandering, aphasia, amnesia, apraxia, sleep-wake cycle disruption with severe insomnia, and delusions. Many patients, particularly children and adult men, also experience seizures, which may present as focal or generalized events. Seizures can become resistant to antiepileptic drugs (AEDs) and may progress to status epilepticus or refractory status epilepticus.

Unresponsive Phase

The psychotic phase may progress to the unresponsive phase, characterized by mutism, reduced motor activity, and catatonia. The subsequent hyperkinetic phase features autonomic instability and prominent movement disorders. Significant autonomic dysfunction, including labile blood pressure and heart rate, cardiac arrhythmias, temperature instability, and central hypoventilation, may require intensive care unit (ICU) admission, mechanical ventilation, and, in some cases, cardiac pacemaker placement.[12]

Hyperkinetic and Recovery Phases

The characteristic movement disorder during the hyperkinetic phase includes oro-lingual dyskinesias with lip-smacking, tongue protrusion, and jaw movements. However, patients may develop a broad range of abnormal movements, including automatisms, dyskinesia, dystonia, choreoathetosis, myorhythmia, blepharospasm, oculogyric crisis, and hemiballismus. Following appropriate immunotherapy and supportive care, patients may progress into the recovery phase after months of treatment. Recovery of language abilities and behavioral symptoms generally occurs later in the recovery process.

Rarely, patients with anti-NMDAR encephalitis develop demyelinating disorders, including neuromyelitis optica spectrum disorder, concurrently with, before, or after the onset of encephalitis. These cases may involve disease-specific antibody production, including aquaporin-4 or myelin oligodendrocyte glycoprotein antibodies.[13][14]

Clinical Feature Distinctions in Pediatric and Adult Populations

Clinical manifestations also differ between pediatric and adult populations. Compared with adults, children with anti-NMDAR encephalitis more frequently present with seizures, movement disorders, irritability, speech dysfunction, and sleep disturbances. Adults, particularly young women, more commonly demonstrate prominent psychiatric symptoms and have a stronger association with ovarian teratoma. Autonomic instability and central hypoventilation generally occur more frequently or with greater severity in adults, whereas pediatric cases demonstrate a lower association with paraneoplastic disease and may occur following herpes simplex virus encephalitis.[15]

Evaluation

Routine laboratory studies in patients with anti-NMDAR encephalitis typically produce nonspecific findings, making a high index of clinical suspicion essential for timely diagnosis. Detection of anti-NMDAR IgG antibodies in the CSF through indirect immunofluorescence assay is the gold-standard diagnostic evaluation for this disorder. Although anti-NMDAR antibodies may also be detected in serum, the clinical significance of isolated serum positivity remains uncertain unless accompanied by supportive electroencephalography (EEG) or magnetic resonance imaging (MRI) abnormalities.[16] Antibody titers generally demonstrate higher concentrations in the CSF, and some patients receive a diagnosis based on positive CSF testing despite concurrent negative serum results. CSF analysis may also reveal inflammatory changes, including lymphocytic pleocytosis, elevated protein levels, and oligoclonal bands.[1] Antibody titers correlate with disease severity and clinical manifestations, providing additional information regarding disease activity.

Brain MRI findings may appear normal, particularly during the early stages of anti-NMDAR encephalitis. When abnormalities occur, MRI commonly demonstrates T2-weighted and fluid-attenuated inversion recovery (FLAIR) signal hyperintensities, most frequently involving the medial temporal lobes, especially the hippocampus. Diffusion restriction may also occur. Cerebellar atrophy has been reported as a rare imaging finding and represents the only recognized irreversible radiologic abnormality associated with this encephalitis.[17]

EEG findings may provide additional supportive information, although most abnormalities remain nonspecific. A characteristic interictal EEG pattern known as extreme delta brushes, consisting of bursts of beta activity superimposed on diffuse delta activity, has been described in anti-NMDAR encephalitis and resembles a pattern commonly observed in healthy premature neonates. Other EEG abnormalities, including generalized theta and delta slowing, subclinical seizures, and nonconvulsive status epilepticus, frequently occur but generally reflect nonspecific features of encephalopathy or encephalitis.

Following confirmation of anti-NMDAR encephalitis, clinicians should perform a comprehensive evaluation for an underlying malignancy. Diagnostic approaches commonly include whole-body computed tomography (CT), abdominal MRI, and transvaginal ultrasonography to identify associated tumors. Transvaginal ultrasonography represents the most important screening test for young women with anti-NMDAR encephalitis because of the strong association with ovarian teratomas. When initial imaging studies fail to identify an underlying tumor, additional evaluation with positron emission tomography (PET) scans and exploratory laparotomy may be considered. [18] Patients with negative initial malignancy screening require continued surveillance, with repeat abdominal and pelvic MRI performed every 6 months for at least 4 years to monitor for delayed tumor detection.[19]

Treatment / Management

Early recognition and prompt treatment significantly improve clinical outcomes in patients with anti-NMDAR encephalitis.[1] Patients who undergo surgical resection of an associated ovarian teratoma experience lower relapse rates than those who do not receive tumor removal.[20] Treatment should begin as soon as clinical suspicion reaches a reasonable threshold after collection of serum and CSF samples for confirmatory autoimmune encephalitis testing, rather than waiting for definitive antibody results.[21](A1)

Immunotherapies

First-line therapy

First-line therapy includes rapid initiation of immunomodulatory and immunosuppressive treatment with corticosteroids, intravenous immunoglobulin (IVIG), and plasmapheresis (PLEX), combined with tumor resection when an underlying neoplasm has been identified and comprehensive supportive care.[22][23] A prospective cohort study demonstrated that prednisone tapering beyond 6 months failed to improve modified Rankin Scale (mRS) scores, Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores, relapse risk, or seizure freedom compared with shorter tapering regimens and produced a higher incidence of adverse events, particularly weight gain. [24](B2)

Controlled studies have not established the optimal sequence for initiating first-line immunotherapies or determined whether combination therapy should routinely begin at treatment onset. Similarly, standardized recommendations regarding the ideal sequence of sequential immunotherapies remain unavailable. PLEX frequently serves as an early therapeutic intervention because of its ability to rapidly remove pathogenic autoantibodies, and recent retrospective studies have suggested that administering PLEX before IVIG may improve clinical outcomes. Approximately 50% of patients respond to first-line therapy alone.

Second-line therapies

Patients who fail to demonstrate meaningful clinical improvement after 4 weeks of first-line treatment commonly receive second-line therapies, including rituximab, cyclophosphamide, azathioprine, or mycophenolate mofetil (see Table 1). Some experts advocate early rituximab administration as part of first-line treatment. A multicenter cohort study found that a single course of rituximab prolonged the time to first relapse. Among patients receiving repeat dosing, the greatest benefit appeared around 6 months, without clear evidence of sustained benefit through 12 months.[25] Another study reported that rituximab initiation within less than 60 days of disease onset reduced relapse risk.[26]

Table 1. Therapy for Anti-NMDAR Encephalitis

Management of Refractory Disease

Patients with refractory disease may benefit from additional therapies, including bortezomib (a proteasome inhibitor), alemtuzumab (a humanized monoclonal antibody targeting CD52), intrathecal methotrexate, or tocilizumab (a monoclonal antibody directed against the interleukin-6 receptor). A prospective multicenter cohort also demonstrated faster clinical improvement and more favorable outcomes among patients with first-line refractory anti-NMDAR encephalitis treated with ofatumumab, without reports of serious treatment-associated adverse events.[27](B2)

Seizure Management

Acute seizure management often presents significant challenges and generally requires AEDs in combination with immunotherapy. Seizures usually resolve as encephalitis improves, and most patients do not develop chronic epilepsy. A retrospective series found similar effectiveness among valproate, levetiracetam, and carbamazepine, although carbamazepine produced fewer adverse effects.[28] Gradual reduction of AED therapy during follow-up remains appropriate, and most patients discontinue antiepileptic medications within 2 years without seizure recurrence.

Management of Behavioral and Movement Disorders 

Antipsychotic medications frequently address severe behavioral manifestations; however, clinicians should remain vigilant for neuroleptic malignant syndrome, which may complicate treatment (see Table 2).[29] Benzodiazepines and electroconvulsive therapy have demonstrated utility in managing catatonia. Movement disorders associated with anti-NMDAR encephalitis often prove difficult to control and may require high-dose sedative medications, botulinum toxin, or tetrabenazine. Severe disease frequently necessitates intensive care unit (ICU) management to provide airway protection, monitor altered cognition, control dyskinesias and seizures, manage abnormal behavior, and treat temperature instability, heart rate variability, and cardiac arrhythmias.[30](B3)

Table 2. Symptomatic Management of Anti-NMDAR Encephalitis

HSV Encephalitis Treatment

HSV encephalitis remains the most common sporadic form of encephalitis. Patients presenting with clinical features consistent with acute encephalitis should receive empiric intravenous acyclovir while awaiting HSV polymerase chain reaction (PCR) results. Continuation or discontinuation of acyclovir depends on PCR findings. Clinicians should also recognize that early recurrence of encephalitic symptoms within 2 to 3 weeks following HSV encephalitis frequently reflects secondary anti-NMDAR encephalitis rather than recurrent viral infection.

HSV demonstrates a strong affinity for limbic gray matter, which contains a high density of NMDA receptors. Viral injury may promote release of NMDA receptor antigens, triggering autoantibody formation and the subsequent development of secondary autoimmune encephalitis. Early recognition of this postinfectious complication supports timely immunotherapy and improves the likelihood of favorable neurological recovery.

Differential Diagnosis

Differential diagnoses that share clinical features with anti-NMDAR encephalitis include:

• Another autoimmune encephalitis
• Primary psychiatric disorder
• Viral encephalitis
• Neuroleptic malignant syndrome
• Catatonia
• Acute disseminated encephalomyelitis
• Mitochondrial encephalitis
• Cerebral space-occupying lesions
• Exposure to drugs, toxins, or withdrawal symptoms

Prognosis

Several independent factors predict worse clinical outcomes in patients with anti-NMDAR encephalitis. These predictors include admission to the ICU, treatment delays exceeding 4 weeks, lack of clinical improvement after 4 weeks of therapy, abnormal brain MRI findings, and a cerebrospinal fluid white blood cell count greater than 20 cells/µL. Each variable contributes 1 point to a validated functional scoring system designed to estimate long-term neurological recovery.

Higher cumulative scores correlate with poorer functional status at 1 year after disease onset. However, clinicians should avoid using this scoring system to direct treatment decisions or establish a definitive prognosis. A substantial proportion of patients continue to recover beyond the first year, with approximately 1-third of those demonstrating poor functional status at 1 year achieving meaningful improvement by 2 years.[31][3] These findings emphasize the importance of continued treatment, comprehensive rehabilitation, and long-term follow-up despite early indicators of severe disease.

Complications

Overall, 20% of patients develop focal deficits or die from anti-NMDAR encephalitis. Approximately 10% of patients may relapse within 2 years of initial presentation but usually with a less severe presentation.[22] More commonly reported long-term deficits involve attention, memory, and executive functions.