Antibody Mediated Autoimmune Encephalitis

Antibody-mediated autoimmune encephalitis is a category of encephalitides characterized by the subacute onset of CNS inflammation.

Each of these neurologic diseases can cause a spectrum of symptoms, including subacute memory loss, changes in cognition, psychosis, seizures, abnormal movements, and depressed level of consciousness, all typically developing within 3 mo.

Antibodies directed against membrane receptors and ion channel-associated proteins expressed on the surface of neurons in the central nervous system are responsible for these clinical manifestations.

Synonyms

Antibody-mediated encephalitis
Autoimmune encephalitis
Autoimmune encephalopathy
Anti-NMDAR encephalitis
Voltage-gated potassium channel antibody syndromes

Epidemiology & Demographics

Incidence

It has been difficult to estimate incidence, as testing for encephalitis is relatively new, but the ability to detect autoimmune encephalitis is rapidly increasing. A recent study showed an incidence of 0.8/100,000.

Prevalence

Prevalence is estimated to be 13.7/100,000.

Predominant Sex and Age

75% of those affected by autoimmune encephalitis are female. Anti-NMDAR, the most common, predominantly affects women with a median age at presentation of 21 to 23 yr.

Peak Incidence

The estimated annual incidence of all types of encephalitis is approximately 5 to 8 cases per 100,000 persons. In nearly 50% of the cases, the cause cannot be established.

Risk Factors

•Prior episode(s) of autoimmune encephalitis, especially if not treated with immunotherapy
•Posttransplant immunosuppression and monoclonal antibody use
•Tumors, particularly small cell lung cancer, thymoma, and teratoma.
•Prior episode of herpes simplex virus encephalitis

Genetics

There are some emerging associations with certain HLA alleles.

Physical Findings & Clinical Presentation

•Typically presents with subacute (days to a few weeks) deficits of memory and cognition, often followed by suppressed level of consciousness. If untreated, may progress to coma.
•Psychiatric manifestations are common early in the course of autoimmune encephalitis. These may include psychosis, panic attacks, aggression, inappropriate sexual behaviors, compulsive behaviors, euphoria, or fear, among many others.
•Physical examination may show neuromyotonia, hyperekplexia, psychosis, or dystonia.

Etiology

One category includes antibodies directed at intracellular antigens, such as anti-Hu. These disorders are strongly associated with cancer and involve T-cell responses targeting neurons.

These disorders have a poor prognosis secondary to irreversible neuronal killing.

Another category involves autoantibodies to extracellular epitopes of ion channels, receptors, and other associated proteins, such as the NMDA receptor. These generally have a less severe prognosis due to reversible neuronal damage.

Differential Diagnosis

•Infectious encephalitis (especially viral)
•Metabolic encephalopathy
•Wernicke encephalitis
•Neuroleptic malignant syndrome
•Serotonin syndrome
•Lymphoma
•Carcinomatous meningitis

Workup

Diagnostic testing to exclude other causes of encephalitis, including infectious and other autoimmune causes, should occur. Definite autoimmune encephalitis (AE) can be diagnosed if clinical symptoms match antibody results. AE is considered highly probable despite negative antibody tests if symptoms and other laboratory results are suggestive.

Laboratory Tests

Autoantibody testing is important for the diagnosis of autoimmune encephalitis.

Tests for autoantibodies include NMDAR, LGI1, Caspr2, IgLON5, AMPAR (GluR1, GluR2 subunits), GFAP, and GABA-B-R, among others. Some of these tests are more sensitive and specific with CSF, and others with serum.

CSF findings of leukocyte count, total protein, and the presence of oligoclonal bands can drastically differ among subtypes of autoimmune encephalitis. Serum testing may offer a lower false-positive rate and a higher false-negative rate.

Imaging Studies

Brain MRI in patients with NMDAR, AMPAR, LGI1, Caspr2, and GABA-B antibodies may be normal or show increased T2 signal, especially in the medial temporal lobes.

Testing with MRI and EEG may also be helpful for excluding other causes. Changes in EEG can show subclinical seizures and nonconvulsive status epilepticus and therefore can be a relatively specific study, especially for anti-NMDA receptor encephalitis.

Treatment

Nonpharmacologic Therapy

Supportive care, including nutrition, is crucial in these patients.

Acute General Treatment

Treatment for suspected autoimmune encephalitis is often begun empirically prior to specific antibody test results.

This may include IVIG, plasmapheresis, and/or steroids. IVIG may be given early, as it is less likely to worsen infectious encephalitis.

If the patient does not respond in 2 wk or is critically ill, second-line therapies, such as rituximab or cyclophosphamide, should be considered.

Chronic Treatment

No chronic suppression is currently recommended for antibody-mediated autoimmune encephalitis, but relapse can occur and tends to follow a similar clinical course to the initial attack.

Early psychotic manifestations lead to frequent psychiatric misdiagnosis; chronic antipsychotic medications may increase the severity of autoimmune encephalitis symptoms if the underlying autoinflammatory process is continuing to predominate. Failure to respond to antipsychotics can be a diagnostic clue.

Complementary & Alternative Medicine

No complementary or alternative medicine options are known.

Disposition

Patients require hospitalization during treatment but are usually discharged home after resolution of disease process.

Referral

Neurology and rheumatology evaluation may be beneficial to help exclude other causes of encephalitis.

Pearls & Considerations

Autoantibody tests may be used to diagnose or exclude particular causes, but these tests are complex, and not every positive result is definite evidence of an autoimmune disorder.

Lack of response to antipsychotic treatment may be a clue to a diagnosis of antibody-mediated autoimmune encephalitis.

Prevention

Cancer screening should be completed for high-risk patients, as tumors can be associated with antibody-mediated autoimmune encephalitis. Known associations are HuD proteins with small cell lung cancer and NMDAR with ovarian teratoma.

Patient & Family Education

The Autoimmune Encephalitis Alliance (https://aealliance.org/) is a resource that can be used by patients and their family for further information and support.

Antibody Mediated Autoimmune Encephalitis