Autoimmune Encephalitis

Indications for Testing

Testing for autoimmune encephalitis is appropriate in individuals with subacute onset of unexplained neurologic symptoms (including changes in mental status, memory problems, and psychiatric symptoms) and other paraclinical findings suggestive of autoimmune or inflammatory causes.   

Laboratory Testing

Laboratory testing for autoimmune encephalitis should be performed in the context of a robust clinical history, thorough neurologic exam, and imaging.   Ensuring that a patient meets the clinical criteria for a diagnosis of autoimmune encephalitis before performing antibody testing reduces the probability of misdiagnosis and associated consequences.  

Diagnosis

Autoimmune encephalitis may be difficult to distinguish from infectious, toxic, and other forms of encephalitis. A careful laboratory workup should be performed to exclude these conditions and avoid missing the diagnosis of a condition that may be treated differently.   

Initial Testing

Initial laboratory testing to rule out common toxic and metabolic causes of encephalitis includes a CBC, an electrolyte panel, liver function tests, and a toxicology screen. Blood cultures may also be performed, in addition to the infectious disease testing detailed below.

Infectious Disease Testing

Infectious diseases are a common cause of encephalitis   and should be thoroughly excluded via laboratory testing. The evaluation for infectious disease should be tailored to an individual’s clinical status and presentation (eg, whether or not they are immunocompromised), recent exposures or travel, and the season.  For more information on laboratory testing for organisms associated with encephalitis, refer to the following ARUP Consult topics:

• Herpes Simplex Virus - HSV
• Varicella-Zoster Virus - VZV
• Treponema pallidum - Syphilis
• Human Immunodeficiency Virus - HIV
• Cytomegalovirus - CMV
• Toxoplasma gondii - Toxoplasmosis
• Mycobacterium tuberculosis - Tuberculosis
• Dengue, West Nile, and Other Mosquito-Borne Arboviruses
• Plasmodium Species - Malaria
• Trypanosoma cruzi - Chagas Disease
• Tickborne Diseases
• Bartonella Infection
• Epstein-Barr Virus - EBV

Additional CSF Examination

CSF testing—including cell count and differential, protein, glucose, gram stain and bacterial culture, fungal and/or acid-fast bacillus testing (if appropriate), and oligoclonal bands with immunoglobulin G (IgG) index—should be performed. If not already performed, testing for cryptococcus and viral testing by nucleic acid amplification testing (NAAT) for enterovirus, herpes simplex virus (HSV), and varicella-zoster virus (VZV) is recommended. 

Antineural Antibody Testing

Antineural antibody testing is useful to confirm the diagnosis of autoimmune encephalitis once other potential etiologies have been excluded. Testing for antineural antibodies simultaneously in both serum and CSF is usually recommended to maximize diagnostic yield; some antibody tests are more sensitive in serum, whereas others are more specific in CSF.   In the majority of cases, only IgG antibodies are relevant to autoimmune encephalitis. 

Detection of a particular antibody in the appropriate clinical context confirms the diagnosis of autoimmune encephalitis.  However, failure to detect an antibody does not exclude autoimmune encephalitis. Empiric acute immunotherapy should not be withheld while waiting for the results of antibody testing. 

Detection and overinterpretation of nonspecific antibodies, such as thyroid peroxidase (TPO) antibodies, may lead to misdiagnosis and inappropriate treatment. All antibody results should be carefully interpreted in the context of the complete clinical picture. 

Using a clinical scoring system may help determine when antibody testing is most likely to be useful.  For example, the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score helps predict whether antineural autoantibodies are likely to be present in patients with epilepsy.  Using such scoring systems to determine when antineural antibody testing is appropriate will improve diagnostic yield.

Paraneoplastic Antibody Testing

An evaluation for paraneoplastic antibodies (well-characterized antibodies that are strongly associated with cancer—including amphiphysin, antineuronal nuclear antibody type 1 [ANNA-1], ANNA-2, CV2, Purkinje cell cytoplasmic antibody type 1 [PCCA-1], PCCA-Tr, PCCA-Tr/DNER, and SRY-box transcription factor 1 [SOX1]) is appropriate in individuals with encephalitis and known or suspected cancer, or in individuals with specific high-risk neurologic phenotypes (eg, encephalomyelitis, limbic encephalitis). 

Testing for intermediate-risk antibodies (eg, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor [AMPAR], gamma-aminobutyric acid receptor, type B [GABA-BR], metabotropic glutamate receptor 1 [mGluR5], and N-methyl-D-aspartate receptor [NMDAR]) may also be appropriate in individuals with intermediate-risk phenotypes (eg, nonlimbic encephalitis such as NMDAR encephalitis). 

Detection of paraneoplastic or intermediate-risk antibodies may support the diagnosis of a paraneoplastic neurologic syndrome, guide the focused search for malignancy, and aid in treatment decision-making. Importantly, phenotype-specific antibody panels usually incorporate these paraneoplastic antibodies within the appropriate panel, so ordering a separate paraneoplastic panel is generally not necessary.

Panel Testing

Autoimmune encephalitis presents with diverse neurologic phenotypes.  Clinical features overlap highly; therefore, the use of a targeted phenotypic panel based on the patient’s predominant clinical features may provide the greatest diagnostic yield.  For example, a number of antibodies are associated with limbic encephalitis (including AMPAR, contactin-associated protein 2 [CASPR2], GABA-BR, glutamic acid decarboxylase 65-kd isoform [GAD65], leucine-rich, glioma-inactivated protein 1 [LGI1], and paraneoplastic antibodies),  but symptoms are generally similar (eg, memory and psychiatric changes with or without new-onset seizures). 

The use of an overly broad antibody panel confers an increased risk of false-positive results and is therefore not recommended. Targeted panels may also have shorter turnaround times relative to larger panels. Regardless of the panel chosen, testing in both serum and CSF is usually recommended to maximize diagnostic yield. 

Individual Antibody Testing

Testing for individual antibodies may be reasonable if clinical features are highly suggestive for a specific antibody (eg, testing for LGI1 antibodies if frequent faciobrachial dystonic seizures are present), and this strategy may reduce turnaround time.  However, many antibodies are associated with overlapping clinical syndromes, and some patients may be positive for multiple antibodies, which may have implications for cancer screening and treatment responsiveness. Therefore, panel antibody testing is usually recommended for autoimmune encephalitis. 

Monitoring

Individual antibody tests may be used to monitor treatment response in individuals who are antibody positive. However, antibody titers do not always correlate with disease severity. Treatment should be based on the clinical picture rather than antibody test results.