Autoimmune Encephalitis Criteria in Clinical Practice

Abstract

Background and objectives: To assess the clinical practice applicability of autoimmune encephalitis (AE) criteria (2016).

Methods: Medical records of 538 adults diagnosed with AE or related autoimmune encephalopathy at Mayo Clinic (not including pure movement disorders) were reviewed and AE guideline criteria applied.

Results: Of 538 patients, 288 were male (52%). The median symptom onset age was 55 years (range, 11-97 years; 16 had onset as children). All had other non-AE diagnoses reasonably excluded. Of 538 patients, 361 (67%) met at least possible criteria, having all 3 of subacute onset; memory deficits, altered mental status or psychiatric symptoms, and ≥1 supportive feature (new focal objective CNS finding, N = 285; new-onset seizures, N = 283; supportive MRI findings, N = 251; or CSF pleocytosis, N = 160). Of 361 patients, AE subgroups were as follows: definite AE (N = 221, 61%, [87% AE-specific IgG positive]), probable seronegative AE (N = 18, 5%), Hashimoto encephalopathy (N = 20, 6%), or possible AE not otherwise categorizable (N = 102, 28%). The 221 patients with definite AE had limbic encephalitis (N = 127, 57%), anti-NMDA-R encephalitis (N = 32, 15%), ADEM (N = 8, 4%), or other AE-specific IgG defined (N = 54, 24%). The 3 most common definite AE-IgGs detected were as follows: LGI1 (76, 34%), NMDA-R (32, 16%), and high-titer GAD65 (23, 12%). The remaining 177 patients (33%) not meeting possible AE criteria had the following: seizures only (65, 12% of all 538 patients), brainstem encephalitis without supratentorial findings (55, 10%; none had Bickerstaff encephalitis), or other (57, 11%). Those 57 "others" lacked sufficient supportive clinical, radiologic, or CSF findings (N = 26), had insidious or initially episodic onset of otherwise typical disorders (N = 21), or had atypical syndromes without clearcut memory deficits, altered mental status, or psychiatric symptoms (N = 10). Fifteen of 57 were AE-specific IgG positive (26%). Among the remaining 42, evidence of other organ-specific autoimmunity (mostly thyroid) was encountered in 31 (74%, ≥1 coexisting autoimmune disease [21, 50%] or ≥1 non-AE-specific antibodies detected [23, 53%]), and all but 1 had an objective immunotherapy response (97%).

Discussion: The 2016 AE guidelines permit autoimmune causation assessment in subacute encephalopathy and are highly specific. Inclusion could be improved by incorporating AE-IgG-positive patients with isolated seizures or brainstem disorders. Some patients with atypical presentations but with findings supportive of autoimmunity may be immune therapy responsive.

Figure 1. Study Inclusion Algorithm

Figure 2. Autoantibody Findings Among All 538 Patients and 221 Cases With Definite AE

Ab = antibody; AGNA = antiglial/neuronal nuclear antibody; AK5 = adenylate kinase 5; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Amphi = amphiphysin; ANNA = antineuronal nuclear antibody; AQP4 = aquaporin-4; CASPR = contactin-associated protein; CRMP = collapsin-response mediator protein; DPPX = dipeptidyl peptidase; GABA = gamma amino butyric acid; GAD65 = glutamic acid decarboxylase 65 kDa isoform; GFAP = glial fibrillary acidic protein; IgLON = immunoglobulin-like cell adhesion molecule; KLHL = kelch-like protein; LGI1 = leucine-rich glioma-inactivated 1; mGluR5 = metabotropic glutamate receptor-5; MOG = myelin oligodendrocyte glycoprotein; NIF = neuronal intermediate filaments; NMDA = n-methyl-d-aspartate; R = receptor.

Figure 3. Diagnostic Categories for 538 Patients After Application of 2016 Autoimmune Encephalitis Criteria

Ab = antibody; ADEM = acute disseminated encephalomyelitis; AE = autoimmune encephalitis; NMDA-R = n-methyl-d-aspartate receptor.

Figure 4. Illustrative MRI Brain Findings

Images are T2 axial FLAIR, except A (T2 coronal FLAIR) and G (T1 axial postgadolinium). (A) Normal appearing hippocampal formations in a patient with anti–NMDA-receptor encephalitis. (B) Bilateral hyperintensity of hippocampal formations in a patient with LGI1 encephalitis. (C) Subtle left hippocampal hyperintensity in a patient with LGI1 encephalitis. (D) Prominent right amygdalar hyperintensity in a patient with anti-Ma2 encephalitis. (E) Multifocal white matter lesions with ill-defined borders in a patient with MOG antibody–associated disease and an ADEM attack. (F) Peri-IVth ventricular hyperintensity in a patient with aquaporin-4-IgG–positive neuromyelitis optica spectrum disorder with brainstem encephalitis; (G) Periventricular leptomeningeal enhancement in a patient with autoimmune GFAP astrocytopathy. (H) Bifrontal lobar hyperintensities in a patient with GABA_A receptor encephalitis. (I) Left frontal hyperintensity in a patient with possible autoimmune encephalitis. (J) Diffuse T2 signal abnormalities in a patient with probable autoimmune encephalitis. ADEM = acute disseminated encephalomyelitis; FLAIR = fluid-attenuated inversion recovery; GABA = gamma amino butyric acid; GFAP = glial fibrillary acidic protein; LGI1 = leucine-rich glioma-inactivated 1; MOG = myelin oligodendrocyte glycoprotein; NMDA-R = n-methyl-d-aspartate receptor.