Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Abstract

Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing.

Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic.

Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%.

Interpretation: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

FIGURE 1

Flowchart with follow‐up diagnosis of all included patients. *This patient had focal onset epilepsy with sporadically occurring focal to bilateral tonic–clonic seizures, and had a recently discovered esophagus carcinoma. Eleven months after inclusion, his seizure frequency increased, and he developed psychotic symptoms. Cerebrospinal fluid was positive for anti–N‐methyl‐D‐aspartate receptor (NMDAR), confirmed with live hippocampal neurons. #According to the criteria. ¹⁴ AES = autoimmune etiology of seizures; CASPR2 = contactin‐associated protein‐like 2; GAD65 = glutamic acid decarboxylase 65; GlyR = glycine receptor; LGI1 = leucine‐rich glioma‐inactivated 1; MRI = magnetic resonance imaging.

FIGURE 2

Overview of the characteristics, signs, and symptoms that occurred more often in patients with neuronal antibodies. *p between 0.05 and 0.005, **p between 0.005 and 0.0001, ***p < 0.0001. The top p values correspond to the values visualized in Table S1. The lighter‐colored lines visualize significance of the post hoc in‐between analysis. (A) Factors that differed significantly between autoimmune etiology (AE) of seizures and non‐AE. (B) Values that differed between the extracellular antigen group and the non‐AE group. (C) Values that differed between the GAD65 and non‐AE groups. In order of appearance, the y‐axis shows: (1) years (age at onset), (2) cumulative percentage (all bar diagrams), (3) months and years (0–12, 1–80 respectively; epilepsy duration). In the bar diagrams, the x‐axis shows the raw values. CASPR2 = contactin‐associated protein‐like 2; GAD65 = glutamic acid decarboxylase 65; LGI1 = leucine‐rich glioma‐inactivated 1; MRI = magnetic resonance imaging; mRS = modified Rankin Scale; NMDAR = N‐methyl‐D‐aspartate receptor. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Autoimmune etiology of seizures (AES) patients as distributed by ACES score. The number of AES patients by ACES score (A) are provided for both the original, Dutch cohort (B) and the Czech validation cohort (C). Only the data of the patients with antibodies targeting extracellular antigens, anti–glutamic acid decarboxylase 65 (GAD65), and no evidence for autoimmunity are shown. The numbers in the bar diagrams correspond with the numbers of patients of each specific group. All patients with an ACES score of ≥2 without AES were tested by commercial cell‐based assay and enzyme‐linked immunosorbent assay post hoc, and all were negative. MRI = magnetic resonance imaging. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 4

Comparison of the ACES score with the Antibody Prevalence in Epilepsy and Encephalopathy (APE) and APE2 score. (A) Visualization of the epilepsy scores per patient, combining the Dutch and Czech cohorts, shows that all patients are identified by the ACES score, whereas a considerable percentage is not identified by the APE or APE2 score. (B) Dissection by duration of epilepsy shows that the difference in performance is caused by the patients with epilepsy for >1 year. * p < 0.05, **p < 0.01. The colors refer to the antibodies identified: red, contactin‐associated protein‐like 2; orange, leucine‐rich glioma‐inactivated 1; green, N‐methyl‐D‐aspartate receptor; blue, glutamic acid decarboxylase 65.

FIGURE 5

Individual treatment responses of patients with anti–leucine‐rich glioma‐inactivated 1 (LGI1), anti–contactin‐associated protein‐like 2 (CASPR2), and anti–glutamic acid decarboxylase 65 (GAD65). The figures visualize the seizure frequency over time per antibody: (A) anti‐LGI1, (B) anti‐CASPR2, (C) anti‐GAD65 with treatment response, (D) anti‐GAD65 without treatment response (both black), or untreated (gray). The Roman numerals correspond to the numbers shown in Table S4. All patients were treated with antiseizure medications (ASM). The figure only shows ASM changes that led to a decrease in seizure frequency. AED = antiepileptic drug; IVIg = intravenous immunoglobulin; −T12 = 12 months before inclusion, T0 = inclusion date, T1 = 1 month after inclusion, T4 = 4 months after inclusion, T8 = 8 months after inclusion, T12 = 12 months after inclusion. [Color figure can be viewed at www.annalsofneurology.org]