Magnetic Resonance Imaging Characteristics of LGI1-Antibody and CASPR2-Antibody Encephalitis

Abstract

Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy.

Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD).

Design, setting, and participants: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023.

Main outcomes and measures: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features.

Results: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala.

Conclusions and relevance: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Figure 1.. Regional T2 Magnetic Resonance Imaging (MRI) Hyperintensities, Diffusion Restriction, and Contrast Uptake

A, T2 hyperintensities across brain regions (red), the presence of diffusion restriction (dark gray), and contrast enhancement (green) in LGI1/CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E, n = 55), viral encephalitis (VE, n = 22), and Creutzfeldt-Jakob disease (CJD, n = 10). Light gray indicates absence; white indicates not performed. C, Raw data for frequencies are available in eTable 2 in Supplement 1. ADC indicates apparent diffusion coefficient; AE, autoimmune encephalitis; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; HSV1, herpes simplex virus 1.

Figure 2.. Magnetic Resonance Imaging (MRI) Features and Distinctions Between LGI1- and CASPR2-Antibody Autoimmune Encephalitis (AE), Viral Encephalitis (VE), and Creutzfeldt-Jakob Disease (CJD)

MRI abnormalities (A) included T2 hyperintensities (B) in almost all LGI1/CASPR2-antibody AE and VE cases and a smaller but high proportion of CJD cases. Fisher exact test was used for data in panels A-H. I, History of seizures was the only clinical feature associated with T2 and/or fluid-attenuated inversion recovery (FLAIR) hyperintensities in the hippocampus on multivariable regression analysis. Data expressed as log of odds ratios from univariable Fisher exact tests. Error bars indicate 95% CI. ERC indicates entorhinal cortex; HAJ, hippocampus-amygdala junction. ^aP < .01. ^bP < .05. ^cP < .001.

Figure 3.. Subgroup Analyses in Combined Discovery and Validation Cohorts of LGI1-Antibody Encephalitis vs CASPR2-Antibody Encephalitis and LGI1/CASPR2-Antibody Autoimmune Encephalitis (AE) vs Viral Encephalitis (VE) Subtypes

LGI1-antibody AE demonstrated higher rates of abnormality than CASPR2-antibody AE but similar rates of T2/FLAIR hyperintensities, temporal lobe involvement, hippocampus/amygdala confinement, and extratemporal extension. Compared with HSV1 VE, other forms of VE demonstrated fewer abnormalities, T2/FLAIR hyperintensities, hippocampus/amygdala swelling, diffusion restriction, and contrast enhancement. Error bars indicate 95% CI. FLAIR indicates fluid-attenuated inversion recovery; HSV1, herpes simplex virus 1. ^aP < .01. ^bP < .001. ^cP < .05.

Figure 4.. Receiver Operating Characteristic (ROC) Curves Reporting the Predictive Value of Diffusion Restriction, Contrast Enhancement, and Extratemporal T2 and/or Fluid-Attenuated Inversion Recovery (FLAIR) Hyperintensity

Distinguishing LGI1/CASPR2-antibody autoimmune encephalitis (AE) from non-AE cases across both cohorts separately and combined. All cases entered into this analysis demonstrated T2 and/or FLAIR hyperintensity of the hippocampus and/or amygdala. Absence of all 3 of these features was predictive of LGI1/CASPR2-antibody AE with an area under the curve (AUC) of 0.97, sensitivity of 90%, and specificity of 95% among cases with hippocampus/amygdala T2/FLAIR hyperintensity. For similar analyses including all cases (including scans without hippocampus/amygdala changes and normal scans) and comparing LGI1/CASPR1-antibody AE against herpes simplex virus 1 cases only, see eFigure 4 in Supplement 1.