Hippocampal network abnormalities explain amnesia after VGKCC-Ab related autoimmune limbic encephalitis

Abstract

Objective: Limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex (VGKCC-Ab-LE) often leads to hippocampal atrophy and persistent memory impairment. Its long-term impact on regions beyond the hippocampus, and the relationship between brain damage and cognitive outcome, are poorly understood. We investigated the nature of structural and functional brain abnormalities following VGKCC-Ab-LE and its role in residual memory impairment.

Method: A cross-sectional group study was conducted. Twenty-four VGKCC-Ab-LE patients (20 male, 4 female; mean (SD) age 63.86 (11.31) years) were recruited post-acutely along with age- and sex-matched healthy controls for neuropsychological assessment, structural MRI and resting-state functional MRI (rs-fMRI). Structural abnormalities were determined using volumetry and voxel-based morphometry; rs-fMRI data were analysed to investigate hippocampal functional connectivity (FC). Associations of memory performance with neuroimaging measures were examined.

Results: Patients showed selective memory impairment. Structural analyses revealed focal hippocampal atrophy within the medial temporal lobes, correlative atrophy in the mediodorsal thalamus, and additional volume reduction in the posteromedial cortex. There was no association between regional volumes and memory performance. Instead, patients demonstrated reduced posteromedial cortico-hippocampal and inter-hippocampal FC, which correlated with memory scores (r = 0.553; r = 0.582, respectively). The latter declined as a function of time since the acute illness (r = -0.531).

Conclusion: VGKCC-Ab-LE results in persistent isolated memory impairment. Patients have hippocampal atrophy with further reduced mediodorsal thalamic and posteromedial cortical volumes. Crucially, reduced FC of remaining hippocampal tissue correlates more closely with memory function than does regional atrophy.

Keywords: MRI; encephalitis; hippocampus; memory.

Figure 1

Grey matter volume reduction in the hippocampus, thalamus, and posteromedial cortex in VGKCC-Ab-LE patients. (A) T1-weighted MRI scans of an example control (left) and patient (right) with corresponding 3D rendering of manual segmentation masks. (B) Graph depicting total hippocampal volumes for patients (z-scores calculated on the basis of mean and SD of TIV-corrected volumes of individually age-matched controls). (C) Hippocampal and thalamic volumes correlated strongly across patients. Dashed lines indicate that there was no thalamic atrophy (z<−1.5) in the absence of hippocampal atrophy. (D) VBM maps overlaid on sagittal sections of DARTEL GM template in MNI space display bilaterally reduced GM volume in patients compared with controls (over and above age, sex, and TIV) in the hippocampus, thalamus, and precuneus-posterior cingulate. Clusters survive correction for non-stationary smoothness and FWE (p<0.05) across the whole brain for cluster size over p<0.001 (smoothing kernel: 8 mm FWHM). Heat bar indicates t-scores. FWE, family-wise error; FWHM, full width at half maximum; GM, grey matter; HPC, hippocampus; MNI, Montreal Neurological Institute; TIV, total intracranial volume; VBM, voxel-based morphometry; VGKCC-Ab-LΕ, limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex.

Figure 2

Resting-state functional connectivity (FC) analyses (whole-brain). (A) A whole-brain, voxel-to-voxel resting-state FC analysis (MVPA) contrasting patients and controls demonstrated that the two groups differed in the FC of the right hippocampus with the rest of the brain (cluster-level p-FWE=0.018; kE=128 vox; peak: 26, –16, −22). Heat bar indicates F values. (B–D) Regions showing reduced FC with patients’ right hippocampi (F contrast: controls <>patients; nuisance covariates: age, sex). (B) Medial prefrontal/paracingulate cortex (cluster-level p-FWE<0.001; kE=547 vox; peak: 10, 48, –6). (C) Left posterior cingulate cluster, extending to precuneus, thalamus, and hippocampal tail (cluster-level p-FWE=0.024, kE=109 vox; peak: –10, –40, 4). (D) Right precuneus-posterior cingulate cluster (cluster-level p-FWE<0.001, kE=434 vox; peak: 6, –48, 6); heat bar indicates T values. (A–D) Clusters are displayed on sagittal sections of ICBM template in MNI space. (E) Correlation between right hippocampal-precuneal (C) FC (residualised for age, sex, and right hippocampal seed volume) with (age-scaled standardised) composite memory scores in patients, surviving correction for multiple testing for all correlations (rest of p-corr>0.459). FWE, family-wise error; HPC, hippocampus; MVPA, multivariate pattern analysis.

Figure 3

Resting-state functional connectivity (FC) analyses (MTL). (A) ROI-to-ROI FC analysis for MTL structures (BOLD time-series extracted from unsmoothed data in native space; contrast: patients <>controls; nuisance covariates: age, sex); orange and red lines indicate FC values that survive Holm-Bonferroni correction (p-corr<0.05) for multiple comparisons (R HPC – L HPC; R HPC – R PHC; R HPC – L TPC; R PHC – L PRC). Colour in squares: average FC of each ROI with other ROIs. (B, C) Inter-HPC FC correlated with (age-scaled standardised) memory composite scores in patients (residualised against age, sex, and total HPC seed volume), and survived correction for multiple testing for all correlations of FC measures with memory scores (rest of p-corr>0.459). (D) Inter-HPC FC correlated with thalamic volumes in patients (residualised against age, sex, and total HPC volume). (E) Patients’ inter-HPC FC (residualised for age, sex, and total HPC volume) declined as a function of time since symptom onset. (D, E) Correlations survived correction for multiple testing for the two FC measures that correlated with memory scores. AMG, amygdala; BOLD, blood oxygenation level dependent; ERC, entorhinal cortex; HPC, hippocampus; L/R: left/right hemisphere; MTL, medial temporal lobe; PHC, parahippocampal cortex; PRC, perirhinal cortex; ROI, region of interest; TPC, temporopolar cortex.