Abstract
MRI-Negative Temporal Lobe Epilepsy: A Network Disorder of Neocortical Connectivity
Vaughan DN, Rayner G, Tailby C, Jackson GD. Neurology 2016;87:1934–1942.
OBJECTIVE: To define the functional network changes that characterize MRI-negative temporal lobe epilepsy (TLE) and TLE with hippocampal sclerosis (HS-TLE). METHODS: We studied 36 patients with medically refractory unilateral TLE, having either a normal clinical MRI (n = 18) or unilateral hippocampal sclerosis (n = 18). Patients were compared to healthy controls of equivalent age and sex (n = 27). Functional connectivity in 10 minutes of task-free functional MRI was assessed using a voxel-resolution graph theoretic analysis, using the metrics of degree, clustering coefficient, eigenvector, and betweenness centrality. Significant clusters were further explored with a seed-based analysis. RESULTS: MRI-negative TLE showed decreased connectivity at the ipsilateral superior and middle temporal gyri compared to controls (decreased eigenvector centrality). No functional abnormality was detected within mesial temporal structures. In contrast, HS-TLE showed increased connectivity within the affected hippocampus and anterior thalamus (increased clustering coefficient) and decreased connectivity of the ventromesial prefrontal cortex (decreased betweenness centrality). Using the detected clusters as seed regions revealed decreased connectivity from the sclerotic hippocampus to both the contralateral temporal lobe and regions of the default mode network. CONCLUSION: MRI-negative TLE is associated with impaired interictal connectivity of the temporal neocortex, lateralized to the epileptic side. HS-TLE shows a different pattern, with functional segregation of the sclerotic hippocampus and impairment of its long-range connectivity. This suggests that MRI-negative TLE is not merely a subtle version of hippocampal sclerosis, but is rather a separate condition that involves distinct brain networks.
Commentary
Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults and adolescents, and the most frequent indication for epilepsy surgery. While temporal lobectomy in patients with TLE associated with hippocampal sclerosis (HS-TLE) is associated with up to 80% chance of seizure freedom (1), the rates of such optimal outcomes in patients with nonlesional MRI range from 18 to 63 percent (2). In the evaluation of a patient with intractable TLE and normal MRI, one has to consider the possibility of an extratemporal seizure focus in a clinically silent region with ictal propagation to the temporal lobe (3), which may explain the lower success of temporal lobectomy in nonlesional TLE. If the seizure focus is within the temporal lobe, one must determine whether it is mesial or neocortical. Such determinations, which can help improve the seizure freedom outcomes and reduce postoperative deficits, often necessitate intracranial monitoring in patients with normal brain MRI.
In TLE, it is important to distinguish between mesial and neocortical generators based on electroclinical features. This may help determine the surgical decisions, including the targets of intracranial monitoring. For example, some authors have found certain features to be more common in mesial than in neocortical TLE. These include history of febrile seizures, contralateral hand dystonia, and abdominal aura (4). Additionally, HS-TLE is generally associated with specific neuropsychological deficits that are different from those of neocortical or nonlesional TLE, suggesting involvement of different networks.
Vaughan et al. used a voxel-resolution connectomics method to investigate network alterations that are associated with nonlesional TLE and differentiate them from those of HS-TLE at high spatial resolution. The authors applied a voxel-wise graph theoretical analysis to task-free fMRI data in 18 subjects with HS-TLE, 18 subjects with nonlesional TLE, and 27 healthy controls of matched age and sex (5). Patients with video-EEG revealing unilateral TLE and congruent PET hypometabolism were selected. Seizure frequency was similar in HS-TLE and nonlesional TLE; however, seizure duration and semiology differed. Age of seizure onset was significantly different in the nonlesional subjects, averaging about 7 years older onset with a corresponding shorter duration of epilepsy. All patients were medically intractable, and most were receiving 2 or 3 antiseizure medications. In the nonlesional group, the volumes of the ipsilateral hippocampi were no different from those of the control group, whereas the sclerotic hippocampi in the HS-TLE group were smaller than in the control and the nonlesional groups. At baseline, the quantity of scalp-EEG-recorded interictal epileptiform discharges did not differ in the two groups, but EEG was not recorded during MRI acquisition. The epileptogenic regions could not be confirmed by seizure freedom after surgery: 15 out of 18 subjects in the HS-TLE group underwent temporal lobectomy (of whom 13 had good seizure outcome) but only 5 out of 18 nonlesional subjects underwent lobectomy (with good seizure outcome in 4).
One of the main findings of this study was decreased connectivity of the ipsilateral temporal neocortex in the nonlesional group. The authors reported decreased eigenvector centrality relative to controls at the anterior part of the superior temporal sulcus. In HS-TLE, however, connectivity was abnormal in the hippocampus, thalamus, and prefrontal cortex. Higher clustering coefficients in this group were noted in the affected hippocampus and in the contralateral anterior thalamic nucleus. Secondary analyses in nonlesional TLE found that the strongest positive seed-based connectivity to the ipsilateral temporal neo-cortex was with bilateral anterior temporal and anterior cingu-late regions, followed by the frontal cortex, insula, and subcortical structures. In contrast, HS-TLE showed decreased seed-based connectivity between the sclerotic hippocampus and default mode network (including, in addition to the mesial temporal structures, the medial prefrontal cortex and the precuneus).
Differences in neuropsychological profiles between nonlesional TLE and HS-TLE can be explained by differing patterns of impaired connectivity. In nonlesional TLE, connectivity of the ipsilateral lateral temporal neocortex is impaired; whereas in HS-TLE, connectivity is increased within the affected mesial temporal lobe and anterior thalamus and decreased with the default mode network.
It is important to study network connectivity in the epilepsies, especially ones with normal MRI, but—heterogeneous as epilepsy is—it is not clear whether this can be done on a group basis unless one confirms localization of seizure focus in the group by intracranial monitoring or, at least, by identical seizure semiology, ictal and interictal EEG findings, and age of onset, among other variables. Additionally, interictal epileptiform discharges influence cerebral blood flow and, thus, the blood oxygenation level–dependent signal fluctuations measured in such connectivity studies, but the authors did not record EEG during MRI acquisition. The analysis by Vaughan et al. is based on the assumption that network changes occur in a similar fashion among all patients with HS-TLE as well as all those with nonlesional TLE; the authors neither specified whether there were any distinguishing semiological or localizing electroencephalographic features in the nonlesional group nor whether the epileptogenic zone was mesial or neocortical in that group. However, one may postulate that resting state connectivity is different in different patients depending on the age of seizure onset, degree of seizure control, particular sequence of ictal semiological signs, seizure duration, and antiseizure medications. An important study found that nonlesional TLE seizure foci may be either mesial or lateral, and one would expect different networks influenced by the localization of these foci (6). Some of these nonlesional TLE patients may have seizure foci in the superior, middle, inferior temporal, fusiform, or parahippocampal gyri (7), amygdala (8), or even extratemporally, e.g. in the orbitofrontal cortex or posterior cingulate gyrus (3). Even in HS-TLE, some patients may experience an epigastric sensation as an aura, while others may have a déjà vu or even a visual aura, suggesting different ictal networks despite identical seizure onset zones, which, in turn, may influence interictal connectivity. A future study may aim to characterize network connectivity on an individual patient level in a manner that may shed light on identifying targets for intracranial implantation or correlating neuropsychological variables with network peculiarities.