Abstract
Bank AM, Kuzniecky R, Knowlton RC, Cascino GD, Jackson G, Pardoe HR; for the Human Epilepsy Project Investigators. Neurology. 2022. doi:10.1212/WNL.0000000000201125. Online ahead of print. Identification of an epileptogenic lesion on structural neuroimaging in individuals with focal epilepsy is important for management and treatment planning. The objective of this study was to determine the frequency of MRI-identified potentially epileptogenic structural abnormalities in a large multicenter study of adolescent and adult patients with newly diagnosed focal epilepsy. Patients with a new diagnosis of focal epilepsy enrolled in the Human Epilepsy Project observational cohort study underwent 3-Tesla (3 T) brain MRI using a standardized protocol. Imaging findings were classified as normal, abnormal, or incidental. Abnormal findings were classified as focal or diffuse, and as likely epilepsy-related or of unknown relationship to epilepsy. Fisher exact tests were performed to determine whether abnormal imaging or abnormality type was associated with clinical characteristics. 418 participants were enrolled. 218 participants (59.3%) had no abnormalities detected, 149 (35.6%) had abnormal imaging, and 21 (5.0%) had incidental findings. 78 participants (18.7%) had abnormalities that were considered epilepsy-related and 71 (17.0%) had abnormalities of unknown relationship to epilepsy. Older participants were more likely to have imaging abnormalities, while participants with focal and epilepsy-related imaging abnormalities were younger than those without these abnormalities. 131 participants (31.3%) had a family history of epilepsy. Epilepsy-related abnormalities were not associated with participant sex, family history of epilepsy, or seizure type. We found that one in five patients with newly diagnosed focal epilepsy has an MRI finding that is likely causative and may alter treatment options. An additional one in five patients has abnormalities of unknown significance. This information is important for patient counseling, prognostication, and management.Background and objectives:
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Commentary
Too often at Comprehensive Epilepsy Centers, we encounter a patient treated for drug-resistant epilepsy for many years to decades, but who was never referred for surgical evaluation. In some of these cases, the patient has never had a magnetic resonance imaging (MRI) to rule out a lesion, or an EEG to diagnose their seizures as epileptic. Serious risks for a patient in this situation include delayed diagnosis of an expanding brain tumor, or unnecessary long-term polypharmacy for nonepileptic events. Since travel to a tertiary center is not easily accessible for some patients, it is important that community practitioners know which diagnostic tests should be obtained after a new diagnosis of epilepsy, and when they should be acquired. For instance, it is critical early in the diagnosis to obtain a high-quality brain MRI with sequences geared toward detection of epileptogenic lesions. The Neuroimaging Task Force of the International League Against Epilepsy (ILAE) recommends the HARNESS-MRI protocol, which includes isotropic millimetric 3D T1 and FLAIR images and high-resolution 2D submillimetric T2 images, with imaging at 3 T preferred over 1.5 T. 1 However, given that patient populations, imaging protocols, and neuroradiological expertise differ between centers, it is not well-known how often early MRI in new onset epilepsy uncovers a potentially epileptogenic lesion.
In the presently highlighted study, Bank and colleagues evaluate a large cohort of 418 individuals (61% female) with recent onset epilepsy who underwent a standardized 3 T MRI protocol. 2 As in the HARNESS-MRI protocol, 3D T1 and FLAIR images were included, although T2 imaging is not mentioned in the study. The cohort is part of the Human Epilepsy Project (http://humanepilepsyproject.org), which is a multicenter prospective observational study of individuals aged 11 to 65 years (mean age, 34 years) who received a diagnosis of focal epilepsy within the preceding 12 months. All participants had fewer than 4 months of treatment with anti-seizure medications, or no prior treatment. MRIs were reviewed by specialists with expertise in epilepsy neuroimaging who were aware of the person’s age and diagnosis of focal epilepsy, but no other clinical information. Imaging features for each study participant were classified following the National Institute of Neurological Disorders and Stroke Common Data Elements for epilepsy neuroimaging. Overall, images were rated as abnormal for 149 (36%) participants and incidental findings were noted in 21 (5%) individuals. Inter-rater agreement was fair (Cohen’s kappa = 0.37), primarily due to disagreements about findings of unknown significance. Of the scans rated as abnormal, 75 contained focal abnormalities, 48 had diffuse findings, and 26 had both focal and diffuse abnormalities. Out of all 418 scans, 78 (19%) were identified as having epilepsy-related abnormalities, and another 71 (17%) had abnormal findings with an unknown relationship to epilepsy. The most common lesions identified were hippocampal malformation (17), tumor (15), other focal temporal lobe abnormality (12), hippocampal sclerosis (11), and extra-hippocampal malformation of cortical development (7). Epileptogenic lesions were more common in younger individuals, while imaging abnormalities of unknown significant and incidental findings were more often seen in older participants. Although nearly one-third of patients had a family history of epilepsy, which is higher than most studies, this was not associated with increased likelihood of abnormal MRI findings, and no relationship between seizure type and imaging findings was observed.
This study from Banks et al highlights that MRI lesions are more common than might be expected in new onset epilepsy, with nearly 1 in 5 participants harboring a likely epileptogenic lesion, and additional individuals have MRI abnormalities that may or may not be related to epilepsy. A high proportion of temporal lobe abnormalities seen in this study of adolescents and adults is not unexpected, and highlights the importance of high-resolution coronal views of the hippocampus in the evaluation of epilepsy. Younger children were not included in the investigation, and they may be expected to have higher rates of extratemporal lesions and malformations of cortical development. Inclusion of multiple centers and the utilization of a standardized imaging protocol are particular strengths of the study, and prior work from the Human Epilepsy Project has highlighted the value of using standardized 3 T MRI protocols. 3 The lack of a T2 sequence, as recommended by the HARNESS-MRI, may potentially be a limitation of this study, as those images can sometimes highlight subtle hippocampal sclerosis or focal cortical dysplasia. Also, multivariate modeling to better understand predictors of abnormal imaging may be considered in the future.
Overall, the highlighted study demonstrates the importance of obtaining a high-resolution 3 T MRI with 3D sequences early after the diagnosis of epilepsy, when possible. How early is early? If the resources are available, one should consider obtaining an MRI after an individual’s first unprovoked seizure, consistent with recommendations of the ILAE Neuroimaging Taskforce. This will allow prompt diagnosis of radiographic abnormalities, including potentially high-grade lesions that require further evaluation or consideration of surgical therapy. Of note, in a recent consensus statement from the ILAE Surgical Therapies Commission, it was recommended that individuals with epilepsy be referred for surgical evaluation as soon as drug resistance is ascertained, but that referral should occur even absent drug resistance if a patient has a brain lesion in a non-eloquent region. 4 Also, it is well established that seizure outcomes are more favorable after surgical resection for lesion-related over nonlesional focal epilepsy, as confirmed in a recent neuropathological study of over 9000 surgical patients. 5
Clearly, there are limitations to 3 T MRI, as lesions are often found on pathological examination from epilepsy resections that are not appreciated on preoperative imaging. The use of higher field strength 7 T MRI will likely improve our ability to identify subtle epileptogenic lesion, as described by the international 7 T Epilepsy Task Force, 6 although availability remains limited to a relatively small number of centers. Furthermore, there are subtle features in structural imaging that are unlikely to be discerned by the human eye at any field strength, and automated analysis pipelines using machine learning methods may improve our ability to localize these regions. 7 Finally, functional and structural network-based approaches to MRI have also demonstrated great promise, but there are several barriers to their implementation in the routine clinical pipeline. 8 While novel neuroimaging tools will undoubtedly improve the diagnosis and treatment of epilepsy, it is even more important that we appropriately utilize the tools that we already have available. Spread the word: Every patient diagnosed with epileptic seizure should have an early 3D 3 T MRI, whenever possible. This “picture” may ultimately help prevent thousands of surgically treatable seizures.
