Epilepsy Research: Neuroimaging
By Kenneth Laxer, M.D.
At no time in history has research in epilepsy been as active as it is now. Despite the intensity of the research effort, there remain large gaps in our understanding of epilepsy, including the underlying causes for most patients, how to prevent the development of epilepsy after a brain insult, and more effective/less toxic treatments. Clearly, the most important future developments will be in the genetics of epilepsy, including the definition of the underlying genes and gene products for the inherited epilepsies and an understanding of the changes in gene expression that are associated with epileptogenesis, how a brain insult evolves into the chronic condition of epilepsy, and how this evolution can be prevented.
Once epilepsy has been established, the goal of treatment can be easily stated as "no seizures no side effects." Despite the large number of anticonvulsant medications available, as many as 30% to 35% of patients with epilepsy are not seizure-free1 (also see the article by Dr. King-Stephens). For many of these patients, depending upon the underlying physiology and etiology, epilepsy surgery is a potential option. Approximately half of the patients with difficult-to-control epilepsy are candidates for seizure surgery (125,000 patients in the U.S.)2. For patients who have undergone three drug trials without seizure control, the likelihood of any additional medication providing seizure control is less than 5% (Ref 1); whereas patients who undergo surgery have a 50% to 90% chance of becoming seizure-free following resection of the epileptogenic focus (Ref 2). Obviously, surgery exposes the patient to a different set of risks (hemorrhage, infection, etc.), but it should be remembered that continued, unabated seizures also expose the patient to a lifetime risk of progressive cognitive difficulties, exposure to additional anticonvulsants, injuries, and death. A successful surgery can eliminate these risks posed by a lifetime of seizures. An additional benefit of effective seizure control is the improved quality of life and increased vocational and avocation opportunities that freedom from seizure provides.
Identifying a Good Surgical Candidate
But not all patients with medically refractory epilepsy are candidates for a focal resection. At a minimum the patient must have localization-related epilepsy. For many patients, the seizure focus cannot be adequately defined, and for those that do undergo surgery, not all patients become seizure free. Thus, for patients with medically refractory epilepsy, surgery is a significant alternative, but there is a need for improved localization techniques and better predictors of surgical outcomes. Surgical resection is predicated on the ability to identify the seizure focus or epileptogenic zone, the area of the brain responsible for the generation of seizures. The removal or disconnection of this region can result in the cessation of seizures.
The guiding principle in the presurgical evaluation of epilepsy patients is to find concordance for localization and lateralization between the various elements of the evaluation (history, physical examination, EEG recordings, structural and functional imaging studies, etc.). Techniques for identifying the seizure focus are continually evolving and being refined, but the gold standard for localization remains the recording of the ictal onsets with EEG. The practical clinical observation is that the confidence of localization and lateralization of an epileptogenic focus is heightened with increasing concordance of these elements. This concordance is directly related to a successful surgical outcome.
No technique since electroencephalography has had a more dramatic effect on the evaluation of epilepsy patients than the introduction of magnetic resonance imaging (MRI). MRI techniques are continually evolving, becoming more sensitive and more specific. When first introduced, MRI could not localize or define mesial temporal sclerosis (MTS), scarring of the medial temporal regions, the most common pathology found in patients with medically refractory epilepsy (Ref 3). But by modifying the way imaging was performed, MTS is now easily detected by MRI (see figure 1).
The finding of a localizing abnormality on MRI can improve the outcome for patients who elect surgery. In patients with neocortical epilepsy (NE), the presence of a lesion on MRI increases the likelihood of becoming seizure-free (67% vs. 44%) (Ref 4). Similarly, there is a clear correlation between MRI/ictal EEG concordance and seizure surgery outcomes in temporal lobe epilepsy. When the MRI demonstrates increased hippocampal T2 signal and/or evidence of hippocampal atrophy (MTS) ipsilateral to the EEG localization, 95% of the patients who undergo temporal lobectomies became seizure-free. In sharp contrast, less than 50% of patients with normal or discordant MRIs became seizure-free (Ref 5); unfortunately, about 50% of temporal lobe epilepsy patients have normal or discordant MRIs. Furthermore, patients with NE are often denied surgery due to the lack of supportive localizing data. For example, 25% of patients with medically refractory partial epilepsy have frontal lobe neocortical epilepsy (Ref 6), but only 15% of these eligible patients have surgery (Ref 7), with variable success. Therefore, improved neuroimaging measures are needed to identify the seizure focus. In summary, because concordance of neuroimaging significantly improves the neurosurgical outcome, there is a need for continued research and further gains in neuroimaging techniques that indicate the location of the focus. Therefore, improved neuroimaging has the potential to significantly increase the efficacy of epilepsy surgery and increase the number of patients that can be offered surgery.
4T MRI Study
Using the high field 4-Tesla MRI (4T MRI) at the Department of Veterans Affairs Medical Center, San Francisco, we have been studying patients with non-lesional, medically refractory, localization related medial temporal lobe epilepsy and neocortical epilepsy, especially frontal lobe epilepsy—the patients with the most refractory epilepsy and the hardest to localize for seizure surgery. The 4T MRI study was obtained as part of the patient’s pre-operative evaluation and the results of the 4T MRI imaging were correlated with the surgical outcomes. Our studies using the 4T MRI and specially designed structural sequences have increased the sensitivity of MRI in this patient population by 30% compared to traditional clinical imaging. Figure 2 shows an image obtained at 4T that reveals a small area of cortical dysplasia that was not seen on conventional clinical MRIs (1.5 and 3T). Scalp and intracranial electrode recordings of his seizures were non-localizing; but based on this MRI finding, repeat recordings were obtained with electrodes placed in the MRI defined abnormality and demonstrated the seizures to be arising from this lesion. Surgical removal has brought about complete seizure freedom. Without the 4T evidence, this patient would not have been offered surgery and would continue having frequent seizures.
In addition to improving the localization of the seizure focus, these new imaging techniques are increasing our understanding of the behavioral and cognitive changes associated with epilepsy. While the seizures may be arising from a restricted brain region, ours and other studies have demonstrated the effects of seizures and the epilepsy pathology is more widespread than previously perceived. Figures 3-A and 3-B show diffuse regions of cortical thinning (both ipsilateral and contralateral) associated with medial temporal epilepsy due to MTS (Ref 8). So while the epileptogenic region can be restricted to the medial temporal region, its effects are diffuse. This finding may help to explain the cognitive and behavioral disturbances seen in such patients that cannot be explained by the medial temporal pathology alone. In addition, we have found that the distribution of the cortical thinning is different, depending on which region the seizures arise in, and the pattern of distribution can also help in the localization of the focus.
MRS Metabolic Imaging
Magnetic resonance spectroscopy (MRS) allows the noninvasive measurement of N-acteylaspartate (NAA), a marker of neuronal viability and functionality, and provides information about important aspects of brain metabolism. Similar diffuse changes found with measures of cortical thinning were found using MRS metabolic imaging with a 3D whole brain echoplanar spectroscopic imaging sequence (Ref 9). As seen with the studies demonstrating widespread cortical thinning, spectroscopy has demonstrated diffuse bilateral alterations, with the distribution dependent on the localization of the epileptogenic zone (see figure 4). In patients with temporal lobe epilepsy with and without mesial temporal sclerosis (TLE-MTS, TLE-no), widespread extrahippocampal NAA reductions were found. NAA reductions had a bilateral frontotemporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no.
The etiology of these extrahippocampal NAA reductions in TLE is unknown. NAA decreases in the hippocampus are usually thought to be caused by neuron loss and/or neuronal dysfunction. Widespread cortical thinning in TLE-MTS and TLE-no with a similar distribution as the NAA reductions could be due to local excitotoxic effects of spreading epileptogenic activity leading to neuronal loss in the extrafocal regions. In addition, extrafocal neuronal dysfunction, as assessed by decreased NAA, could also be caused by deafferentation due to loss of input from the focus. These studies provide evidence that at least metabolically and structurally, non-lesional TLE is neither a focal nor a homogeneous disease.
Clearly, these MRI findings are only scratching the surface of the potential for this diagnostic modality. As MRI machines are developed with increased field strength (studies with 7 Tesla imagers are under way) and as new sequences are developed, there will be increased spatial resolution resulting in higher sensitivity and specificity. By extension, these improvements will increase the number of patients who are candidates for epilepsy surgery and will improve the outcome from surgery.
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- Engel J Jr., Van Ness PC, Rasmussen TB and Ojemann LM: Outcome with Respect to Epileptic Seizures. In Engel Jr. ed. Surgical Treatment of the Epilepsies, Second Edition. Raven Press, New York, 1993, 609-621.
- Mueller SG, Laxer KD, Barakos J, Cheong I, Garcia P, Weiner MW. Widespread neocortical abnormalities in temporal lobe epilepsy with and without mesial sclerosis. Neuroimage 46:353-9, 2009.
- Mueller SG, Ebel A, Barakos J, Scanlon C, Cheong I, Finlay D, Garcia P, Weiner MW, Laxer KD. Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis. J Neurol. 2010.
California Pacific Medical Center
- Neuroscience Institute Epilepsy Program -
Diagnosis, Medical Management, Epilepsy Surgery, Neuropsychology
San Francisco | Marin | San Mateo | San Francisco Bay Area
3B. Regions with significant neocortical thinning in the TLE-no compared to age matched controls.