Epilepsy is one of the most prevalent neurological diseases in the world, affecting some 50 million people worldwide, according to data released by the World Health Organization in 2017. It is also one of the most studied: descriptions of its symptoms have been found in Egyptian and Sumerian reports from as long ago as the year 3500 B.C. However, elucidating the causes and progress of the disorder, which is associated with multiple factors and clinical manifestations—from absence seizures (lapses of awareness that last a few seconds) to convulsions—remains a challenge.
But neuroimaging techniques have recently enabled researchers to take a significant step in the right direction. Confirming the findings of previous research, a global study using magnetic resonance imaging in patients with epilepsy associated the occurrence of cerebral atrophy with all forms of the disease, even those previously considered idiopathic—where no cerebral alterations are observed in standard clinical exams.
The results were published in scientific journal Brain in February. The data analyzed came from 24 research centers in 14 countries in Europe, North and South America, Asia, and Australia. Structural measurements of the brain were taken from the MRI scans of 2,149 individuals with epilepsy, and compared to 1,727 healthy control cases.
“It is the largest study ever conducted in this area in terms of the number of cases analyzed,” says neuroscientist Fernando Cendes, from the University of Campinas (UNICAMP) and coordinator of the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), one of the Research, Innovation, and Dissemination Centers (RIDCs) supported by FAPESP, which contributed Brazilian data to the study.
The results of this joint effort suggest that in all cases of epilepsy, structural impairment is more widespread than previously thought. Compared with healthy brains, all epilepsy groups showed lower volume in the right thalamus (the area responsible for the integration of nerve impulses) and lower thickness in the precentral gyrus (which contains the primary motor area of the cerebral cortex).
In epilepsies associated with brain lesions, neuronal loss causes seizures, as already widely described in other studies. This is the case, for example, in temporal lobe epilepsy, which is linked to atrophy of the hippocampus, an important area of the brain related to emotions, learning, and memory. “Over time and after repeated seizures, this lesion begins to affect other areas of the brain. It will now be possible to monitor this alteration over the years,” says the Cendes.
There are, however, a large number of epilepsies that are not related to any lesions detectable in clinical—and probably genetic—exams. They respond well to currently available drug-based treatment options, sometimes even going into spontaneous remission. These forms of epilepsy were previously considered relatively benign, but not anymore. “The study supports recent observations that common types of epilepsy cannot always be considered benign. Even when seizures are under control, there are still consequences for the brain,” says the researcher.
Cendes explains that the volume of cases examined makes the study highly important given the subtlety of the brain alterations analyzed, which can be as small as a few millimeters. “The alterations we see are very small—some are undetectable in clinical exams. The measurements are thus susceptible to biases and errors. The large quantity of data analyzed dilutes the error rate, making the results more robust and reliable. Several similar studies have already been conducted, but the sample size was too small to provide conclusive answers like we are getting now,” says the researcher.
According to neurologist Laura Ferreira Guilhoto, from the Epilepsy Research and Treatment Unit at the Federal University of São Paulo (UNIFESP), the study corroborates the idea that we should always try to find an identifiable cause for this type of brain disorder, especially in patients who do not respond to conventional drug treatments. “In cases where the disease is more difficult to control, MRI scans can even identify a lesion responsible for the seizures that can be removed through surgery,” says the physician, who did not participate in the research.
Data from all the research centers participating in the study was pooled and analyzed by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) consortium, a collaborative research network based at the University of Southern California (USC). As the name implies, ENIGMA studied the data using meta-analysis, a statistical method that analyzes and integrates the results of numerous independent studies.
Formed in 2009 by USC neuroscientist Paul Thompson and geneticist Nick Martin, from the Queensland Institute of Medical Research, Australia, ENIGMA is the world’s largest neuroimaging project, bringing together 900 scientists from 35 countries, specializing in 18 different brain diseases. In 2015, the group opened a specific line of research on epilepsy, and the first results were released the following year. “The article in Brain is the first publication resulting from this joint effort,” says Cendes. He explains that the speed with which the consortium has been able to present its conclusions is due to its research methods: “Each group works in its own research center, and instead of sending raw data, submits the results that the data generates, which then undergo statistical analyses.”
Brazil has been working with the ENIGMA-Epilepsy project since the beginning. According to Clarissa Lin Yasuda, a professor at the Neurology Department of the UNICAMP School of Medical Sciences and a participant in the study, the Brazilian group submitted the largest sample. “We analyzed about 700 individuals, including epilepsy patients and healthy people, whose MRI scans were stored in our database from various other projects conducted since 2010. We probably have one of the largest neuroimaging databases in the world,” says the researcher. It took a team of six neurologists and one computer engineer about 10 months to organize and process all the information.
According to Yasuda, another ENIGMA project is already underway with the aim of identifying more details on the different types of epilepsy and confirming the relationship between cerebral atrophy and certain parameters, such as length of time a patient has had the disease, and frequency of seizures. “New results could be released later this year.”
Brazilian Institute of Neuroscience and Neurotechnology (BRAINN) (No. 13/07559-3); Grant Mechanism Research, Innovation, and Dissemination Centers (RIDC); Principal Investigator Fernando Cendes (UNICAMP); Investment R$20,735,974.24 (for the entire project).
WHELAN, C. D. Structural brain abnormalities in the common epilepsies assessed in a worldwide Enigma study. Brain. Vol. 141, no. 2, pp. 391–408. Jan. 30, 2018.