Cerebellar atrophy in epilepsy patients is linked to the disease, not to medication use, says study

Discovery contributes to advances in understanding of the disorder; study is one of the most comprehensive on the subject, with samples from 1,600 patients, including Brazilians.

By Luciana Constantino  |  Agência FAPESP – An international study with the participation of Brazilian scientists shows that cerebellar atrophy in patients with epilepsy is linked to the disease, that is, it is a characteristic that could open up new avenues of study. Until now, it was believed that the reduction in the volume of this region, which is responsible for balance and motor coordination, was directly related to the use of a type of anticonvulsant drug (phenytoin).

The study analyzed data from 1,602 patients from 22 countries, including 209 Brazilians, and another 1,022 controls (382 from Brazil). It is believed to be the largest quantitative analysis of the structures (morphometry) of the cerebellum in epilepsy – including size, shape and volume.

It was concluded that all types of the disease – focal and generalized – showed “significant” reductions in cerebellar volume, especially in the posterior lobe, compared to controls. The smaller volume in the posterior lobe regions was also associated with a longer duration of epilepsy. For the researchers, the results raise important questions about the potential vulnerability of different cerebellar subregions in the causes, consequences, and clinical expression of specific features of the disease.

The study was carried out by the Enigma Consortium, with the participation of the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), a FAPESP Research, Innovation and Dissemination Center (RIDC) based at the State University of Campinas (UNICAMP). It was published in the scientific journal Epilepsia, considered the most important in the field.

The consortium is an international network that brings together scientists in imaging genomics, neurology and psychiatry to understand the structure and function of the brain based on magnetic resonance imaging, genetic data and other patient information. In addition to epilepsy, the consortium is investigating several neuropsychiatric diseases, including Parkinson’s, Alzheimer’s, autism, schizophrenia and others.

“There are still many things we don’t know about epilepsy. Just as we were unclear about the extent to which cerebellar atrophy was linked to the disease. With this work, we’ve made progress in understanding that epilepsy has an impact not only on the brain but on other regions as well. It’s a network disease. Now we need to start thinking about the cerebellum as part of our understanding of the disorder,” Clarissa Lin Yasuda, professor at UNICAMP’s School of Medical Sciences and member of BRAINN, explained to Agência FAPESP.

Yasuda co-authored the article with neurologist Fernando Cendes, the researcher in charge of BRAINN, and Ítalo Karmann Aventurato, who is currently doing a sandwich doctorate at King’s College London (United Kingdom) with the support of FAPESP.

“The association between volume reduction in the posterior cerebellar region and disease duration demonstrates a more widespread and potentially progressive neurodegeneration in all forms of epilepsy. These findings support the inclusion of subregional cerebellar damage in the neurobiology of epilepsies and have implications for the treatment and clinical management of these patients,” says Cendes.

In April, the International League Against Epilepsy (ILAE) announced that Cendes had been selected as the new editor-in-chief of the journal Epilepsia. It is the first time that a researcher from outside the United States and Europe has been chosen for the position, which he assumed in September.

The disease

The result of a combination of genetic and environmental factors, and with no cure, epilepsy is a neurological condition in which a part of the brain sends incorrect signals for seconds or minutes at a time, causing seizures that can manifest as convulsions – a type of generalized epileptic seizure – or other types of seizures, focal or generalized.

Patients with the most severe cases experience up to 40 or 50 seizures a day, with loss of consciousness and falls. Uncontrolled seizures not only disrupt the patient’s daily life but also pose a serious risk of sudden and premature death.

There are an estimated 2 million Brazilians with epilepsy, at least 25% of whom are uncontrolled, according to the Ministry of Health. Worldwide, the World Health Organization (WHO) estimates that 70 million people are affected by the disorder, a third of whom are resistant to the treatments available on the market, which consist of a combination of drugs that are not always effective.

Most available medications reduce the activity of neurons across the board, controlling seizures, but cause side effects. In some cases of focal epilepsy, an alternative is surgery to remove the part of the brain that causes the seizures.

Last year, a study published in the journal Nature Genetics revealed a kind of “genetic architecture” of the disease, showing specific alterations in DNA that signal a greater risk of the brain disorder and advancing the possibility of new treatments. BRAINN researchers also participated in the study (read more at: agencia.fapesp.br/51140).

“The South American population, especially Brazil, with its large racial mix, has always been underrepresented in international studies of this kind. Our participation, with the large quantity, richness and robustness of the data we offer, is extremely important for Brazilian science. Few centers in the world have the quantity and quality of information that we’ve obtained here,” emphasizes Yasuda.

Methodology

The scientists worked with magnetic resonance images of the patients and statistical analyses of cerebellar volume. Linear regression models were used to test associations between cerebellar volume and epilepsy duration.

Indicators were also used to investigate the association between phenytoin treatment and organ size. The study showed that although phenytoin is associated with cerebellar atrophy, it does not explain the reduction in size that occurs in all regions of the cerebellum in these patients. Therefore, part of the cerebellar atrophy process is independent of the drug and related to the disease.

The Brazilian group also received support from FAPESP through three other projects (20/04032-8; 19/11457-8; and 21/09230-5).

The article “Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study” can be read at onlinelibrary.wiley.com/doi/full/10.1111/epi.17881#.