ARTICLE IN BRIEF

REPRESENTATIVE HISTOLOGICAL FEATURES in surgical sample from a patient with type IIb focal cortical dysplasia. (A) Neuronal nuclei (NeuN) immunoreactivity. (B) Neurofilaments SMI (C) Glial fibrillary acidic protein (GFAP) The core of the lesion (L), localized at the bottom of the cortical sulcus, is characterized by the total disruption of the cortical lamination and reduced neuronal density (A, D), by the presence of numerous dysmorphic neurons (B, E, arrows and inset), and by intense gliosis (C). In the perilesional area (P), scattered and isolated DNs (F, G, arrows and inset) were visible. (H).

Seizure activity alone does not promote the expression of brain injury biomarkers, at least in type II focal cortical dysplasia (FCD II) or cryptogenic disease, researchers reported. The findings dispel the long-held belief that recurrent focal seizure activity, over time, can damage tissue away from the primary site.

An analysis of brain tissue from patients with recurrent seizures due to type II focal cortical dysplasia or cryptogenic disease found no sign of cell loss, gliosis, or inflammation — all biomarkers indicative of brain damage.

The findings appear to dispel the long-held belief that recurrent focal seizure activity, over time, can damage tissue away from the primary site.

“Despite thousands of focal seizures over a lifetime, cortical areas involved in seizure generation showed no abnormal structural changes,” said Rita Garbelli, PhD, a researcher with the division of clinical epileptology and neurology at the Carlo Besta Neurological Institute in Milan, Italy.

Dr. Garbelli and her colleagues evaluated expression of brain injury biomarkers in 20 patients with a history of frequent seizures and drug-resistant focal epilepsy. None of the biomarkers revealed abnormal tissue changes, according to the retrospective study, which was published in the August 30 issue of Annals of Neurology.

“The public and a large majority of neurologists, and even epileptologists, believe that seizures damage the brain, despite the fact that there is no scientific evidence that they cause structural changes in brain matter,” she told Neurology Today.

The findings suggest that seizure activity alone does not promote the expression of brain injury biomarkers, at least in the type II focal cortical dysplasia (FCD II) or cryptogenic disease, she noted.

The knowledge that seizures do not alter the structure of the brain in this specific form of epilepsy, and maybe others, may reduce patient concerns associated with seizures, especially for patients with a long history of recurrent seizures, Dr. Garbelli said.

About 30 percent of epilepsy patients do not respond to pharmacological therapy, and 30 percent of these can be candidates for surgery, she explained. A favorable seizure outcome strictly depends on the exact localization and removal of the epileptogenic brain area.

“In patients who are seizure-free after surgery, antiepileptic drugs can be gradually withdrawn, with important implications for the social life, quality of life and productivity, and for the costs charged to the health care system,” she noted.

STUDY METHODS, RESULTS

The researchers examined tissue samples collected from the patients during surgical resection for drug-resistant epilepsy. Among the patients, 16 had FCD-II, including 11 with type IIb and five with type IIa disease, with disrupted cortical lamination, dysmorphic neurons, and balloon cells. The other four subjects had cryptogenic epilepsy with no signs of structural lesions.

There were no signs of structural lesions on imaging or by neuropathological investigation.

The mean age of seizure onset in the FCD-II patients ranged between one and 34 years, and the frequency of seizures at the time of surgery ranged from one to 300 per month (with a mean of 80 ± 94 per month). Duration of disease ranged from one to 40 years (mean 18 ± 14 years). For cryptogenic patients, the mean onset age ranged from eight to 39 years, with seizure frequency ranging from of two to five per month (mean 4 ± 1), and average epilepsy duration of four to 28 years (mean 17 ± 10).

Using immunohistochemical analysis, the investigators looked for signs of damage in expression patterns of glial, neuronal, and inflammatory molecules in the core of the lesion, at the FCD boundary, and in the adjacent area. While they found signs of astroglial and microglial activation, as well as reduced neuronal density, perivascular CD3-positive T-lymphocyte clustering, and fibrinogen extravasation, in the core of FCD-II lesions, no pathological immunoreactivity was found anywhere outside the core or in any of the cryptogenic specimens.

The findings do not contradict substantial evidence that seizures can produce structural changes in the limbic system, nor do they exclude the possibility that seizures may induce functional changes, but these are not associated with the standard neuropathological changes typically associated with brain injury, Dr. Garbelli told Neurology Today.

“In cryptogenic cases it is obvious that a functional alteration not associated with the analyzed damage biomarkers must be present in the epileptogenic zone. Countless possible abnormalities could be involved in this malfunction, and whether these are secondary to seizure activity is not defined.”

Additional research is needed to identify the pathogenic elements that generate seizures in such patients and in nonlesional epileptogenic zones, said Dr. Garbelli, as well as subtler morphological alterations or functional alterations.

“This and other research on the correlation between invasive recordings and neuropathological evaluation strongly suggest that the cortical tissue around the FCD lesional core is locally recruited in the generation of seizure activity.”

Markers of tissue damage, including neuronal paucity, extended gliosis, presence of inflammatory molecules/cells, and protein extravasation, were all detectable in the lesional FCD area, particularly in the FCD-IIb subtype. However, these were not seen in adjacent perilesional/nonlesional areas or in cryptogenic tissue. “This suggests that injury biomarker expression is an intrinsic feature of the focal cortical malformation and is not triggered by chronic seizure activity per se.”

EXPERT COMMENTARY

Jeffrey L. Noebels, MD, PhD, professor of neurology, neuroscience, and molecular and human genetics, and vice chair for neurological research at Baylor College of Medicine in Houston, TX, told Neurology Today that the findings are in stark contrast to the widely known and profoundly brain-damaging effects of prolonged generalized status epilepticus.

“It is surprisingly unclear whether brief, intermittent focal neocortical seizures arising from a small patch of developmentally disorganized neurons induce further local neuronal damage beyond the irritated discharge zone, and should therefore be considered actively ‘epileptogenic,’” he told Neurology Today.

Local expansion of these pharmacologically-resistant lesions could aggravate the course of the disorder, necessitating their earliest possible removal, he noted.

“The authors present a convincing analysis. These welcome and seminal findings may reassure epileptologists and their patients during the systematic and sometimes lengthy search for effective management of these cases. However, as the authors point out, the results cannot be extrapolated to other brain regions or seizures of alternate origins.”

Excitotoxic and inflammatory damage to neighboring neurons and synapses can both create, and arise from, a wide biological spectrum of microcircuit and microvascular dysfunction, including some of genetic origin, he noted.

“Some functional pathology may be visible only through the oscilloscope, not the microscope. A similar analysis of many other types of epileptic foci will be needed to better understand how, where, and when cell death is promoted by excessive discharge activity in neocortical circuitry. In FCD-ll lesions, the pathology drives the EEG, and not the other way around.”

Selim R. Benbadis, MD, FAAN, professor and director of the Comprehensive Epilepsy Program at the University of South Florida and Tampa General Hospital, told Neurology Today he also welcomed the findings.

“Patients always ask about this, so it is very helpful to have data like these. I usually tell them that it depends, but that partial seizures do not cause irreversible damage,” he told Neurology Today, adding that he suspects the findings are probably true for all focal epilepsies.