Focal cortical dysplasia (FCD) represents a heterogeneous group of morphological changes in the brain tissue that can predispose the development of pharmacoresistant epilepsy (recurring, unprovoked seizures which cannot be managed with medications). This group of neurological disorders affects not only the cerebral cortex but also the subjacent white matter. This work reviews the literature describing the morphological substrate of pharmacoresistant epilepsy. All illustrations presented in this study are obtained from brain biopsies from refractory epilepsy patients investigated by the authors. Regarding classification, there are three main FCD types, all of which involve cortical dyslamination. The 2022 revision of the International League Against Epilepsy (ILAE) FCD classification includes new histologically defined pathological entities: mild malformation of cortical development (mMCD), mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy (MOGHE), and \"no FCD on histopathology\". Although the pathomorphological characteristics of the various forms of focal cortical dysplasias are well known, their aetiologic and pathogenetic features remain elusive. The identification of genetic variants in FCD opens an avenue for novel treatment strategies, which are of particular utility in cases where total resection of the epileptogenic area is impossible.

OBJECTIVE: The observation of mild malformation of cortical development (mMCD) has yet to have a major clinical impact due to the lack of clinical and research data. We characterized the clinical features, surgical outcomes, and postoperative seizure control patterns in pediatric patients with mMCD.
METHODS: We examined 40 patients with isolated mMCD who underwent resective surgery during a 10-year period.
RESULTS: The median age at seizure onset was 1.2 years, and the median age at surgery was 7.9 years. Twenty-seven patients (67.5%) presented with childhood-onset epileptic encephalopathy (21 Lennox-Gastaut syndrome, 6 West syndrome), and 13 patients (32.5%) presented with intractable focal epilepsy (10 extratemporal lesions, 3 temporal lesions). Twenty-one patients (52.5%) showed \"suspected focal cortical malformation\" on MRI, whereas 16 patients (40.0%) and 3 patients (7.5%) showed normal MRI findings or mild brain atrophy, respectively. The most common surgical procedures were two lobar resections (18 patients, 45.0%), followed by unilobar resections (12 patients, 30.0%) and resections exceeding two lobar boundaries (10 patients, 25.0%). As a final surgical outcome, 24 patients (60.0%) were ILAE Class 1-3. Discontinuation of all AEDs was possible for 36.8% of ILAE Class 1 patients. Regarding the seizure control pattern, fluctuating seizure control was observed most frequently (21 patients, 52.5%).
CONCLUSIONS: Our results suggest that mMCD is an important pathological finding in children related to a significant degree of epileptogenicity, and resective surgery can have positive outcomes. However, these patients showed unstable postoperative seizure control patterns with a high rate of late recurrence, suggesting difficulties in the surgical treatment of intractable epilepsy.

Recent studies suggested a possible association between malformations of cortical development and microvascular density. In this study we aimed to further elucidate the relation between microvascular density and cortical developmental abnormalities in a cohort of 97 patients with epilepsy and histologically proven mild malformation of cortical development (mMCD), focal cortical dysplasia (FCD) or tuberous sclerosis complex (TSC). Surgical tissue samples were analyzed with quantitative measures of vessel density, T-cell response, microglial activation and myelin content. Subsequently, the results were compared to an age- and localization matched control group. We observed an increase in microvasculature in white matter of TSC cortical tubers, which is linked to inflammatory response. No increase was seen in mMCD or FCD subtypes compared to controls. In mMCD/FCD and tubers, lesional cortex and white matter showed increased vascular density compared to perilesional tissues. Moreover, cortical vessel density increased with longer epilepsy duration and older age at surgery while in controls it decreased with age. Our findings suggest for that the increase in white matter vascular density might be pathology-specific rather than a consequence of ongoing epileptic activity. Increased cortical vessel density with age and with longer epilepsy duration in mMCD/FCD\'s and tubers, however, could be a consequence of seizures.

Mild malformation of cortical development (mMCD) and focal cortical dysplasia (FCD) subtypes combined are by far the most common histological diagnoses in children who undergo surgery as treatment for refractory epilepsy. In patients with refractory epilepsy, a substantial burden of disease is due to cognitive impairment. We studied intelligence quotient (IQ) or developmental quotient (DQ) values and their change after epilepsy surgery in a consecutive series of 42 children (median age at surgery: 4.5, range: 0-17.0 years) with refractory epilepsy due to mMCD/FCD. Cognitive impairment, defined as IQ/DQ below 70, was present in 51% prior to surgery. Cognitive impairment was associated with earlier onset of epilepsy, longer epilepsy duration, and FCD type I histology. Clinically relevant improvement of ≥10 IQ/DQ points was found in 24% of children and was related to the presence of presurgical epileptic encephalopathy (EE). At time of postsurgical cognitive testing, 59% of children were completely seizure-free (Engel 1A). We found no association between cognitive outcome and seizure or medication status at two years of follow-up. Epilepsy surgery in children with mMCD or FCD not only is likely to result in complete and continuous seizure freedom, but also improves cognitive function in many.