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Purpose: Prenatal and perinatal adverse events are reported to have a pathogenetic role in focal cortical dysplasia (FCD). However, no data are available regarding the prevalence and significance of this association. A cohort of children with significant prenatal and perinatal brain injury and histologically proven mild malformations of cortical development (mMCD) or FCD was analyzed.
Methods: We retrospectively evaluated a surgical series of 200 patients with histologically confirmed mMCD/FCD. Combined historical and radiologic inclusion criteria were used to identify patients with prenatal and perinatal risk factors. Electroclinical, imaging, neuropsychological, surgical, histopathologic, and seizure outcome data were reviewed.
Results: Prenatal and perinatal insults including severe prematurity, asphyxia, bleeding, hydrocephalus, and stroke occurred in 12.5% of children with mMCD/FCD (n = 25). Their epilepsy was characterized by early seizure onset, high seizure frequency, and absence of seizure control. Patients with significant prenatal and perinatal risk factors had more abnormal neurologic findings, lower intelligence quotient (IQ) scores, and slower background EEG activity than mMCD/FCD subjects without prenatal or perinatal brain injury. MRI evidence of cortical malformations was identified in 74% of patients. Most patients underwent large multilobar resections or hemispherectomies; 54% were seizure-free 2 years after surgery. Histologically “milder” forms of cortical malformations (mMCD and FCD type I) were observed most commonly in our series.
Conclusions: Surgically remediable low-grade cortical malformations may occur in children with significant prenatally and perinatally acquired encephalopathies and play an important role in the pathogenesis of their epilepsy. Presurgical detection of dysplastic cortex has important practical consequences for surgical planning.
Focal cortical dysplasia (FCD) and mild malformation of cortical development (mMCD) are common causes of focal intractable epilepsy, cognitive disability, and other neurologic disorders. mMCD and FCD are frequent etiologies in pediatric and adult epilepsy surgery series (Harvey et al., 2008; Lerner et al., 2009; Blümcke et al., 2009).
Previous studies analyzed prenatal and perinatal factors in various MCDs including lissencephaly, polymicrogyria, hemimegalencephaly, and nodular heterotopia (Palmini et al., 1994; Raymond et al., 1995; Montenegro et al., 2002, 2005). Other studies focused only on the relationship of histopathology to etiopathogenetic factors (Marin-Padilla, 1996, 1997, 1999, 2000). To our knowledge, there has been no systematic study of the clinical features of patients with mMCD/FCD and associated prenatally and perinatally acquired encephalopathies.
The present study aims to analyze a cohort of children with significant prenatal and perinatal insults and histologically proven mMCD/FCD. We sought to identify distinctive characteristics of epileptic and neurologic syndromes in these patients in order to achieve earlier diagnosis and enhance surgical management.
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Our study, conducted on the largest population of pediatric patients with histologically proven mMCD/FCD, demonstrated a frequent association with significant prenatal and perinatal risk factors. We further showed that children with acquired prenatal or perinatal brain lesions associated with cortical malformations benefit from epilepsy surgery. The size of the dataset, all collected at one institution, facilitated the identification of distinct clinical features that may assist the surgical management of these patients.
There is consensus that the pathogenesis of mMCD/FCD involves events taking place during human corticoneurogenesis. The development of the human cerebral cortex can be divided into three overlapping stages: (1) proliferation of stem cells into neuroblasts or glial cells; (2) migration from the periventricular germinal matrix to the developing cortex; (3) cortical organization of the six-layer neocortex associated with synaptogenesis and apoptosis (Raymond et al., 1995; Barkovich et al., 1996, 2005). Regarding the timing of these events, the proliferative stage is believed to range from the 5th or 6th until the 16th or 20th gestational week, migration from the 6th or 7th until the 20th or 24th gestational week, and organization from the 16th until approximately the 24th gestational week (Rakic, 2000). However, there is growing evidence that some migration and organization may occur during the third trimester of pregnancy (Cepeda et al., 2006).
It is a matter of ongoing debate as to when developmental alterations accounting for individual types of MCD might occur. Although previous studies assumed these events take place before the 24th week of intrauterine life (Barkovich et al., 1996; Rakic, 2000), recent observations suggest that much later insults may be important. It was proposed that the presence of abnormal cell types in dysplastic tissue could be explained by the failure of prenatal cell degeneration before birth. According to this hypothesis, histologically severe types of FCD such as type II are caused by alterations in the late second or early third trimester, whereas events occurring closer to birth account for milder forms of cortical malformations such as FCD type I and mMCD (Cepeda et al., 2006). A recent report described neuropathologic changes typical for FCD in two infants who survived a severe brain injury (shaken baby syndrome) shortly after birth (Marin-Padilla et al., 2002). These observations lend support to the hypothesis that besides prenatal insults, perinatal insults may also play a causal role in the pathogenesis of mMCD/FCD.
The migration of neuroblasts to their final destination and their organization within the cortical mantle may be disturbed by different genetic and environmental factors. The latter are more frequently suspected in mMCD/FCD, since there is no description of familial cases of these malformations, except for those associated with specific syndromes, such as tuberous sclerosis complex. Observations from experimental models and anecdotal reports suggest the possible importance of several candidate extraneous insults such as toxins (Baraban & Schwartzkroin, 1995), intrauterine infections (Iannetti et al., 1998), and ionizing radiation (Marin-Padilla et al., 2003).
In the clinical setting, the relevance in the pregnancy history of events potentially harmful to the ultimate cortical malformation remains speculative. Prenatal and perinatal risk factors were identified in a series of 40 patients with different types of MCD (22 had FCD). Potentially harmful prenatal environmental events were reported in 58% of cases; however, they included questionable factors such as maternal bicornuate uterus, ingestion of laxative during the first trimester, or maternal hyperglycemia during pregnancy. The significance of the insults was not verified by MRI or histologic findings (Palmini et al., 1994). Other reports of patients with cortical malformations found the following incidence of prenatal and perinatal risk factors: 32% in MCD (Raymond et al., 1995), 29% in FCD (Widdess-Walsh et al., 2005), and 10% in FCD (Krsek et al., 2009a). Adverse events were reported less frequently in the histories of patients with FCD than in those with other types of MCD (Montenegro et al., 2002). However, the types of insults were usually not specified.
We verified the significance of prenatal and perinatal insults using strictly combined clinical and radiologic criteria and verified the diagnosis of mMCD/FCD by direct histopathologic confirmation. Hypoxic–ischemic and hemorrhagic brain lesions were frequently associated with shunted hydrocephalus in our patients. The impact of these insults on cortical development was neuropathologically studied in children who survived perinatally acquired encephalopathies (Marin-Padilla, 1996, 1997, 1999). It was demonstrated that intrauterine insults could produce cytoarchitectural alterations of the developing neocortex that eventually give rise to neuropathologic findings compatible with “acquired” cortical dysplasia. These postinjury alterations represent dynamic processes that begin after the brain injury and continue to evolve over weeks, months, or even years after the original insult. It was also suggested that if a child eventually develops epilepsy, further secondary alterations might be caused by the seizures themselves (Marin-Padilla, 2000).
A second possible explanation for the association between cortical malformations and prenatal and perinatal risk factors is that MCD itself predisposes to perinatal distress. Montenegro et al. (2005) reported that patients with cortical malformations frequently experience intrapartum complications. It was hypothesized that MCD could predispose to decreased fetal movements due to preexisting neurologic impairment during pregnancy that in turn predispose to intrapartum complications. However, their series included mostly severe types of MCD such as lissencephaly, schizencephaly, and polymicrogyria. The majority of mMCD/FCD cases have an uncomplicated birth, normal neurologic findings, and normal early psychomotor development (Widdess-Walsh et al., 2005; Krsek et al., 2008; Lerner et al., 2009). In our series, prenatal and perinatal adverse events were significantly associated with histopathologically “milder” forms of cortical malformation (mMCD and FCD type I) than FCD type II, in accord with our previous observations (Krsek et al., 2009a). Findings of FCD type II in the setting of severe prenatal and perinatal brain damage are anecdotal (Wyllie et al., 1996; Kremer et al., 2002). We suggest that our results support the above-mentioned hypothesis that mMCD/FCD might be caused by the third trimester and perinatal adverse events. Notwithstanding, the possibility that the presence of some mMCD/FCD predisposes to perinatal distress cannot be excluded.
In addition to the high frequency of abnormal neurologic findings and mental retardation, clinical syndromes in our series were characterized by severe pharmacoresistant epilepsy with very early seizure onset, high seizure frequency, and absence of long periods of seizure control. We proved that children with significant prenatal and perinatal risk factors exhibited a higher frequency of abnormal neurologic findings, lower IQ scores, and higher incidence of slow EEG background activity compared to patients with mMCD/FCD without known prenatal and perinatal brain injury. These observations could be explained by the presence of widespread cortical and subcortical brain injury. However, our patients had the same epilepsy syndrome characteristics as control subjects. These results might suggest that cortical malformations represent the pathologic substrate of epilepsy that is independent of prenatally and perinatally acquired encephalopathy.
The incidence of epilepsy in patients with cerebral palsy has been reported to range from 15–41.8% (Steffenburg et al., 1995; Hadjipanayis et al., 1997). Seizures could be controlled by antiepileptic drugs in approximately 60% of cases (Singhi et al., 2003), but catastrophic drug-resistant cases referred for epilepsy surgery are well recognized (Battaglia et al., 2005; Guzzetta et al., 2006; Oguni et al., 2008). There are only a few anecdotal reports attributing the pathogenesis of drug-resistant epilepsy in these children to cortical malformations, and these are usually different from mMCD/FCD: polymicrogyria (Bordarier & Robain, 1992), focal pachygyria (Watanabe et al., 1990), and neuronal heterotopias (Reutens et al., 1993). Our results suggest that mMCD/FCD could play an important role in the genesis of epilepsy in children with acquired neonatal encephalopathies. Prospective studies including comparisons with a control group of subjects with perinatally acquired encephalopathy without associated cortical malformation should provide further information about the role of mMCD/FCD in the pathogenesis of epilepsy and neurologic deficits in these children.
The preoperative identification of mMCD/FCD in children with significant prenatally or perinatally acquired brain damage is highly challenging. Retrospective MRI review in our population consistently revealed lobar atrophy, blurring of the gray–white matter junction, increased signal intensities on T2W and FLAIR sequences, predominating in the white matter always ipsilateral to the resection site. Although nonspecific, these radiologic findings are suggestive of cortical malformations (Palmini et al., 2004; Widdess-Walsh et al., 2006). They were recently recognized as distinctive radiologic features of mMCD and FCD type I (Krsek et al., 2008, 2009a; Colombo et al., 2009), and are consistent with our pathologic results. However, similar radiologic findings in the absence of histopathologic examination could be interpreted as a consequence of ischemic insults. We speculate that since the MRI features of cortical malformations could easily be overlooked or misinterpreted in these patients, the true incidence of mMCD/FCD in children with acquired neonatal encephalopathies might be considerably underestimated.
Our observation that cortical malformations associate with severe prenatal and perinatal brain injury has practical consequences for surgical planning. The dysplastic cortex is likely to be at least a part of the epileptogenic zone and its complete resection critical for obtaining a seizure-free outcome (Paolicchi et al., 2000; Krsek et al., 2009b; Lerner et al., 2009). Presurgical delineation of associated cortical malformations in patients with prenatally and perinatally acquired brain lesions may, therefore, considerably influence the type and extent of the resection. Because MRI detection of the dysplastic cortex is not always possible, we suggest that intracranial EEG (either intraoperative electrocorticography or chronically implanted intracranial electrodes) may be required to assess the extent of dysplastic cortical areas. In our series, all cases except for two hemispherectomy cases had at least intraoperative electrocorticography, and 10 subjects underwent chronic invasive monitoring using implanted subdural electrodes. The standard criteria for evaluating intracranial EEG data were used (Jayakar et al., 1994; Krsek et al., 2009b). Although mMCD/FCD was detected retrospectively in the majority of our subjects, use of a definition of completeness of surgery based on careful evaluation of both MRI and intracranial EEG data enabled us to achieve seizure freedom in 54% of the patients.
Our patients underwent larger resections than subjects with isolated mMCD/FCD, but the ultimate postoperative seizure outcome of both groups was comparable. This result lends support to indications for epilepsy surgery in children with cortical malformations in the setting of severe prenatal and perinatal brain injury. Further studies are necessary to optimize diagnostic and surgical approaches in these subjects. We hope our observation might promote an interest in the association between prenatally and perinatally acquired brain lesions and cortical malformations as well as initiate multicenter cooperation that could ultimately improve prognosis of individual patients.