22 Surgical Approaches in Cortical Dysplasia
Cortical dysplasias are malformations of cortical development initially identified as a pathological substrate in individuals with intractable epilepsy by Taylor and colleagues in 1971.1 They are characterized by a disruption of the normal lamination of the cortex that can vary in severity, ranging from mild disruption of lamination and normal-appearing neurons to significant loss of laminar organization with neuronal clustering, dysmorphic abnormally oriented neurons, cytomegalic neurons, and balloon cells2–4 (see Figs. 22.1, showing a lesion at the base of a right frontal sulcus, and 22.2, showing left occipital cortical dysplasia). In addition, there is gliosis of the white matter with heterotopic neurons.2–4 Cortical dysplasias are reported as the most common underlying pathology in children undergoing surgical resection for medically resistant partial epilepsy.5,6 Advances in structural neuroimaging and the increased use of multimodal imaging have improved the ability to recognize cortical dysplasia resulting in the development of classification systems and increased interest in the epileptogenic mechanisms of these lesions.3,5–9 Despite these advances, long-term surgical outcomes remain poor, with significant challenges regarding the localization of the epileptogenic zone and the extent of the surgical margin allowing for a complete resection.10–13
Epidemiology of Cortical Dysplasia in Intractable Epilepsy
The clinical presentation of cortical dysplasias is variable and depends on the function of the involved region. Children may exhibit epilepsy, developmental delay, and, often, motor impairment. Epilepsy is usually chronic and consists of partial or generalized seizures, depending on the lesion. Not all individuals with cortical dysplasias will have seizures, and their response to antiepileptic medications is variable.
The Pediatric Epilepsy Surgery Subcommission of the International League Against Epilepsy conducted a survey of 20 programs in the United States, Europe, and Australia. The study found that in 42% of children undergoing surgical resection, the pathological diagnosis was cortical dysplasia, representing the most common underlying etiology in this cohort.14 This diagnosis was more common in younger children and in those with extratemporal or multilobar seizures.14 These findings are similar to those previously reported in the literature.6,15,16
Classification of Cortical Dysplasia
Advances in neuroimaging, improved understanding of pathogenetic mechanisms, the development of animal models, descriptions of clinical–electrographic correlations, and the delineation of surgical strategies have resulted in the proposal classification schemes.
In 1996, a classification system was proposed for malformations of cortical development based on the timing at which the developmental process was disturbed.17 In 2001, this classification was revised as a result of increased knowledge of biologic mechanisms and the discovery of new malformations.18 A subsequent revision was undertaken in 2005, with revision made predominantly related to advances in genetics and neuroimaging.19 In this classification, cortical dysplasias are categorized as malformations of cortical development associated with abnormal neuronal and glial proliferation or apoptosis and as malformations caused by abnormal late neuronal migration and cortical organization, depending on the timing in development. This classification, however, does not focus on focal cortical dysplasias increasingly recognized in individuals with medically resistant epilepsy undergoing surgical resection.
In 2004, Palmini and colleagues suggested that cortical dysplasias should be applied only to the subtype of malformations of cortical development in which the abnormality was, for the most part, intracortical.3 They proposed a detailed classification system for focal cortical dysplasia using predominantly histopathological features. This classification is outlined in Table 22.1 .
Why Do Malformations of Cortical Development Cause Epilepsy?
Studies on the epileptogenesis of cortical dysplasia have been performed both on resected human tissue and in animal models. Animal models of cortical dysplasia include in utero manipulation (methylazoxymethanol [MAM] injection, γ irradiation), manipulations in the newborn (ibotenate cortical injection, cortical freeze lesions), spontaneously epileptic animals with cortical malformations (Ihara’s genetically epileptic rat, telencephalic internal structure heterotopia [TISH] rat) and knockouts (PAFAH β subunit knockouts, tuberous sclerosis complex 2 knockouts). Although these models may help in determining why dysplastic cortex is hyperexcitable, it is less clear how well they can be related to the human condition, because phenotypes in animal models are often much milder and many, although showing enhanced sensitivity to seizure-inducing agents, are not associated with spontaneous seizures.
Abnormal cells or abnormal neuronal circuitry may explain the epileptogenicity in cortical dysplasia. In general, more focal malformations of cortical developments (MCDs) often have abnormal cells that may act as pacemakers of epileptiform discharges.20 By contrast, more diffuse MCDs have normal-appearing cells but abnormal connectivity of the cellular aggregate.20
Abnormal Neurons
Epileptiform discharge in a large group of neurons can be triggered by a small group of abnormal cells that generate bursting behavior. The most dramatic examples of abnormal neurons in cortical dysplasia are the balloon cell, which stains positively for markers of both neurons and glia, and has multiple dendritic trees that show little orientation specificity, and the giant cell, which is often found together with balloon cells in Taylor-type focal dysplasia.
These neurons have been known to display intrinsic hyperexcitability,21 possibly because of modification of N-methyl-D-aspartate (NMDA) receptors predisposing to hyperexcitability. NR1 and NR2 are the two subunits of the NMDA receptor. In vitro studies have shown that NR2 alone is nonfunctional, whereas NR1 alone produces only weak currents to glutamate. Heteromeric co-assembly of NR1 and NR2 subunits, however, leads to marked increases in the NMDA channel current.22 In studies on human surgical specimens, Ying et al noted that dysplastic neurons have increased NMDA receptor subunits NR1 and NR2A/B.23 Furthermore, in human epileptic focal cortical dysplasia, NR1 co-assembled with NR2,24 and NR1-NR2A/B were co-expressed in single dysplastic neurons,25 leading to neurons that are hyperexcitable to glutamate.
MAM-treated rats showed an increased number of bursting neurons in regions of heterotopia and dysplastic cortex,26 which supports the concept that epileptogenesis may result from a few abnormal cells. Evidence of decreased binding to γ-aminobutyric acid (GABA) receptors using autoradiography27 and decreased sensitivity of GABAA receptors to zolpidem, a benzodiazepine agonist,28 in the freeze lesion cortical dysplasia model, also suggests a role for decreased inhibition in dysplasia.
Altered Synaptic Connectivity
Cortical dysplasias are associated with reorganization of cortical circuitry. Abnormal connectivity has been best studied in the freeze lesion model of cortical dysplasia. In this model, the epileptogenic zone is actually adjacent to the microgyrus of the lesion, and the cells in this adjacent region appear normal.
Jacobs and Prince have shown that the pyramidal neurons adjacent to the dysplastic microgyrus receive more excitatory input, perhaps because of hyperinnervation by excitatory cortical afferents that were originally destined for the mi-crogyrus.29 Furthermore, axons that would normally project out of the epileptic zone may also be interrupted and instead make excitatory synapses locally. In addition, in the MAM model of cortical dysplasia, aberrant connections have been shown between the heterotopic cell regions and other, more distant brain regions, facilitating spread of abnormal epileptiform activity.30 Decreased numbers of inhibitory neurons have also been noted in and around dysplastic lesions, which would contribute to the overall hyperexcitability.31,32
Do Uncontrolled Seizures Worsen Long-Term Outcome in Children with Cortical Dysplasias?
Single electroencephalography (EEG) discharges have been shown to cause transient cognitive impairment.33,34 If single spikes can cause cognitive impairment, frequent multifocal discharges might be expected to more profoundly affect cognition. Frequent epileptiform discharges during sleep may have a particularly disruptive effect on memory consolidation by interfering with storage of memory in the neocortex.35
Epilepsy may be progressive, with resulting cognitive decline. Oki and colleagues reported on two children with focal cortical dysplasia in their dominant hemispheres who experienced significant decline in verbal IQ with recurrence of frequent seizures in mid to late childhood.36 An adult study tested cognitive function on two occasions separated by at least 10 years.37 The onset of epilepsy was in childhood (median of 8 years of age). The study showed severe cognitive decline that occurred across a wide range of cognitive functions. Generalized tonic–clonic seizure frequency was the strongest predictor of decline. Complex partial seizure frequency correlated with a decline in memory and executive skills but not in IQ. Seizure-related head injuries and advancing age were associated with a poor prognosis, and periods of remission were associated with a better cognitive outcome.
There is further clinical evidence that in certain patients, particularly those with recurrent, generalized seizures or status epilepticus, epilepsy may be a progressive disease, with cognitive deterioration, progressive brain atrophy, and potential development of intractable seizures. In a study of temporal lobe epilepsy, Hermann et al found that patients with childhood onset (younger than 14 years) had significantly reduced intellectual status and memory function compared with those with onset later in life, and the longer the epilepsy duration was, the worse the cognitive problems were.38 They also found reduced total brain tissue on volumetric magnetic resonance imaging (MRI) in the childhood onset group. There is ongoing debate as to whether seizures beget seizures, with this argument being predominantly refuted by large epidemiological studies and supported by experimental animal models of epilepsy.39,40
Structural Neuroimaging in Children with Cortical Dysplasia
Although the presence of an abnormality on MR Neuroimaging has not been a predictor for successful long-term seizure freedom in children with cortical dysplasia after surgery,11,12 it is a critical tool in the evaluation of for surgical candidacy ( Figs. 22.1 and Fig. 22.2 ). Over the past decade, there have been significant advances in structural neuroimaging in an attempt to improve the signal-to-noise ratio (SNR) and therefore optimize the quality of such studies. The use of high field strength (>1.5 T) and, more importantly, phased array head coils, have enhanced spatial and contrast resolution compared with routine quadrature head coils.41 At 1.5 T using an eight-channel phased array coil, the SNR is increased by approximately fourfold. In a study of 13 children in which 9 had normal neuroimaging on 1.5 T MRI, 4 were found to have a cortical abnormality on subsequent imaging using phased array head coils.41 Phased array coils have also been used at 3 T with approximately a twofold increase in SNR. A prospective study of 40 patients with epilepsy, using phased array coils at 3 T, yielded additional diagnostic information in 19 cases compared with clinical read at 1.5 T.42 In 14 of these cases, the information resulted in a change in clinical management. Further advances involving the application of 7-T phased array technology has the potential to allow visualization of structure at or below the 100-μm level.43
Quantitation of cerebral structures is still, for the most part, a research tool.44,45 Reports of cortical segmentation and thickness in patients with cortical dysplasia are emerging.46–48 This may be a useful tool in the future in patients for whom the MRI is negative. As both structural and quantitative neuroimaging continue to evolve with ongoing improvements SNR, standardized use of high-resolution MRI in the clinical setting, the clinical application of segmentation, and improved recognition of cortical dysplasias in children may lead to improved outcomes in this group.
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