Polymicrogyria and epilepsy

The term polymicrogyria defines an excessive number of abnormally small, and partly fused, cortical gyri that produce an irregular cortical surface (Barkovich et al., 2005). Polymicrogyria is a common cortical malformation and is associated with a wide spectrum of anatomic patterns. Brain pathology demonstrates abnormal development or loss of neurons in middle and deep cortical layers, variably associated with an unlayered cortical structure. The spectrum of associated clinical manifestations ranges from normal individuals with only selective impairment of cognitive function (Galaburda et al., 1985) to patients with severe encephalopathies and intractable epilepsy (Guerrini et al., 2008). To date, polymicrogyria has been associated with mutations of only a few genes including SRPX2, PAX6 TBR2, KIAA1279, RAB3GAP1, and COL18A1 (Guerrini et al., 2008), which account for a small minority of cases. Several polymicrogyria syndromes have been described that are characterized by different patterns of lobar expression, suggesting mutations of regionally expressed developmental genes. However, little is known about their genetic causes. The most frequently observed syndromes of regional polymicrogyria include bilateral perisylvian polymicrogyria, bilateral frontal and frontoparietal polymicrogyria, bilateral parasagittal parietooccipital polymicrogyria, and unilateral multilobar polymicrogyria. Bilateral perisylvian polymicrogyria is genetically heterogeneous but is mainly X-linked, with a few families mapping to chromosome Xq28 (Villard et al., 2002). A missense mutation in the Xq22 gene SRPX2 was found in an affected male (Roll et al., 2006). However, SRPX2 does not account for X-linked pedigrees. Perisylvian polymicrogyria, frequently asymmetric and with a striking predisposition for the right hemisphere, has also been reported in children with the chromosome 22q11.2 deletion (Robin et al., 2006). Its clinical expression includes cognitive impairment and pseudobulbar palsy in almost all patients, and severe focal or generalized epilepsy of the Lennox-Gastaut type in most (Fig. 1) (Kuzniecky et al., 1993). Fourteen-year-old boy with bilateral perisylvian polymicrogyria and Lennox-Gastaut syndrome. Sleep electroencephalography (EEG) recording showing bilateral spike activity over the temporal regions and generalized discharges of multiple spike and wave discharges. Generalized discharges are accompanied, at their onset, by a contraction of perioral muscles. This electroclinical pattern is typically seen in this malformation. Bilateral frontal and frontoparietal polymicrogyria (BFPP) have been reported in sporadic patients and in recessive pedigrees (Guerrini et al., 2000; Piao et al., 2005). BFPP has been reported in several consanguineous and nonconsanguineous families and has been associated with mutations of the G protein–coupled receptor gene 6 (GPR56) (Piao et al., 2005). The topography of the cortical abnormality, as well as the pattern of expression of mouse Gpr56, suggest that GPR56 regulates cortical patterning. The imaging characteristics of BFPP (myelination defects, cerebellar cortical dysplasia with cysts, and frequent involvement of the medial aspects of the cerebral hemispheres) resemble those of the cobblestone malformative spectrum (muscle-eye-brain disease and Fukuyama congenital muscular dystrophy) that are also associated with N-glycosylation defects in the developing brain. Therefore, it has been suggested that this disorder might be best classified as a cobblestone malformation (Guerrini et al., 2008). The main clinical features of BFPP include severe mental retardation, developmental delay, gait and language impairment, and epilepsy, which is usually severe and often manifested as Lennox-Gastaut syndrome (Parrini et al., 2009). Bilateral parasagittal parietooccipital polymicrogyria has been reported only in sporadic patients, all having a homogeneous clinical syndrome associating mild cognitive impairment and complex partial seizures of occipitotemporal origin (Guerrini et al., 1997). Unilateral multilobar polymicrogyria is, with few exceptions, sporadic, and is often associated with mild cognitive impairment, hemiparesis, and an age-related syndrome of epilepsy with sleep-related electrical status epilepticus and cognitive deterioration (Guerrini et al., 1998). Numerous observations have linked polymicrogyria with a spectrum of epilepsy phenotypes. Epileptogenicity of polymicrogyria and its mechanisms are not known, but a considerable number of patients do not have epilepsy. Experimental models produced by localized freezing suggest widespread functional disruption, with downregulation of different γ-aminobutyric acid (GABA)A receptor subunits extending far beyond the visualized abnormality (Redecker et al., 2000). Diffuse epileptogenesis is frequently encountered, even with seemingly limited abnormalities. Intracranial recordings suggest large epileptogenic networks, which extend well beyond the limits of the visible abnormality (Chassoux et al., 2008). Epilepsy related to polymicrogyria has variable severity, including cases with good outcome and spontaneous remissions, even after a period of intractability (Guerrini et al., 1998). Surgical treatment of epilepsy is applicable to a very limited number of patients in whom large resections are feasible (Chassoux et al., 2008). Numerous observations have linked polymicrogyria with a spectrum of patterns of reorganization of cortical function (Guerrini et al., 2008), with remarkable variability in cortical representation (Fig. 2), probably in relation to both the severity of anatomic disruption and the involved modality. When assessing cortical organization and the representation of function in patients with polymicrogyria, generalization of findings may be inappropriate, in view of causal heterogeneity and high degree of histopathologic variability. T1-weighted functional magnetic resonance imaging (fMRI). Fifteen-year-old girl with left perisylvian polymicrogyria. Three contiguous axial sections showing bold activation of the hand area in the polymicrogyric, distorted left perirolandic and opercular region, as well as in the supplementary motor area, during a simple motor task involving the right hand. The author has no conflicts of interest to disclose.