Contralateral hemimicrencephaly and clinical–pathological correlations in children with hemimegalencephaly

Abstract

In paediatric epilepsy surgery patients with hemimegalencephaly (HME; n = 23), this study compared clinical, neuroimaging and pathologic features to discern potential mechanisms for suboptimal post-hemispherectomy developmental outcomes and structural pathogenesis. MRI measured affected and non-affected cerebral hemisphere volumes for HME and non-HME cases, including monozygotic twins where one sibling had HME. Staining against neuronal nuclei (NeuN) determined grey and white matter cell densities and sizes in HME and autopsy cases, including the non-affected side of a HME surgical/autopsy case. By MRI, the affected hemisphere was larger and the non-affected side smaller in HME compared with non-HME children. The affected HME side showed enlarged abnormal deep grey and white matter structures and/or T2-weighted hypointensity in the subcortical white matter in 75% of cases, suggestive of excessive pre-natal neurogenesis and heterotopias. Histopathological examination of the affected HME side revealed immature-appearing neurons in 70%, polymicrogyria (PMG) in 61% and balloon cells in 45% of cases. Compared with autopsy cases, in HME children NeuN cell densities on the affected side were increased in the molecular layer and upper cortex (+244 to +18%), decreased in lower cortical layers (-35%) and increased in the white matter (+139 to +149%). Deep grey matter MRI abnormalities and/or T2-weighted white matter hypointensity correlated with the presence of immature-appearing neurons and PMG on histopathology, decreased NeuN cell densities in lower cortical layers and a positive history of infantile spasms. Post-surgery seizure control was associated with decreased NeuN densities in the molecular layer. In young children with HME and epilepsy, these findings indicate that there are bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly is a likely explanation for poorer post-surgery seizure control and cognitive outcomes. In addition, our findings support the hypothesis that HME pathogenesis probably involves somatic mutations that affect each developing cerebral hemisphere differently with more neurons than expected on the HME side.

Aberrant Midsagittal Fiber Tracts in Patients with Hemimegalencephaly

“…25 These findings may correspond to our white matter-intensity structures between the 2 anterior horns. Furthermore, the latter article noted that the incidence of these findings was 75%, 25 and almost the same as in our study. However, to our knowledge, no previous study displayed aberrant FTs in patients with hemimegalencephaly.…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Microscopically, the cortex displays alterations in cortical dyslamination with the presence of hypertrophic and dysmorphic neurons, as well as heterotopic neurons in the white matter and leptomeningeal glioneuronal heterotopia (Fig. 1o) [238,[240][241][242][243][244][245] (for reviews see [233,238] and [239]). The presence of balloon cells has been also reported in HME [244,246].…”

“…1o) [238,[240][241][242][243][244][245] (for reviews see [233,238] and [239]). The presence of balloon cells has been also reported in HME [244,246]. Moreover, a recent report shows enhanced levels of phosphorylated tau protein and evidence of neuronal lipidosis in 3 male infants with HME [246].…”

“…On the basis of the histopathologic features, it has been suggested as a primary deregulation of proliferation [247], or a disturbance of cellular growth and cellular lineage [233,234]. Salamon et al [244] indicate an increased proliferation of the progenitor cells together with partial failure of postneurogenesis apoptosis in the molecular layer and subplate as possible mechanisms underlying the pathogenesis of HEM. The possibility of an accelerated neuronal differentiation has also been suggested, emphasizing the importance of migration abnormalities [239].…”

Etiology associated with developing posthemispherectomy hydrocephalus after resection-disconnection procedures

“…9,10 Seizure etiology categories, which were based on MRI and histopathological features, include the following: hemimegalencephaly in which 3 of 4 lobes were larger than expected; 18 hemispheric or multilobar cortical dysplasia; perinatal cerebral ischemia/infarction (stroke); Rasmussen encephalitis; history of mostly unilateral CNS infection (3 cases of herpes simplex virus and 1 case of prior bacterial encephalitis); Sturge-Weber syndrome; and other (2 cases of extensive tumors [1 dysembryoplastic neuroepithelial tumor and 1 ganglioglioma]), history of cerebral trauma (n = 2), and deep thalamic damage and seizures after a prior ventricular endoscopic procedure (n = 1). 6 Additional information gathered for this study included maximum daily temperature (Tmax), blood white blood cell (WBC) count and differential, CSF laboratory results, and incidence and location of positive bacterial cultures for the first 12 days posthemispherectomy.…”