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  • Updated 10.06.2020
  • Released 07.28.1994
  • Expires For CME 10.06.2023

Schizencephaly

Introduction

Overview

Schizencephalies are fetal brain disruptions characterized by cerebral clefts lined by dysplastic polymicrogyric cortex extending medially from the pial surface to the lateral ventricles. Schizencephaly is the result of a disruption of cerebral development, most probably arising during the early second trimester of pregnancy. The severity of the clinical picture, made up by motor deficits, intellectual disability, and epilepsy, is related to type, location, and size of the clefts and the presence of associated brain abnormalities and identified genetic defects. Schizencephaly may be unilateral or bilateral and is not limited by gender or ethnicity.

Key points

• Polymicrogyria, ie, patches of minute gyri are present in open and closed lip schizencephaly, borders the defect. These mini-gyri have pial discontinuities that enable synaptic short-circuiting between adjacent gyri.

• Schizencephaly associated with porencephaly is secondary to genetic or environmental causes that interfere with circulation resulting in infarction, usually in the middle cerebral arterial territory, but also from venous obstructions.

• Careful history taking may reveal acquired epigenetic damage in utero (eg, by use of cocaine and other teratogens).

• Molecular genetic studies may reveal defects commonly associated with hemorrhagic or thrombotic disease, mimicking acquired lesions. The most frequent is COL4A1 mutation.

Historical note and terminology

Schizencephalies are congenital clefts that unilaterally or bilaterally extend from the pial surface of the lateral parts of the cerebral cortex to the lateral ventricle. The opposing borders of each separate cleft are covered by abnormal neocortex, structured as polymicrogyria, a developmental anomaly. The presence of polymicrogyria is consistent with an origin during the migratory or early postmigratory period of neocortical development, including lamination of the cortical plate to produce mature cortical organization.

Schizencephaly was first described by Wilmarth in 1887 (90). The term is derived from the Greek word “schizen,” which means to divide and was introduced by Yakovlev and Wadsworth in 1946. There are 2 types of schizencephaly as defined by these authors: the closed lips and the open lips types (95; 96). In the closed lips type, the defects that connect the arachnoid and ventricular spaces are lined by pial-ependymal seams. The seams merge tightly like a zipper, isolating the arachnoid space from the lateral ventricle. The dysplastic neocortex beneath the seam manifests polymicrogyria, an anomaly of cortical development that is detectable on MRI, adding evidence of the fetal origin of the lesion. The open lips type of schizencephaly presents as an open connection between arachnoid and ventricular spaces. Viewed from the outside of the brain, the opercula are malformed and not fully approximated (75). Some authors attempt to classify schizencephalies by criteria of morphology and other associated brain anomalies such as the state of the septum pellucidum (34).

Porencephaly, a related defect, denotes a transmantle defect without grey matter lining the borders (lips) of the defect. Porencephaly and schizencephaly are related pathologies that differ by the presence of polymicrogyria bordering the lips of the defect in schizencephaly. The distinction between porencephaly and schizencephaly is due to different fetal ages at their time of origin, with porencephaly originating in the later fetal period when the process of neocortical neuron migration has ended and cortical layering well established. Schizencephaly may be unilateral in which case a patch of superficial polymicrogyria may be present in the same cortical region in the opposite hemisphere.

Porencephaly, an inborn unilateral or bilateral cerebral mantle defect shares some properties with schizencephaly but differs from the latter by the absence of ectopic abnormal grey matter lining the defect. It arises as a later disruption of cerebral development after cortical development has reached a mature stage, with migration of cortical neurons completed. Insights in the morphogenesis of both disorders has deepened in the last decades due to refined imaging techniques and discoveries in the field of genetics. Breedveld and colleagues showed mutations of COL4A1, associated with porencephaly (10). COL4A1 encodes a vascular basement protein, known from previous studies to be involved in cases of cerebral hemorrhage and thrombosis. Yoneda and colleagues showed pathogenic mutations of COL4A1 to be linked to schizencephaly (97). The convergent findings support a link between cases of porencephaly and schizencephaly. From these and later studies it transpires that the morphological difference between schizencephaly and porencephaly depends on the stage of neocortical development at the time of the insult: schizencephaly resulting from a lesion during corticogenesis, whereas porencephaly has its time of origin after a stable ordering of cortical layers is reached. These and other studies point to a vascular/ischemic mechanism underlying schizencephaly. Not all cases are related to genetic defects. Exogenous causes cannot be dismissed. Indeed, epidemiologic findings indicate that exogenous causes interfering with pregnancy have to be considered in addition to genetic defects. Exogenous causes also include cytomegalovirus and possibly toxic agents in early pregnancy including the use of cocaine (42).

Schizencephalies originate in the middle fetal period when neocortical neurons have not yet established their definite place in vertical and horizontal organization and movement of the neuronal somata is still possible. Disruptions affecting the evolution of the neocortex during this period may result in disordered vertical and horizontal register of the cortical layers, presenting as polymicrogyria. Polymicrogyria arises during the neuronal migration period, extending to the stabilization period during which connectivity within and to the outside connections of the neocortex is achieved. Polymicrogyria presents on MRI as very small fused gyri.

Porencephalies are generally thought to arise from a destructive process. Porencephaly and schizencephaly share morphological features, but the term schizencephaly, first coined by Yakovlev and Wadsworth, is reserved for cases in which polymicrogyric cortical tissue overlies the defects (95; 96). These authors emphasized the malformative nature and early ontogenetic origin of schizencephalies. They also distinguished type 1 (or closed-lip) schizencephaly, in which the walls of the cleft are in contact with each other, and type 2 (or open-lip) schizencephaly, characterized by separated lips and cerebrospinal fluid-filled clefts. Although type 1 is well defined, type 2 is much more diverse in shape, extent, and associated abnormal findings. In some patients bilateral schizencephaly may be closed on 1 side and open on the other side.

Schizencephaly has been increasingly recognized in vivo due to the progressive refinement of neuroimaging techniques (05; 39; 03; 04). Although first-generation MR scanners did not achieve sufficient resolution to differentiate polymicrogyria from pachygyria, improvements have made this possible, and indeed imperative for a definite diagnosis.

Sometimes full-thickness defects without polymicrogyria bordering the defect but with associated cortical malformation distant from the defect are classified as schizencephaly (50). In this way the definition, especially of type 2, sometimes tends to become overstretched.

Genetic studies initially focused on EMX2, a homeobox gene, which could not be confirmed (23). Genetic, neuroradiological, and experimental studies have given ground to the vascular origin (fetal cerebral artery occlusion) as the most common etiology (47). The most frequent genetic mutation, usually de novo, associated with schizencephaly, particularly with arterial occlusive or hemorrhagic infarcts, is of the COL4A1 gene (60; 79; 01; 14; 47; 77). Because this mutation primarily involves endothelium of blood vessels, not only is the nervous system a target, but multiple organs might be affected and develop malformations. Congenital cataracts are seen in some patients.

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