MRI analysis of sulcation morphology in polymicrogyria

Polymicrogyria (PMG) is a malformation of cortical development in which the process of normal cortical development is interrupted during the late stages of neuronal migration and during the stages of cortical organization; the result is the abnormal development of the deeper layers of the cerebral cortex and the formation of multiple small gyri. Patients with PMG may present with developmental delay, focal neurologic signs and symptoms, or epilepsy, depending upon the portion(s) of brain involved. Affected patients may be micro-, normo-, or macrocephalic (Dobyns et al., 2008). PMG may be associated with congenital infection (Barkovich & Linden, 1994; Wright et al., 1997), in utero ischemia (Hallervorden, 1949), or chromosomal mutations (Kuzniecky, 1994; Bingham et al., 1998; Leventer et al., 2001; Piao et al., 2002; Villard et al., 2002; Roll et al., 2006; Dobyns et al., 2008). No difference in neurologic manifestations has been detected in patients who have PMG of different causes (Barkovich & Kjos, 1992; Guerrini et al., 1992; Barkovich & Linden, 1994), but the severity of the clinical presentation depends upon the extent of cortical involvement; bilateral involvement and involvement of more than half of a single hemisphere are poor prognostic indicators, portending moderate to severe developmental delay and significant motor dysfunction (Barkovich & Kjos, 1992). PMG has a range of histologic appearances, all having in common a derangement of the normal six-layered lamination of the cortex (Evrard et al., 1989), with an associated derangement of sulcation. Therefore, it would seem likely that the gross morphologic appearance of PMG might vary, as well, perhaps depending upon the underlying cause or the pattern of distribution of the anomalous sulcation within the brain. However, this topic has not heretofore been addressed in the literature. We report the imaging characteristics of a large number of patients with PMG and attempt to determine specific sulcation patterns and their variability. Clinical information was not often available; when available, it was usually brief, reporting mental retardation and seizures and, sometimes, family history. Therefore, this report focuses almost exclusively on the imaging features. All magnetic resonance imaging (MRI) studies were of good to excellent quality. Studies contained images that were found, after analysis, to have at least one small region of small gyri separated by thin or shallow sulci or an area of apparently thick cortex (5–7 mm) with irregularity of the cortical surface or the cortical–white matter junction; these images are the basis of this study. A total of 159 MRI scans were analyzed (seven excluded because of unsatisfactory images). All studies had images acquired in three planes (sagittal, axial, and coronal) and had both T1- and T2-weighted images. All images were reviewed by the author for the following characteristics: extent and location of the abnormal sulcation, characteristics of the gyri and sulci, and associated anomalies. Based on the location, extent, and associated anomalies, as well as the clinical history (when available), the studies were classified into known categories of PMG that are based largely upon the location and extent of the morphologic abnormality. Several patients with known clinical diagnoses [nine patients with Aicardi syndrome; nine with Zellweger syndrome; three with megalencephaly, PMG, and hydrocephalus (MPPH) syndrome; and seven with congenital cytomegalovirus (CMV) infection] were grouped together; other than CMV, all patients in a group had similar localization of PMG. Those that did not correspond to known genetic or familial disorders were grouped by morphology into the following nine categories: bilateral perisylvian PMG (Kuzniecky et al., 1993), unilateral hemispheric PMG (Chang et al., 2006), bilateral frontal PMG (Guerrini et al., 2000), bilateral frontoparietal PMG (Chang et al., 2004), bilateral parasagittal parietooccipital PMG (Guerrini et al., 1997), bilateral lateral parietal PMG (Barkovich et al., 1999), bilateral asymmetric PMG, focal PMG (restricted to less than one lobe of a single hemisphere, grouped together despite being in multiple different locations), and diffuse PMG (involving at least three of the four lobes in each hemisphere) (Chang et al., 2004). By far, the most common distribution of PMG in this group was bilateral perisylvian (Table 1); these 50 patients accounted for 31% of the studies analyzed. The next most common distribution was unilateral hemispheric, with 31 patients (19%); of note, all of these patients had PMG centered in the sylvian regions. The remainder of the distributions were considerably less common: focal PMG in 16 patients (10%); bifrontal PMG in 12 (8%); diffuse, Aicardi syndrome (with unilateral frontal PMG in all cases), and Zellweger syndrome (with bilateral perirolandic PMG) in 9 (6%) each; congenital infections [diffuse in 7 (4%), with CMV infection in six and lymphocytic choriomeningitis infection in one); bilateral frontoparietal in 6 (4%); bilateral asymmetric PMG and MPPH in three each; and bilateral parasagittal parietooccipital and bilateral lateral parietal PMG in two each (Table 1). A range of gyral–sulcal dysmorphisms were seen and divided into three main categories, called coarse, delicate, and sawtooth PMG based on morphologic appearance, although a range of morphology was seen within these groups. Coarse PMG was the term used to describe a thick (5–7 mm) cortex with irregular surfaces on both the pial and gray–white junction sides (1, 2). On these images, the sulci identified are not normal sulci (i.e., are not in locations where normal, named sulci tend to form), but abnormal infoldings of the dysmorphic cortex. Coarse PMG was most commonly found in perisylvian PMG, whether unilateral or bilateral, and in deep infoldings of focal PMG into the underlying white matter. Of note, many patients with coarse PMG also had multiple longitudinal sulci, bordered by thick, irregular cortex, coursing in the axial plane over the cerebral convexities on axial and sagittal images (Fig. 2); we suggest that this phenomenon be called palisades of cortex, as it resembles lines of deep gorges descending into the cerebral mantle from the cortical surface. Delicate PMG was used to describe a multiple small gyri of thin cortex in which the undulations are only a few millimeters in depth and, therefore, the cortex remains thin even after myelination; the delicate pattern is seen most clearly in unmyelinated PMG (Fig. 3) but can be seen in myelinated brain, as well (Fig. 4). Delicate PMG was seen primarily in bilateral frontal PMG, but was also seen in patients with Aicardi syndrome (Fig. 4) and in one case of hemispheric PMG. Sawtooth PMG consisted of multiple thin gyri separated by shallow, steep, deep sulci (Fig. 5); it was seen primarily in diffuse PMG. Of note, before myelination develops, the individual thin, sawtooth gyri can be seen to be composed of multiple microgyri (Fig. 5). Coarse polymicrogyria (PMG). Axial T2-weighted image at a higher level shows markedly abnormal sulcation over the posterior frontal and parietal lobes, with deep infoldings (large black arrows) of dysmorphic cortex. The apparent curvilinear heterotopia in the right frontal subcortical white matter (small black arrows) was an infolding of cortex from an adjacent image. Coarse polymicrogyria (PMG) with palisades. (A) Axial T1-weighted image in a patient with perisylvian PMG shows coarse cortex throughout most of both hemispheres. In addition, there are some abnormal cortical infoldings. (B) Axial T1-weighted image at a higher level shows deep infoldings (black arrows) that run parallel to the overlying cortex, giving the appearance of palisades of dysmorphic cortex. Delicate polymicrogyria (PMG). Axial T2-weighted image in an infant with developmental delay and seizures due to bilateral frontal PMG shows multiple areas (arrows) of shallow microgyri in the bilateral frontal lobes. Contrast this with the coarse appearance in Fig. 1. Localized delicate polymicrogyria (PMG). Localized delicate PMG in an infant with Aicardi syndrome. Delicate PMG with thin cortex and small, shallow sulci is present throughout much of the anterior right frontal lobe (arrows) and, to a lesser extent, the left frontal lobe. The asymmetry in hemisphere size is due to ventricular cysts on the left. Sawtooth polymicrogyria (PMG). Axial T2-weighted image in an infant with seizures and severe developmental delay shows multiple long, narrow gyri separated by deep sulci. On close examination, the cortex of each long, narrow gyrus is composed of many microgyri. Ventricles are enlarged and white matter is markedly diminished. Focal PMG, whether consisting of deep infoldings of the abnormal cortex (Fig. 6) or as a region of relatively flat, thick cortex without normal sulcation, was classified as coarse PMG, generally appearing thick cortex with an irregular cortical and in deep infoldings focal PMG into the underlying white matter white matter junction. Even before myelination, the cortex did not have the delicate branching seen in patients with delicate PMG but, instead, consisted of rather deep undulations. The pattern of PMG in the bilateral frontoparietal PMG scans differed from all of the others. The cortex was coarser, tended to more frequently involve the medial surface of the cerebral hemispheres, had delayed myelination of the cerebral white matter (younger patients) or patchy areas of T2 hyperintensity in myelinated white matter (older patients), and had dysmorphic cerebella associated with mild pontine hypoplasia (Fig. 7). Overall, these patients more resembled those with dystroglycanopathies (Clement et al., 2008) than other patients with PMG. Focal coarse polymicrogyria (PMG). Axial T1-weighted image shows a deep infolding of thick cortex with irregular inner and outer margins, characteristic of coarse PMG. Bilateral frontoparietal polymicrogyria (PMG). Axial T2-weighted image shows coarse PMG that extend to the medial surfaces of the cerebral hemispheres (typically PMG relatively spares the medial and inferior surfaces of the cerebral hemispheres) and associated with subcortical regions of abnormal myelination (also unusual for PMG). This study of MRI morphologies of PMG has revealed differences in the imaging appearance of the sulci that seem to, to some extent, correlate with the topology of the malformation. Three main MRI morphologies of the abnormal cortex were identified: a coarse PMG with thick cortex and, often, palisades of sulcation; a delicate PMG with small branches of myelinated white matter intercalating into a finely microgyric cortex; and a sawtooth pattern, with thin gyri (composed of microgyri) separated by deep sulci. Coarse PMG was most common in perisylvian and focal involvement; delicate PMG was most often seen in bilateral frontal PMG, Aicardi, and Zellweger syndromes, and some cases of unilateral hemispheric PMG (not centered in the sylvian fissure); whereas sawtooth PMG was seen exclusively in diffuse PMG. Different gross morphologic patterns of PMG have not been discussed in the pathology literature, although pediatric neuropathologists have commented upon the varied appearance of PMG in small meetings and private discussions (Jeff Golden, Philadelphia, International Symposium on Polymicrogyria, Montreal, December 1, 2005). Most neuropathology textbooks, even those on developmental disorders (Friede, 1989; Norman et al., 1995) describe only two types of PMG, layered and unlayered; no discussion is made of any gross morphologic differences between these two histologic subtypes. Some chapters discuss a continuum of histologic appearances in PMG (Evrard et al., 1989), but the morphologic consequences of these varying histologic appearances are not described. It is hoped that this small study will serve as a stimulus to pursue such studies. The imaging appearance of PMG changes as the brain myelinates; individual microgyri are seen in unmyelinated brain, but not after myelination is completed (Takanashi & Barkovich, 2003). This changing appearance has been postulated to result from partial myelination of a band of subcortical white matter tracts that ultimately becomes isointense to cortex. As these fibers myelinate, the appearance of the cortex changes from that of a thin cortical layer composed of multiple small gyri to one of a thick, relatively smooth cortex with a gently undulating inner surface (Takanashi & Barkovich, 2003). The difference in morphologies that were noted in this study cannot be explained by myelination-associated phenomena alone. The depth of cortical microundulations in the coarse patterns (1, 2) was deeper than that in the delicate patterns (3, 4). Myelination of subcortical fibers would not be sufficient to convert shallow microundulations into a coarse pattern. In addition, deeper, coarser microgyri were seen before myelination began (Fig. 1). Finally, the narrow gyri and deep sulci of the sawtooth patterns (Fig. 5) were superimposed upon microgyri within the “tooth-like” gyri. Neither functional nor etiologic associations of these different patterns can be commented upon based on the information available in this study. However, it is noteworthy that the appearance of the cerebrum in bilateral frontoparietal PMG, caused by mutations of GPR56 (Piao et al., 2002), is distinctive (Table 1 and Fig. 7) with myelination abnormalities in deep and subcortical white matter, and extension of the cortical abnormality into the medial aspects of the cerebral hemispheres, as well as associated pontine and cerebellar dysmorphisms/hypoplasia. These are similar to what is described in so-called “cobblestone” malformations, such as muscle-eye-brain disease (Haltia et al., 1997), caused by abnormal development of the pial basement membrane and abnormal anchorage of radial glial endfeet, with resultant neuronal overmigration into the subarachnoid space (Van Reeuwijk et al., 2005; Kanagawa & Toda, 2006; Van Reeuwijk et al., 2007). Indeed, recent work demonstrated that a mouse model with loss of function mutations of GPR56 has similar underlying pathology (gaps in the pial limiting membrane, overmigration of neurons) to that in cobblestone malformations (Li et al., 2008). The cortical malformation associated with this group of disorders has been called PMG by some neuropathologists (Takada, 1988; Takada et al., 1988) and cobblestone malformation by others (Haltia et al., 1997). Perhaps there are multiple morphologic types of PMG and cobblestone malformations; perhaps it is time for a dedicated study of a large number of both types of disorders by an experienced group of neuropathologists and neuroscientists. These disorders will not be understood and properly classified until their developmental processes and histology are properly understood. The study reported here will hopefully be motivation for this process to begin. This work was supported by the NIH/NINDS R37NS035129 and R01NS058721. The author has no conflict of interest to disclose.

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