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MR Imaging of

A. James Barkovich 1,2 MR imaging was used to evaluate six patients who had schizencephaly, a disorder of David Norman2 cell migration characterized by holohemispheric, gray-maHer-lined clefts. Clinically, these patients presented with intractable and variable developmental delay. Although three of these patients had previous CT scans, the diagnosis was made only by MR. MR was more sensitive than CT in detecting thl:! clefts as well as the accompa­ nying abnormalities, including areas of , , and heterotopic gray maHer. The possible pathogenesis of schizencephaly is discussed. MR provides excellent demonstration of the anatomic changes in schizencephaly.

Schizencephaly is a congenital anomaly characterized by clefts spanning the cerebral hemispheres. This disorder has been detected in vivo by CT [1 , 2] and sonography [3] and is well-characterized pathologically [4-6]. MR imaging is uniquely suited to the study of this anomaly because of its superior differentiation of gray and and its high-resolution, multiplanar display of anatomy. In a review of 980 MR examinations of the brain, we identified si x patients who had schizencephaly. Here, we discuss the characteristic clinical , pathologic, and radio­ graphic features of schizencephaly, compare the efficacy of CT and MR in its detection, and relate the pathologic anatomy to proposed theories of pathogenesis.

Patients and Methods

The six patients in our study included fi ve males and one female, ages 7 months, 12 months, 3 years, 17 years, 21 years, and 23 years, respectively (see Table 1). The four youngest patients were developmentally delayed; the two oldest patients had normal devel­ opment and normal intelligence. All patients had motor dysfunction and intractable seizures. Two of the patients (ages 3 years and 17 years) had hypoplastic optic nerves and hypothalamic dysfunction, and were diagnosed as having septooptic dyspl asia. Three of the patients were This article appears in the March/April 1988 included in a previous report dealing with migration anomalies [7]. issue of AJNR and the June 1988 issue of AJR. Patients 3, 4, 5, and 6 were imaged on a 1.5-T General Electric Signa unit; patients 1 and Received June 18, 1987; accepted after revi sion 2 were examined on a 0.35-T Diasonics MT/S scanner. Slice thickness was 5 mm with a 2.5- September 23, 1987. mm inters lice gap. Spin echo (SE) sequences with repetition/echo times (TRITE) of 2000 The views expressed in this article are those of msec/35 and 70 msec were obtained in the transverse plane. Sagittal SE 600/20 sequences the authors and do not refl ect the official policy or were obtained in five patients and coronal (S E 600/20) images were acquired in th ree patients. position of the Department of the Arm y, Department All patients were imaged in a minimum of two orthogonal planes . Postcontrast CT scans of Defense, or the U.S. Government. using 10-mm sections were available on three of the six patients. 1 Department of Radiology, Letterman Arm y Pathologic confirmation was not possible. The diagnosis of schizencephaly was determined Medical Center, Presidio of San Francisco, CA from the characteristic gross morphology of the affected , which has been established 941 29-6700. Address reprint requests to Technical Publications Editor. from pathologic and CT experience.

2 Department of Radiology, Section of Neurora­ diology, University of Cali forni a School of Medicine , San Francisco, CA 94143. Results AJNR 9:297-302, March/April 1988 01 95- 6108/88/0902-0297 Two patients (patients 5 and 6) had unilateral , vertically oriented clefts with fused © American Society of Neuroradiology lips; that is , in one spot the opposing wall s touched across the cleft (Fig. 1). In both 298 BAR KOVICH AND NORMAN AJNR:9, March/April 1988

TABLE 1: Summary of Patient Data

Patient Age Gender Clinical Findings Radiographic Findings No. 7 mo M Seizures; moderate developmental Bilateral, narrow, horizontal frontal clefts; delay frontal pachygyria; polymicrogyria along cleft; absent septum pellucidum 2 12 mo M Seizures; severe developmental Large rig ht cleft, separated lips; small left delay cleft, separated lips; polymicrogyria along cleft; absent septum pell ucidum 3 3 yr M Seizures; severe developmental Large right cleft, separated lips; small left delay; hypoplastic optic nerves; cleft, separated li ps; polymicrogyria hypothalamic dysfunction along cleft; absent septum pellucidum 4 17 yr M Seizures; severe developmental Large right cleft, separated lips; subep- delay ; hypoplastic optic nerves; endymal heterotopia; polymicrogyria hypothalamic dysfunction along cleft; absent septum pell ucidum 5 21 yr M Seizures; normal development Right unilateral cleft, fused lips; polymi- crogyria along cleft; absent septum pell ucidum; subependymal heterotopia 6 23 yr F Seizures; normal development Left unilateral cleft, fused lips

A 8 c

Fig. 1.-Patient 5. Unilateral schizencephaly with fused lips. A, Axial contrast-enhanced CT scan. Cortex is seen to extend down to lateral wall of the body of lateral ventricle (arrowheads). A true "cleft" is not appreciated. Septum pellucidum is absent, as it was in five of the six patients imaged in this study. B, Axial SE 2000/ 35 MR image shows vertical holohemispheric cleft extending into lateral ventricle. Irregularity of gray matter lining cleft (arrowheads) suggests polymicrogyria and heterotopias, common findings along clefts in schizencephaly. C, Coronal SE 2000/35 MR image through region of cleft reveals dimple along the ependymal wall and asymmetry of opercular gray matter; the cleft, however, is not appreciated. Clefts with fused lips were not seen in any patients when plane of image was parallel to cleft.

patients, the CT scans were interpreted prospectively as an abnormal contour of the ventricular wall was apparent. normal. In retrospect, one patient had what appeared to be Patient 4 had a large unilateral cleft with unfused lips. In an abnormally deep sulcus in the appropriate hemisphere, but th is patient, the CT scan showed the midportion of the cleft the entire cleft and its communication with the lateral ventricle but failed to show communication of the cleft with the lateral could not be appreciated (Fig . 1 A). The CT scan (obtained ventricle medially and the subarachnoid space laterally; the with an EMI 1010 model scanner) in the other patient was continuity of the gray matter along the cleft was not initially normal on retrospective evaluation. The MR images of both recognized. The MR scan clearly showed communication with these patients showed a cleft lined with gray matter extending the lateral ventricle, gray matter lining the cleft, and thickened from the cortex to the ipsilateral lateral ventricle (Fig . 1 B). In cortex adjacent to the cleft. Medially, there was a focus of both cases, a small dimple was seen in the lateral wall of the subependymal heterotopic gray matter. These fi ndings were ventricle where the cleft communicated . The cortex within and not detected on retrospective review of the CT scan (Fig . 2) . adjacent to the cleft was irregularly thickened. Although cor­ The three youngest patients had bilateral nonfused clefts. onal images obtained in one patient failed to show the cleft, In patient 1, the clefts were narrow and oriented horizontally. AJNR :9, March/April 1988 MR OF SCHIZENCEPHAL Y 299

Sagittal and coronal MR images showed gray matter lining patients 4 and 5 had subependymal heterotopias lining a the clefts; the clefts were not apparent in the axial images. portion of the lateral ventricle (Fig. 2). Patient 1 had extensive The gray matter at the lateral margins of the clefts was thick areas of thickened cortex with large, broad gyri consistent and the gyri consequently enlarged. In patients 2 and 3, the with pachygyria in the frontal lobes. In the four patients who clefts were wide on the right and vertical and narrow on the had clefts with separated (nonfused) lips, the septum pelluci­ left. MR clearly showed gray-matter-lined clefts bilaterally with dum was completely absent. The most rostral 1 cm of the thickening and irregularity of the gray matter within the narrow septum was present in one of the patients who had a small clefts (Fig. 3) . The latter three patients were not evaluated fused unilateral cleft, and the entire septum was present in with CT. the other. The corpus callosum, to which the septum pelluci­ Gyral anomalies were noted within and adjacent to the dum is attached superiorly, was fully formed in all patients, clefts in five of the six patients. In these cases, irregular although there was some thinning of this commissure in the thickening of the gray matter evident within the cleft was region of clefts, as previously reported [7]. The fornix, with believed to represent foci of polymicrogyria [7]. Patients 2 which the septum pellucidum is continuous inferiorly, was and 6 had nodules of heterotopic gray matter adjacent to the present and appeared normal in all patients, although its clefts, deep to the gray matter lining the cleft (Fig. 1), and position was low in those with absence of the septum.

Fig. 2.-Patient 4. Unilateral schizencephaly with separated lips. A, Contrast-enhanced axial CT scan shows deep infolding of cortex in right frontal region, apparently pressing upon right lateral ventricle (arrowheads ). B, Coronal SE 600/20 MR image shows this infolding to be a large cleft in continuity with lateral ventricle. Continuity of gray matter through cleft is clearly shown (arrowheads) as is the focus of heterotopic gray matter along roof of right lateral ventricle (open arrow). Once again, there is absence of septum pellucidum. This patient also carries a diagnosis of septoop­ tic dysplasia.

Fig. 3.-Patient 3. Bilateral schizencephaly with separated lips. Axial (A) and coronal (B) SE 600/20 MR images show a thick layer of gray matter within clefts (open arrows) and thickened, broad, flat gyri (arrowheads) adjacent to clefts, which presumably represent pachygyria or polymicrogyria. Notice in larger cleft that the arc of missing cortex is proportionally larger, which suggests that destruction of a portion of the subependymal germinal matrix is the origin of the cleft. 300 BAR KOVICH AND NORMAN AJNR:9, March/April 1988

Discussion primitive cells begin to migrate along radially oriented glial cells to predetermined, relatively distant final positions, form­ The term schizencephaly refers to full-thickness clefts ing the (Figs. 4 and 5) [10]. Detailed anatomic within the cerebral hemispheres. Pathologically, these clefts evaluation of the cerebral vascular system in fetal life is not are characterized by an infolding of gray matter along the available; however, DeReuck and associates [11] and Ta­ cleft from the cortex into the ventricles and a fusion of the kashima and Tanaka [12] have shown that in premature cortical pia and ventricular within the cleft, the so­ infants there are watershed zones between the ventriculofu­ called pial-ependymal seam [4]. Gray-matter heterotopias and gal and ventriculopetal arteries in and around the walls of the areas of poly microgyria are frequently found within and near lateral ventricles. Moreover, the ventriculofugal branches the cleft [4-6]. (leading from the ventricle toward the cortex) are not devel­ In their 1946 articles, in which they coined the term , Yakov­ oped until the seventh month, suggesting that, before the lev and Wadsworth [4, 5] described a broad range of schi­ third trimester, watershed zones are situated along the ven­ zencephalies. In seven brain specimens, the clefts ranged tricular walls. from extremely narrow with actual fusion of the gray-matter­ On the basis of these observations, we hypothesize that a lined walls of the cleft (fused lips) to quite large with wide gray-matter-lined cleft can develop secondary to an episo~e separation of the walls and absence of large portions of the of hypotension, causing infarction of the watershed area-In involved hemispheres. The cases they classified as bilateral this case, a focus of the germinal matrix in the wall of the large clefts would today be classified as . On lateral ventricle. The areas of polymicrogyria and heterotopias the basis of this series of seven specimens, Yakovlev and commonly seen surrounding the cleft could then be secondary Wadsworth defined schizencephaly as being characterized to ischemic changes in the less severely affected surrounding by bilateral clefts that are fairly symmetrical and that charac­ areas of germinal matrix. The association of optic nerve teristically occur along the course of normal sulci. hypoplasia with schizencephaly [9] could also be explained in Over the past 40 years, the understanding of schizence­ this schema, since the retinal layers and optic nerve fibers phaly has slowly evolved as advances in imaging techniques also form during the seventh week of gestation. have resulted in a steady improvement in the in vivo evaluation Skarf and Hoyt [13] have presented clinical, experimental, of this anomaly. Holohemispheric clefts, both unilateral and and embryologic evidence that hypoplastic optic nerves result bilateral, have been demonstrated in patients who have min­ from an excessive degeneration of optic nerve axons and imal symptoms [1], or no symptoms (personal communica­ retinal ganglion cells during the development of the and tion, Dr. Steve Holmes). These patients may exhibit a broad visual pathway. A hypotensive episode during the seventh range of neurologic disability, which is presumably related to week of gestation, when the retinae and nerves are forming , the amount of brain tissue involved [1, 8]. Our data further could cause such a degeneration. The frequent absence of support this concept. The two patients in our study who had unilateral clefts with fused lips were of normal intelligence. The patient with the large unilateral cleft had moderate de­ velopmental delay. The patients with bilateral clefts had se­ vere developmental delay. All the patients, however, had disorders that were refractory to medical therapy, and all had motor dysfunction, ranging from mild unilateral weak­ ness in the patients who had unilateral, fused clefts to severe spastic diplegia in the patients who had bilateral clefts. The pathogenesis of schizencephaly has not been firmly established. The fact that there is continuity of the gray matter through the cleft plus the high frequency of associated het­ erotopias and polymicrogyria led Yakovlev and Wadsworth [5] to classify schizencephaly as a dysgenetic (as opposed to encephaloclastic) process. It is known that schizencephaly and septooptic dysplasia frequently coexist [9] and that both are associated with absence of the septum pellucidum in 75- 100% of patients [1 , 2]. In view of these associations and the Cortical plate known embryologic facts discussed below, we propose that an ischemic episode occurring during the seventh week of Fig. 4. -Schematic drawing shows relationship of the germinal matrix gestation is the underlying cause of these anomalies. This in wall of lateral ventricle to the developing cortical plate. There is a one­ to-one correspondence between the site of cell proliferation within the proposal is a hypothesis based on review of previous discus­ germinal zone and its eventual destination within the cortical plate. Cor­ sions [9-14] and not based on the results presented in this responding regions are connected by radial glial cells that span entire paper. thickness of hemisphere. migrate along these radial cells, even­ tually arriving at predestined locations on the enlarged, convoluted cortical In the normal embryo, beginning at the seventh week of surface. If there is damage to a portion of the germinal matrix before gestation, are generated in the proliferative zones migration begins, a cleft will necessarily result from the ventricle to the situated along the ventricular surface of the developing brain, corresponding section of cortex. The larger the area of destruction in the germinal matrix, the proportionately larger the arc of missing cortex. the so-called germinal matrix. During the eighth week these (Adapted from [10]. Reprinted with permission from [7].) AJNR:9, March/April 1988 MR OF SCHIZENCEPHAL Y 301

with CT. In one case, this might be attributed to suboptimal resolution of a first-generation scan; in the other cases, inter­ pretation of the CT images was limited as a result of poor Leading differentiation of gray and white matter, imaging in a single process plane, and the use of a 10-mm slice thickness. Although the abnormality probably should have been recognized on CT in patient 5, the diagnosis was more obvious and more easily made on MR. Radial fiber Identification of the gray-matter lining of the cleft is critical in differentiating schizencephaly from . This dif­ ferentiation may be important for genetic counseling , since the reported incidence of brain anomalies is 5-20% in sub­ sequent siblings of children who have anomalies of cell migra­ tion [15 , 16]. The improved differentiation of gray and white matter with MR also aids in the identification of associated anomalies. Pachygyria was well-demonstrated by MR in one of our patients. Pachygyria is sometimes difficult to diagnose by CT because of beam hardening by the overlying calvarium as well as the lower contrast resolution. Gray-matter hetero­ topias and foci of polymicrogyria were shown on MR in three patients, but not detected on CT. All of the patients in our series had seizure disorders, and Germinal Glial cell four of six were developmentally delayed. In addition to schi­ zone zencephaly, seizure disorders in children and young adults can be caused by a variety of congenital and acquired disor­ ders, including the other anomalies of cell migration, phako­ matoses, vascular accidents, asphyxia, trauma, infections, degenerative disorders, metabolic derangements, and tumors [17]. MR has been shown to be efficacious in the evaluation of migration anomalies [7], tuberous sclerosis [18], trauma Fig. 5.-lIIustration of relationship of migrating neurons to fibers of the [19], and tumors [20, 21]. Moreover, assessment of brain radial glial cells. Migrating is seen ascending the glial fiber (radial myelination by MR imaging [22-24] promises to be useful in fiber) led by multiple pseudopodia. Any damage to radial glial fiber will the assessment of developmentally delayed patients. In view presumably cause an arrest of cell migration at that point. Incomplete destruction of the germinal matrix cells will result in an abnormal migration of this increased sensitivity and specificity, we believe that of neuroblasts, this presumably is the cause of the abnormal cortex that MR imaging should be the primary method of screening lines and frequently surrounds the cleft. (Adapted from [10]. Reprinted with permission from [7].) children who have seizures or developmental delay. We rec­ ommend 5-mm thick (2 .5-mm gap) SE 2500/35-70 images in both the axial and coronal planes as a screening exam for patients older than 18 months. In patients between 8 and 18 months of age, there is little contrast between gray and white the septum pellucidum, in both schizencephaly and optic matter on these sequences [24]. For optimal evaluation, nerve hypoplasia [1,2], can also be explained on an ischemic therefore, we recommend imaging patients in this age group basis, if one postulates that the developing septum pellucidum with an SE 600/20 sequence in at least one plane. is also a watershed area that is supplied by tenuous trans­ In summary, schizencephaly is probably more common and callosal branches of median artery of the corpus callosum, more frequently unilateral than has been generally accepted. which Padget [14] has shown to be present in the 7 -week­ This anomaly presents with a variably severe clinical picture, old embryo. This vascular supply in the embryo would be depending on the amount of brain involved, but nearly all analogous to that in the adult whereby the septum pellucidum patients have intractable seizures. MR provides excellent is supplied by transcallosal branches of the pericallosal artery. demonstration of the anatomic changes in schizencephaly. Further definition of the cerebral blood supply of the 7-week­ Evidence is mounting that MR should be the imaging method old fetus is necessary if this theory is to be verified . of choice in the evaluation of patients who have seizures or An alternative explanation may be offered as well. If the developmental delay. genes for the optic nerves and septum pellucidum lie near to one another and to the gene for the germinal matrix, a genetic factor may be present. Further investigations in chromosomal mapping may clarify this matter. REFERENCES

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