* Address correspondence to Vernon D. Byrd, MD, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 21^st and Garland Ave, Nashville, TN 37232-2675. Ph 615-322-0999 Fax 615-322-3764

Synonyms: None.

Prevalence: Approximately 70 cases have been described in children, including two in utero.

Definition: Clefts in the cerebral mantle (usually bilateral), lined by pia-ependyma, with communication between the ventricles and subarachnoid space.

Etiology: Two theories are currently accepted. One argues a failure in neuronal migration from the germinal matrix, while the other argues a post-migrational vascular insult.

Associated anomalies: Ventriculomegaly, microcephaly, polymicrogyria, gray matter heterotopias, dysgenesis of the corpus callosum, absence of the septum pellucidum, and optic nerve hypoplasia.

Differential diagnosis: Holoprosencephaly, hydranencephaly, porencephaly, arachnoid cysts.

Prognosis: Variable. Generally suffer from mental retardation, seizures, developmental delay and motor abnormalities.

Management: As for diseases with extremely poor outcome.

MESH Brain-abnormalities, -pathology; Cerebral-Palsy-diagnosis; Cerebral-Cortex-abnormalities, -pathology; Leukomalacia,-Periventricular-diagnosis; Hemiplegia-congenital BDE 3001 ICD9 742.4 CDC 742.280

Introduction

Schizencephaly is a disorder characterized by congenital clefts in the cerebral mantle with communication between the subarachnoid space laterally and the ventricular system medially. The disorder was originally characterized by Yakovlev and Wadsworth^1,2. They described two variants of schizencephaly by the presence of "fused" clefts in the cerebral mantle (type I) as opposed to separated clefts of mantle with concordant "hydrocephalus" (type II).

Both of the previously reported cases diagnosed in utero by sonography involve the type II variety^3,4,5. We present the third case of prenatally diagnosed schizencephaly (type II) by sonography followed by a discussion of the theories of pathogenesis, the sonographic characteristics, and salient features distinguishing schizencephaly from other intracranial malformations.

Case report

A 39-year-old G1 was referred to our institution at 35 weeks from her last LMP for fetal evaluation. She had no prenatal care and had developed pregnancy-induced hypertension. The prenatal course was otherwise unremarkable.

Examination of the fetal head (fig 1-3) demonstrated absence of cortical mantle in the distribution territory of the middle cerebral artery.

  Figure 1: A band of cortex is seen below the sagittal suture. The lateral aspect of the brain (middle cerebral artery distribution) is absent.

  Figure 2: The midbrain structure in this low section are visible and unremarkable. In the front of the brain, a sliver of brain is visible (arrow).

  Figure 3: In a higher section than fig. 2, the top of the thalami and the choroid plexuses are seen. The cortical mantle is absent. The arrow points to side-lobe artifacts.

A band of cortex was seen below the sagittal suture. The midline cranial structures, including the falx and thalami, were present. The posterior fossa and remaining fetal anatomy were also unremarkable. The cerebrospinal fluid from the lateral ventricle was in continuity with the fluid along the convexity. The absence of lateral brain, and the distribution of the remaining cortex was consistent with schizencephaly. The estimated gestational age was 34 weeks, and the estimated fetal weight was appropriate.

The patient was hospitalized and one week later, labor was induced at 36 weeks. A 2780g female was born by vaginal delivery, with Apgar scores of 8 and 9 at 1 and 5 minutes. No resuscitative efforts were needed. The only physical abnormality noted was slightly increased tone.

Further study was obtained with ultrasound (fig 4) and MRI.

 

  Figure 4: Post natal examination. This coronal section demonstrates a band of cortex below the sagittal suture, with a large void on the lateral aspect of both hemispheres.

These studies confirmed the prenatal diagnosis of schizencephaly and the presence of the corpus callosum, while demonstrating absence of the septum pellucidum.

The child"s course was unremarkable until 2 months of age, when an increase in head size and an increase in tone were discovered. A ventriculoperitoneal shunt was placed, and the patient recovered well. At 22 months, the child was readmitted for the onset of seizures. After appropriate therapy and seizure prophylaxis, the infant now has moderate delay in social skills and severe motor development delay.

Discussion

Prevalence

Schizencephaly is a rare congenital brain malformation with approximately 70 cases described in children, including two in utero^3,5.

Pathogenesis

The development of the cerebral cortex begins near the end of the second gestational month with the migration of neuroblasts from the germinal matrix (neopallium), located lateral to the developing lateral ventricle⁶. Wave after wave of neuroblasts will assume a deeper position in the cortex, as the newly released neuroblasts migrate to a more superficial location⁶. The majority of cell migration occurs from weeks eight through sixteen⁷. These cells migrate radially to assume a predetermined position within the cerebral cortex⁷. In theory, a defect in this migratory process would give corresponding defects in the associated cortex.

The precise etiology of schizencephaly remains unknown. The original work of Yakovlev and Wadsworth^1,2 contends that a failure of normal migration of the primitive neuroblasts results in the cerebral cleft. The continuity of gray matter along the associated cerebral malformations supports this theory^8,9. Others argue that schizencephaly is a part of a spectrum of encephaloclastic disorders^10,11. Documentation of progressive, destructive changes in an apparent case of schizencephaly in utero adds support to the hypothesis of an encephaloclastic event³. They propose bilateral vascular insults in the distribution of the middle cerebral artery as the encephaloclastic event³ (fig 5). This is the only reported case of such progression in utero. More recently, Barkovich and Norman¹² have hypothesized a vascular etiology. They proposed the abnormality results from an infarction in an area of the germinal matrix during the seventh week of embryogenesis. Their theory is based upon the demonstration of watershed zones in the gray matter along the lateral ventricles in the area of the germinal matrix^13,14.

Figure 5: One of the theories to explain the formation of schizencephaly, is an infarction of the middle cerebral artery territory (black vessels) with preservation of the anterior cerebral territory, and basilar artery flow. The infarction might be due to a transient hypotension. The resulting anomaly (right) is a direct communication between the lateral ventricle and the convexity through a large defect of the lateral aspect of the cortical mantle.

Diagnosis

The neuropathological features of schizencephaly are as follows: 1) hemispheric clefts, lined with pia-ependyma, usually bilateral, in the area of the Sylvian fissure 2) communication of the subarachnoid space with the lateral ventricle medially, with infolding of gray matter along the cleft, and 3) multiple associated intracranial malformations, including polymicrogyria, gray matter heterotopias, absent septum pellucidum, optic nerve hypoplasia and agenesis of the corpus callosum^1,3 (Table 1 ). The ultrasonographic diagnosis depends upon the demonstration of a defect in the cerebral mantle in the area of the Sylvian fissures and establishing communication between the enlarged lateral ventricle medially and the subarachnoid space laterally^3,4,5,15. One should also expect to see some of the associated malformations, such as an absent septum pellucidum and agenesis of the corpus callosum, by ultrasound.

Table 1: Neuropathological Features of Schizencephaly

g Pia-ependymal lined clefts in the hemispheres in the area of the sylvian fissures (usually bilateral).

g Communication between the subarachnoid space and the lateral ventricle, with infolding of gray matter along the cleft.

g Multiple associated cranial malformations: 1 polymicrogyria 1 gray matter heterotopias 1 absent septum pellucidum 1 agenesis of the corpus callosum 1 optic nerve hypoplasia

Differential diagnosis

The differential diagnosis for similar appearing CSF fluid containing spaces by ultrasonography, in addition to schizencephaly, includes the following: holoprosencephaly, hydranencephaly, porencephaly, and bilateral subarachnoid cysts (Table 2).

Table 2: Differential diagnosis of schizencephaly

Holoprosencephaly	Hydranencephaly
Monoventricular cavity with a single midline thalamic mass. Midline facial anomalies.	Near complete absence of the cerebrum. Intact meninges and cranial vault.
Porencephaly	Arachnoid cysts
May appear similar to schizencephaly if bilateral and near the sylvian fissures (CT and MR may demonstrate lack of gray matter lined cleft).	Less likely to be symmetric. Typically do not communicate with lateral ventricle.

Holoprosencephaly consists of a monoventricular cavity with a single midline thalamic mass. In addition, there are midline facial anomalies and absence of the falx with holoprosencephaly, not with schizencephaly¹⁵.

Hydranencephaly, the more severe form of porencephaly, consists of near total absence of the cerebrum, but with intact meninges and cranial vault, the latter being the distinguishing factor from that of anencephaly^5,15.

Differentiation from focal areas of porencephaly, especially in the area of the sylvian fissures could pose a diagnostic dilemma by ultrasound. Of course, this would imply accepting the theory of schizencephaly as a dysgenetic anomaly, as previously discussed.

Bilateral subarachnoid cysts typically do not communicate with lateral ventricles and are less likely to be symmetric⁵. Furthermore, subarachnoid cysts do not cause hydrocephalus¹⁵ and therefore would be less likely to cause differential problems.

It should be noted that the previously reported cases of schizencephaly characterized by ultrasound^3,4,5 include the type II variety described by Yakovlev and Wadsworth^1,2.

We suppose that the type I variety, which consists of "fused" clefts without hydrocephalus, may not be detected by sonography. The type I lesion is less commonly recognized but readily identified by CT and MRI^8,12. Further study will be necessary to determine the relative incidence of this variant.

Associated anomalies

As described previously, associated cerebral anomalies include ventriculomegaly, polymicrogyria, heterotopias, agenesis of the corpus callosum, and absent septum pellucidum^{1-2,4-5,8-9,12,16-20}. The incidence of an absent septum pellucidum is reported to be near 50%¹⁷. In addition to these well known associations, optic nerve hypoplasia has been identified along with schizencephaly, simulating septo-optic dysplasia^21,22.

Comments

Schizencephaly is a disorder over which there is much debate concerning the precise pathogenesis. As mentioned previously, theories consist of those who argue an abnormality in neuronal migration^1,2 and those who include schizencephaly as a part of a spectrum of encephaloclastic disorders^10,11. One might argue that determining the precise etiology of such malformations is of no clinical concern. However, there is evidence of cerebral malformations in 5-20% of siblings of children with neuronal migration disorders ^24,25. Patients with schizencephaly tend to suffer from more neurological impairment than those with cases of porencephaly¹⁵. Schizencephalic patients generally suffer from varying degrees of mental retardation and developmental delay, as well as seizures and various motor abnormalities⁹.

As more cases of schizencephaly are diagnosed and followed in utero, the pathogenesis may be better understood.

References

 

1. Yakovlev PI, Wadsworth RC. Schizencephalies: a study of the congenital clefts in the cerebral mantle. I: Clefts with fused lips. J Neuropatol Exp Neuro 5:116-130, 1946.

2. Yakovlev PI, Wadsworth RC. Schizencephalies: a study of the congenital clefts in the cerebral mantle. II: Clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol 5:169-206, 1946.

3. Klingensmith WC, Coiffi-Ragan DT. Schizencephaly: Diagnosis and progression in utero. Radiology 159:617-618, 1986.

4. Di Pietro MA, Brody BA, Kuban K, Cole FS. Schizencephaly: Rare cerebral malformation demonstrated by sonography. AJNR 5:196-198, 1984.

5. Komarnski CA, Cyr DR, Mack LA, Weinberger E. Prenatal diagnosis of schizencephaly. J Ultrasound Med 9:305-307, 1990.

6. Sandler TW. Langman"s Medical Embryology. 5th Edition Williams and Wilkins. pp. 355-359, 1985.

7. Rackic P. Neuronal migration and contact guidance in the primate telencephalon. Postgrad Med J (suppl. 1) 54:25-37, 1978.

8. Bird CR, Gilles FH. Type I schizencephaly: CT and neuropathologic findings. AJNR 8:451-454, 1987.

9. Miller GM, Stears JC, Guggenheim MA, Wilkering GN. Schizencephaly: A clinical and CT study. Neurology 34: 997-1001, 1984.

10. Muir SC. Hydranencephaly and allied disorders. Arch Dis Child 34:231-246, 1959.

11. Dekaban A. Large defects in cerebral hemispheres associated with cortical dysgenesis. J Neuropathol Exp Neurol 24:512-530, 1965.

12. Barkovich AJ, Norman D. MR imaging of schizencephaly, AJR 50:1391-1396, 1988.

13. DeReuck J, Chatta AS, Richardson EP, JR. Pathogenesis and evolution of periventricular leukomalcia in infancy. Arch Neurol 27:229-236, 1972.

14. Takashima S., Ta