Unilateral right closed-lip schizencephaly

Abstract

Schizencephaly is a rare central nervous system (CNS) malformation secondary to neuronal migration defects. The pathogenesis is complex and is secondary to environmental and genetic factors. Clinically, the majority of patients present with varying degrees of motor and psychological disturbances. Imaging plays a cornerstone in the diagnosis by identifying the characteristic lesional features and recognising other associated abnormalities such as an absent septum pellucidum and corpus callosum dysgenesis. Here, we present a male paediatric case who presented with an interestingly asymptomatic unilateral right closed-lip schizencephaly and review the aetiology, clinical presentation and imaging characteristics of the disease and associated literature.

Background

Schizencephaly is a rare central nervous system (CNS) malformation first described in 1885 in which a cleft extends from the ependymal surface of the brain to the pia mater. Although in the vast majority of cases a neurological deficit is detected, schizencephaly can rarely pass unnoticed, particularly when a small unilateral defect is present. Imaging plays a cornerstone in diagnosis, and MRI can exquisitely depict the open-lip or closed-lip variants of the schizencephalic cleft both in utero and postnatally.

The correct identification of this rare condition, especially in the presence of motor and psychological disturbances, is paramount as it facilitates the provision of early and comprehensive neuropsychological, speech, and language support, which will significantly alter the overall disease prognosis. Here, we present a male paediatric case who presented with a unilateral asymptomatic right closed-lip schizencephaly and review the literature on the condition.

Case presentation

A 9-year-old boy with no medical or developmental background presented to emergency department following a fall. The fall was followed by a 30 s transient loss of consciousness and three episodes of vomiting. No witnessed seizure or aura was associated with the presentation. On assessment, the patient scored 15/15 on the Glasgow coma scale. Clinical examination was unremarkable. Initial laboratory evaluation, including a full blood count, renal, liver and electrolyte panels, were all within normal limits. A chest X-ray and a baseline ECG were unremarkable.

Investigation

A head CT scan demonstrated a deep cerebrospinal fluid (CSF) filled cleft extending from the lateral wall of the body of the right lateral ventricle to the right lateral frontoparietal cortex. No intracranial haemorrhage was present. A brain MRI scan confirmed the presence of a deep cleft in the right frontoparietal region close to the right Sylvian fissure. The cleft extended through the full thickness of the right cerebral mantle into the body of the right lateral ventricle and appeared to be lined by heterotopic grey matter. The midline structures, corpus callosum, ventricles and CSF spaces were unremarkable. The left cerebral hemisphere was radiologically normal. The MRI features were consistent with the diagnosis of unilateral right closed-lip schizencephaly (figures 1A–3C).

Figure 1.

Non-enhanced CT scan of the brain. (A) Axial image showing a deep CSF-filled cleft extending from the lateral wall of the body of the right lateral ventricle (yellow arrow) to the right lateral frontoparietal cortex (red arrow). Note the unremarkable left hemicranium. (B) coronal image again showing a deep CSF-filled cleft extending from the lateral wall of the body of the right lateral ventricle (yellow arrow) to the right lateral frontoparietal cortex (red arrow). Note the lips of the cleft are lined with cortical grey matter and abutting each other, consistent with the diagnosis of right closed-lip schizencephaly. (C) Axial bone window image showing a left occipital subgaleal hematoma (yellow arrow) without underlying skull fracture (red arrow).

Figure 2.

Non-enhanced MRI of the brain. (A) T2-weighted sequence. (B) T1-weighted sequence. (C) T2 fluid attenuation inversion recovery (FLAIR) sequence. The images depict a CSF-filled cleft (red arrow) extending medially from the body of the right lateral ventricle (yellow arrow) to the right lateral frontoparietal cortex. The cleft is lined with grey matter and the lips are marginated by polymicrogyria. The images also show periventricular gliotic changes and diffuse volume loss of the right hemisphere with an asymmetry of the right hemicranium suggesting an in utero focal injury as a cause of schizencephaly.

Figure 3.

Non-enhanced MRI of the brain. (A) Sagittal T1-weighted sequence showing the right frontoparietal cleft. Note the intact right temporal lobe. (B) Coronal T2 FLAIR sequence showing an intact septum pellucidum. Note the normal appearance of the left cerebral hemisphere. (C) sagittal T1 sequence showing an intact corpus callosum.

Differential diagnosis

The main differential diagnoses are transmantle heterotopia, porencephaly and focal cortical dysplasia (FCD). Transmantle heterotopia is differentiated from the closed-lip variant of the disease by the presence of tenting of the ventricular wall in schizencephaly rather than the lesion abutting the wall in transmantle heterotopias. Porencephaly is considered a differential diagnosis for the opened-lip schizencephaly in which imaging depicts a cleft lined by gliotic white matter and not grey matter, as in schizencephaly. FCD is a possibility, but here a cleft with no complete ventricular extension is usually seen. Furthermore, the absence of FCD-associated features such as hippocampal atrophy, blurring of the gray-white matter junction, cortical thickening and glioneuronal tumours favours schizencephaly.¹

Treatment

As the patient was asymptomatic, he was discharged the following day and was referred to the routine outpatient neurology clinic for follow-up.

Outcome and follow-up

On 3-month follow-up, the patient remained asymptomatic. The fall was deemed to be mechanical, and the patient was discharged to his general practitioner with a diagnosis of an incidentally detected asymptomatic unilateral right closed-lip schizencephaly and advised to seek medical advice if he develops any seizures or a focal neurological deficit.

Discussion

Schizencephaly, derived from the Greek word schizen, that is, to divide, is a rare CNS malformation secondary to neuronal migration defects. The condition was first described in 1885 as a cleft extending from the ependymal surface of the brain to the pia mater, where the two layers meet in the so-called pial-ependymal seam.^{2 3} In type I or ‘closed-lip’ schizencephaly, a strip of grey matter tissue connects one of the divided ends of the cortex to the other. In type II or ‘open-lip’ schizencephaly, the cleft extends through the hemispheres from the ependyma centrally to the pia peripherally, without a connecting band of grey matter.

The reported incidence of schizencephaly is 1 per 100 000 live births.⁴ In a study examining 4 million births, isolated schizencephaly carried a prevalence of 1.06/100 000 births, whereas schizencephaly plus at least one other major extracranial malformation had a prevalence of 0.49/100 000 births; leading to a combined overall prevalence of 1.54/100 000.⁵ Here, there was a fourfold increased risk for isolated schizencephaly in young parents (<20 years), while a threefold increased risk for non-isolated schizencephaly was observed with young maternal age. No gender predilection was noted.

The intrauterine pathogenesis of schizencephaly is complex and related to genetic and environmental factors. The developmental disturbances affecting both the germinative zones and migrating neurons on radial glial fibres occurs in the beginning of migrational events in the third month of gestation.^6–9 EMX2 gene mutation, which plays an important role in neuronal migration, has been linked with the development of schizencephaly in a few familial cases were as LHX2, HESX1, and SOX2 mutations (previously thought to be involved) have been refuted.¹⁰ More recently, the role of WDR62 and COL4A1 gene mutations has been described.^11–17 In utero Cytomegalovirus (CMV) and Herpes Simplex virus (HSV) infections have been associated with schizencephaly.^18–23 Furthermore, animal vaccination studies have linked the Rift Valley fever, bovine-virus diarrhoea and mumps viruses to the haemorrhages, necrosis and damage to migration of radial glial cells, a hallmark in the pathogenesis of the disease.^24–26 Vascular disruption is a commonly proposed mechanism of action of viral triggers and drugs (such as warfarin and cocaine) and can be linked to the periventricular gliotic and diffuse right-hemispheric volume loss as seen on our patient’s imaging, suggesting a perinatal/in utero injury in our case.

Given its rarity, the literature describing the clinical features of the disease is vastly based on case reports and short case series.^27–30 The rate of preterm delivery is double that of the general population.³¹ Postnatally, there is an increased motor and psychological disturbances risk. In a recent descriptive study examining 734 schizencephalic cases, 90% of patients had motor impairments ranging from hemiparesis to tetraplegia. Additionally, 78% of patients had neurocognitive dysfunction, and 68% experienced seizures.³ An absent septum pellucidum, cortical dysplasia, corpus callosum agenesis and microcephaly were associated with a twofold to ninefold increased risk of neurocognitive dysfunction. Early diagnosis (age <4 years) and neurocognitive dysfunction were associated with a fourfold to fivefold increased risk for a motor deficit. Similarly, diagnosis at <10 years, seizures and the presence of a motor deficit carried a threefold to fourfold increased risk for neurocognitive dysfunction. These markers can be used to predict the patient’s clinical decline and guide patient selection for future clinical and radiological follow-up.

Interestingly, as in our case, nearly 10% of patients can present without any motor deficit.³ Small unilateral schizencephaly can be asymptomatic with patients having an excellent developmental prognosis, especially when the motor cortex is spared.³² This is supported by various publications in which patients either led a silent clinical course or exhibited minor functional disruptions until schizencephaly being diagnosed in the fourth, fifth or even sixth decade of life.^33–36 Unfortunately and to the best of our knowledge, little is known regarding the incidence of asymptomatic adult schizencephaly as most of the literature is based on individual paediatric case reports and short case series. Such valuable information is paramount in helping avoid unnecessary panic or overzealous imaging and management strategies.

Radiological imaging plays a cornerstone in diagnosis and displays the open-lip or closed-lip variants of the cleft that tend to involve the Rolandic region, Sylvian fissures and the frontal areas as in our case.³⁷ Radiological suspicion should be triggered whenever a focal ventricular dilation is seen on prenatal ultrasonography (US) or CT scan or occasionally following visualisation of a grey matter-lined cleft on CT scan.17 34 37 38 However, MRI is far more sensitive for the identification of schizencephaly than other imaging modalities.^{32 38–41} The noticeable finding is the lining of the cleft by the cerebral cortex, often thickened by pachygyric or polymicrogyric cortex with heterotopia. Hydrocephalus complicates approximately 50% of open-lipped lesions although the mechanism for the impaired CSF dynamics is unclear.³¹ Agenesis of the septum pellucidum occurs in 70% of cases, and accompanying septo-optic dysplasia occurs in a further 10%–25% of patients. Agenesis or hypoplasia of the corpus callosum affects 30% of schizencephalics.³⁸

The prenatal diagnosis of schizencephaly would be helpful in guiding patient counselling and pregnancy management. In a national UK study evaluating 38 cases, schizencephaly was diagnosed via prenatal US in 47% of cases at a mean gestational age of 26 weeks with the vast majority of cases being of the open-lip variety. Only three antenatally detected cases were identified before 21 weeks' gestation (ie, within the period of the mid-pregnancy anomaly scan) and none before 20 weeks, unlike other structural cerebral defects.⁴² Several antenatally diagnosed cases displayed evidence of progressive change, with ventriculomegaly being present several weeks before recognition of the schizencephaly. In a comparably larger but earlier USA study, only 1.6% of cases were recognised antenatally.⁵ The UK authors attributed their higher antenatal detection rate to the improvement in the quality of anomaly scanning and the availability of MRI in assessing antenatal brain abnormalities, identifying cases that would have been missed by US alone.

The earliest report of MR imaging prenatally diagnosing schizencephaly was published in 1989 using a combination of US and MRI in a 29-week-old fetus.⁴³ Although serial follow-up prenatal US did not detect intracranial deterioration, progressive asymmetrical intrauterine retardation was noted. In the current era, a study examining 18 clefts correlated MR findings of schizencephaly on antenatal and postnatal scans and assessed possible changes that may occur.⁴⁴ Patients were scanned following a 27 weeks’ gestation suspicious US scan and the majority (80%) demonstrated bilateral clefts on MR imaging, which was higher than previously published data.32 37 45 46 Prenatally, 83% displayed the opened-lip variant, while only 53% remained open on postnatal scans. Antenatally, 67% had grey matter completely lining the cleft margins, while this jumped to 100% postnatally, confirming the diagnosis of schizencephaly. Dysmorphic grey matter with polymicrogyria was detectable prenatally along the cleft in 17% subjects with the remainder showing an apparent smooth lining. Polymicrogyria separate from the defect was found in 11% of cases antenatally which increased to 17% postnatally. This study showed that nearly half of open schizencephaly defects seen on fetal imaging will be closed on postnatal MR imaging. Prenatal MR imaging can only demonstrate some of the associated anomalies such as an absent septum pellucidum and corpus callosum agenesis.⁴⁴

Learning points.

• Schizencephaly is a rare CNS malformation secondary to neuronal migration defects and is associated with varying degrees of neurological and psychological dysfunction.

• Imaging plays a cornerstone in diagnosis, and in utero ultrasonography and MRI can exquisitely depict the open-lip or closed-lip variants of the schizencephalic cleft as early as 21 weeks of gestation.

• The number of cases of schizencephaly that have been reported worldwide is not currently known. However, the estimated prevalence of schizencephaly is 1/64 935 births.

• Up to 10% of patients can be asymptomatic with a further percentage presenting late in adulthood. Given the lack of published figures regarding the true incidence of asymptomatic adult cases, imaging and management strategies should be based on predictors of poor motor and psychomotor outcomes.

• Being a rare disease, there is a need to report more of such cases and advocate for long-term follow-up studies to better understand the natural history of the disease, which will influence overall imaging and management strategies.