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Case Report

Fetal Schizencephaly Associated With Middle Cerebral Artery Occlusion and Maternal Second-trimester Methamphetamine Exposure

Ziad A. Haidar, MD; Gokhan Anil, MD; Christos G. Hatjis, MD

Schizencephaly is a rare neuronal-migration disorder characterized by clefts lined with gray matter in the primary cerebral fissure of the cerebral hemispheres.1 It is usually discovered after birth. Only a few cases have been diagnosed in utero.2 Schizencephaly is a heterogeneous disorder that can be caused by environmental factors (eg, brain ischemia), or less frequently by genetic diseases. The extent of the neuronal disorder in the cerebral mantle determines the severity of the clinical presentation. Computed tomography (CT) and magnetic resonance imaging (MRI) are helpful in establishing the diagnosis before age 1 year.

The case presented here involves prenatal diagnosis of schizencephaly by ultrasonography and fetal color-flow Doppler velocimetry. The authors postulate that the disease was caused by occlusion of the fetal left middle cerebral artery (MCA) secondary to prenatal maternofetal amphetamine exposure in the late second trimester.

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CASE REPORT

An 18-year-old woman (gravida 3, para 1) presented at 14 weeks’ gestation for prenatal care. Her medical history was unremarkable, except for oral contraceptive use during the first 6 weeks of this pregnancy. Results of level II screening obstetric ultrasound at 18.5 weeks were normal, including the width of the fetal lateral ventricles.

At 30 weeks, the patient admitted to manufacturing and distributing methamphetamines. Ultrasonography at 37.8 weeks’ gestation revealed fetal hydrocephalus. Both lateral ventricles were dilated, the left ventricle being more involved than the right. The lateral wall of the left ventricle and the cerebral mantle on that side were not visible. Color-flow Doppler velocimetry failed to delineate the left MCA. The right MCA and circle of Willis were visible (Figure).

Figure not available online

Color-flow Doppler real-time ultrasonogram of the fetal head at 37 weeks' gestation showing the circle of Willis and nonvisualization of the left middle cerebral artery (arrow head). The cleft defect is indicated by the arrow. Courtesy of Christos G. Hatjis, MD.

Following extensive counseling, the patient underwent primary cesarean delivery at 39 weeks' gestation. The liveborn 2,950-g female infant had Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. Results of a maternal urine toxicology screen were negative prior to delivery. No other urine toxicology findings were available.

The newborn had normal muscle tone and symmetrical movements. Ultrasonography followed by MRI of the baby's head confirmed the diagnosis of bilateral, open-lip schizencephaly (type II), with partial agenesis of the corpus callosum. Ophthalmologic evaluation revealed small optic discs and temporal pallor. Hearing abnormalities were reported, but no other anomalous findings were noted. Results of neonatal viral cultures and serology tests were all negative.

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DISCUSSION

Schizencephaly is a developmental brain malformation due to abnormal neuronal migration. It is characterized by congenital clefts of the cerebral mantle, mainly at the level of the primary cerebral fissure. The clefts can be unilateral or bilateral. Concomitant central nervous system (CNS) structural abnormalities are common, such as agenesis of the corpus callosum. Hydrocephalus is usually not present in schizencephaly type I ("fused clefts"). In type II, hydrocephalus is invariably present, with an open cleft connecting the subarachnoid space to the ventricles.

Clinical manifestations depend on the extent of the underlying CNS disease. They include developmental and mental retardation, hypotonia, focal or generalized motor abnormalities, and seizures. Diagnosis is usually established by imaging via ultrasound, CT, and/or MRI.

The underlying etiologies for schizencephaly can be divided into acquired and congenital.1,2 Vascular abnormalities or occlusions, maternal trauma, fetal viral infections or prenatal exposure to drugs (eg, cocaine)3 have been associated with the development of schizencephaly. Most reports suggest that acquired schizencephaly usually develops in the first trimester of pregnancy.1-3 Similarly, congenital or developmental schizencephaly1,4,5 that is due to the primary failure of neuronal development and/or migration also occurs in early gestation. Inheritance may be either autosomal-recessive or autosomal-dominant, with incomplete penetrance. The risk of recurrence is 25% to 50%, depending on the mode of inheritance. In some cases, mutations in the human homeobox gene EMX-2 are thought to be responsible for hereditary schizencephaly.5 This gene family appears to play a critical role in the formation of CNS tissues during embryonic development.

Prenatal diagnosis of schizencephaly can be achieved via second-trimester ultrasound.2 Doppler velocimetry can also be used to detect vascular abnormalities or occlusions. Rare cases have been reported associating the occurrence of schizencephaly with a history of maternal cocaine abuse in early pregnancy.3

In this case, schizencephaly was not diagnosed until late in the third trimester. Second-trimester ultrasound did not reveal any CNS abnormalities. Although that observation does not rule out the presence of schizencephaly, it is unlikely given the normal findings at 18 weeks and the extensive defect noted in the third trimester. The authors postulate that because of the maternal exposure to methamphetamines at about 30 weeks' gestation, fetal schizencephaly developed late in pregnancy due to occlusion or vasoconstriction of MCAs.

A search of the literature was conducted to identify cases associating prenatal maternal methamphetamine use and fetal schizencephaly or other fetal anomalies.6,7 Several series and case reports failed to demonstrate a definite relationship between congenital defects and maternal methampheta- mine use during pregnancy. However, prenatal maternal methamphetamine use has been associated with fetal withdrawal syndrome, mental and developmental delays, and neonatal behavioral abnormalities.

Methamphetamines are known to be CNS sympathetic stimulants and vasoconstrictive agents. In adults, methamphetamine use has been associated with hypertensive crisis, tachycardia, cardiac arrhythmias, hyperthermia, ischemic stroke, seizures, rhabdomyolysis, acute renal failure, and thrombocytopenia.8

The authors cannot conclusively prove a cause-and-effect relationship between maternal methamphetamine use at 30 weeksê gestation and fetal MCA vasoconstriction or occlusion associated with schizencephaly. However, the normal ultrasonographic fetal CNS appearance at 18 weeksê gestation, as well as the temporal relationship between maternal methamphetamine exposure at 30 weeksê gestation and the subsequent development of fetal schizencephaly, are highly suggestive. It is certainly possible that antenatal methamphetamine exposure in the late second or early third trimester was a contributing factor to, or even the principal cause of, the late development of fetal schizencephaly.

The potential for vasocon-striction and resulting ischemic fetal damage can also be inferred on the basis of reports describing an increased incidence of intrauterine growth restriction, premature birth, low birthweight, fetal distress, and fetal demise relative to maternal methamphetamine exposure in utero.6,7 This hypothesis is further supported by reports of maternal and fetal hypertension in the pregnant sheep model, as well as the occurrence of decreased fetal hemoglobin oxygen saturation and increased vascular resistance resulting from maternal methamphetamine exposure.

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CONCLUSION

This is the first reported prenatal diagnosis of late-onset (ie, third-trimester) schizencephaly. It emphasizes the importance of eliciting accurate, detailed information about maternal alcohol and drug abuse throughout pregnancy via specific, nonjudgmental questioning—especially in teenaged and young adult gravidas who exhibit other high-risk behaviors.

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Ziad A. Haidar, MD, is attending obstetrics and gynecology physician, Cumberland, MD. Gokhan Anil, MD, is chief obstetrics and gynecology resident, Department of Obstetrics and Gynecology, West Virginia University of Medicine-Charleston Division and Charleston Area Medical Center. Christos G. Hatjis, MD, is associate chairman, Division of Maternal-Fetal Medicine, Childrenês Hospital Medical Center of Akron, Ohio; chief of Maternal-Fetal Medicine, Summa Health System, Akron, Ohio; and professor, Department of Obstetrics and Gynecology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio.

References

1. Jeng LB, Tarvin R, Robin NH. Genetic advances in central nervous system malformations in the fetus and neonate. Semin Pediatr Neurol. 2001;8(2):89-99.
2. Nyberg DA, McGahan JP, Pretorius DH, Pilu G, eds. Diagnostic Imaging of Fetal Anomalies. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:256-257.
3. Suchet IB. Schizencephaly: antenatal and postnatal assessment with colour-flow Doppler imaging. Can Assoc Radiol J. 1994;45(3):193-200.
4. Haverkamp F, Zerres K, Ostertun B, Emons D, Lentze MJ. Familial schizen- cephaly: further delineation of a rare disorder. J Med Genet. 1995;32(3): 242-244.
5. Brunelli S, Faiella A, Capra V, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet. 1996;12(1):94-96.
6. Teris: Methamphetamines. Teratogen Information System Web site. Available at: http://depts.washington.edu/terisweb/teris/. Accessed December 9, 2004.
7. Reprotox: Methamphetamines. Reproductive Toxicology Web site. Available at: http://www.reprotox.org/Default.aspx. Accessed Decem-ber 9, 2004.
8. Martindale Complete Drug Reference:Methamphetamines Thomson Micromedex Web site. Available at: http://www.micromedex.com/products/martindale/. Accessed December 9, 2004.

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