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Intracranial arteriovenous malformation with maternal carbamazepine use
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     1 Department of Pediatrics, University College of Medical Sciences and GTB Hospital, Delhi, India

    2 Department of Radiology, Aruna Asif Ali Government Hospital, Delhi, India

    1 month old child born to primigravida mother on prolonged carbamazepine therapy presented with recurrent seizures. The child had abnormal facies and was diagnosed to be having arteriovenous malformation with intracranial hemorrhage on neuroimaging. This case suggests that development of arteriovenous malformation in a child with maternal carbamazepine therapy may occur as a part of clinical profile of 'fetal anticonvulsant syndrome'.

    Keywords: Intracranial arteriovenous malformations; Maternal carbamazepine therapy; Fetal anticonvulsant syndrome

    Arteriovenous malformations (AVM) are thought to be congenital lesions that derive from the failure of normal maturation of primitive vascular networks during embryogenesis. Here it is reported the association of a cerebral arteriovenous malformation in an infant with the maternal use of carbamazepine.

    Case report

    A 1-month-old child was brought to emergency room with history of mild intermittent fever for 2 days and multiple episodes of left focal convulsions in the last 12 hours. Child was born to 24-year-old primigravida at term, cried soon after birth and was on exclusive breast feeds. Mother was known epileptic and was on carbamazepine (900 mg daily) for last 9 years. The seizures were well controlled except at 6 month of gestation when the dose had to be hiked to 1200 mg daily.

    The child weighed 3.75 Kg and had occipitofrontal circumference of 38 cm. Abnormal facial features present in the child were hypertelorism, midface hypoplasia and micrognathia. He also had feeble cry and poor activity. Anterior fontanelle was not bulging. Tone was increased with brisk deep tendon reflexes and ill-sustained ankle clonus. Possible diagnosis of hypocalcemic convulsion was kept and child was started on intravenous calcium gluconate but child continued to have left focal convulsions. Lumbar puncture done on admission revealed hemorrhagic cerebrospinal fluid (CSF) and was presumed to be traumatic. Repeat lumbar puncture done on day-3 of admission revealed xanthochromic CSF having plenty of RBCs with protein of 128 mg/dL and sugar of 58 mg/dL.

    On day-4 of admission child developed excessive cry followed by apneic episodes. In view of hemorrhagic CSF and a deteriorating child, diagnosis of intracranial bleed was suspected. Ultrasonography of skull was done which showed right parietal cystic space occupying lesion. Child developed several episodes of left focal convulsions on day-6 and was started on phenobarbitone. On careful auscultation, bruit was heard on anterior fontanelle. CT scan (brain) suggested the presence of an AV malformation in right fronto-parietal region and surrounding hemorrhage with intraventricular extension. MRI brain was suggestive of a large AV malformation with nidus in right high fronto-parietal region. The malformation had a feeding vessel from right middle cerebral artery and drainage to superior sagittal sinus [Figure - 1]. There was also a subacute hematoma in right fronto-temporal lobe with mass effect and midline shift with obstructive hydrocephalus and intraventricular hemorrhage.

    Child was managed conservatively and was referred for neurosurgical intervention when stabilized. The baby was operated for AV malformation elsewhere but died later as reported by parents in follow up.

    Discussion

    Proper seizure control with appropriate anticonvulsant therapy is the primary goal in treating women with epilepsy.[1] The commonly used anticonvulsants are established human teratogens.[2] Congenital malformations were more common among offspring of women on antiepileptic medications (4.6%) than among offspring of untreated patients (2.8%).[3] The neonate born to mothers on anticonvulsant therapy should therefore be assessed carefully for epilepsy and anticonvulsant associated dysmorphology.

    In the present case, the mother took anticonvulsant therapy for 8 years which continued throughout conception. This baby had abnormality of facial features consistent with fetal carbamazepine teratogenecity.[4] Maternal carbamazepine has been shown to be associated with fetal cardiac malformations like atrial septal defect, transposition of great arteries and ventricular septal defect.[5] The association of carbamazepine with arteriovenous malformations has not been reported in literature to the best of author's knowledge. However, as carbamazepine is known to be associated with cardiovascular teratogenecity, it is possible that arteriovenous malformation in the present case was due to carbamazepine therapy.

    AVMs are considered congenital lesions and are characterized by failure of the embryonic vascular plexus to fully differentiate and develop a mature capillary bed in the affected area. AV malformations are typically located in cerebral hemispheres, but may be situated in cerebellum, brain stem or spinal cord.[6] The formation of AVMs probably relates to sequential formation and resorption of cerebral surface veins. Their structure may change and grow postnatally but only in relation to a prenatally existing lesion. Molecular biologic factors are thought to be important to AVM development. These may include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Anticonvulsant induced teratogenecity has been suggested to be due to inhibition of enzyme epoxide hydrolase resulting in accumulation of teratogenic epoxide intermediates of antiepileptic drugs.[7] Perinatal events disrupting angiogenesis thus have a potential to cause arteriovenous malformations.

    The author's believe that the development of AV malformation in the child of mother with carbamazepine therapy during pregnancy represents a possible etiology and adds to the clinical profile of "fetal anticonvulsant syndrome". Considering the fact that cardiovascular malformations can be successfully tackled surgically; it may be worthwhile screening babies of mothers with long term anticonvulsant therapy for any cardiovascular malformation including AVM. Since this is a surgical emergency, the need for early diagnosis cannot be overemphasized.

    References

    1.Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia 2005; 46 (Suppl 9) : 117-124. [PUBMED]

    2.Yerby MS, Leavitt A, EricKson B, McComick KB, Loewenson RB, Sells CJ et al. Antiepileptic drugs and the development of congenital anomalies. Neurology 1992; 42 : 132-140.

    3.Artama M, Auvineu A, Raudaskoski T, Isojarvi I, Isojarvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 2005; 64 : 1874-1878.

    4.Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320: 1661-1666. [PUBMED]

    5.Gupta G, Bansal A, Singh M. Antenatal Carbamazepine use associated with d-TGA and ASD. Indian Pediatr 2002; 39: 101-102. [PUBMED] [FULLTEXT]

    6.Halem RHA. The nervous system: Intracerebral hemorrhage. In Behrman, Kliegman, Jenson, eds. Nelson Textbook of Pediatrics . Philadelphia; WB Saunders Co; 1999; 1856.

    7.Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984; 25 : 77-83. [PUBMED](Narang Manish, Shah Dheeraj, Natasha Gup)