Multiple strokes in a newborn

Perinatal arterial ischemic stroke (AIS) is an increasingly recognized cause of neurological disability. A heterogeneous variety of diseases and triggers can be synergistically related to pediatric AIS, including congenital heart malformations, sickle cell disorders, vasculopathies, hypertension, dyslipidemia, infections, and inherited pro-thrombotic predisposition. Herein, we report a case of multiple AIS in a newborn with two concomitant thrombophilic gene variants encoding enzymes involved in homocysteine (Hcy) metabolism. An apparently healthy 7-day-old Caucasian female underwent ophthalmologic examination participating in the vision-screening program for full-term newborns. Eye assessment was bilaterally normal with the exception of a marked pallor of the left optic nerve head (Figure 1; available at http://aaojournal.org). Optic neuropathy was suspected and, thus, additional clinical and laboratory exams were scheduled. Brain magnetic resonance identified an infarcted area involving the territory of the left middle cerebral artery (Figure 2; available at http://aaojournal.org). Magnetic resonance angiography revealed occlusion of the left internal carotid artery (Figure 3; available at http://aaojournal.org). Laboratory serum analyses showed slight decrease of folate (16.7 nmol/L) and cystathionine (0.41 µmol/L) concentrations, with concomitant increase of methionine (24.2 µmol/L). Plasmatic levels of vitamin B12 and fasting total Hcy were normal, but after oral methionine load an anomalous elevation of Hcy occurred (408%). Urine analyses were unremarkable. DNA genotyping revealed two hyperhomocysteinemic heterozygosis predisposing to thrombophilia: c.677C>T in methylenetetrahydrofolate reductase (MTHFR) gene, and c.833T>C/c.844-872ins68bp in cystathionine beta-synthase (CBS) gene. The final diagnosis was unilateral occlusion of internal carotid artery, ipsilaterally complicated by ischemic optic neuropathy and cerebral infarction, in a 7-day-old carrier of thrombophilic gene variants affecting pivotal Hcy metabolism-related enzymes, with abnormally elevated post-methionine Hcy plasma levels. Neonatologic data of the newborn, as well as the detailed reports of all investigations performed at her ninth day of life and the informations regarding the subsequent clinical management, are summarized in Table available at http://aaojournal.org. Inherited or acquired clotting abnormalities, associated with unbalanced hemostatic condition, can represent the cause of perinatal AIS. 1 Pediatric hyperhomocysteinemia (HHcy) is frequently related to low nutritional intakes of folate, vitamins B12 and/or B6, but also to several genotypic determinants. Polymorphisms in MTHFR gene, such as the common c.677C>T, result in a reduced function of this enzyme producing thermolabile enzymatic form. The relatively rare c.833T>C/c.844-872ins68bp mutation of CBS gene is not per se an ischemic risk but, when it is combined with an inefficient MTHFR, the thrombotic diathesis markedly increases. 4 Dodelson de Kremer and Grosso have studied the prevalence of hyperhomocysteinemic MTHFR 677 T-allele in newborns with hypoxic-ischemic encephalopathy and in their mothers, concluding that maternal mutated genotypes increase the chance of cerebral occlusive damage in the offspring. These lesions, often characterized by hypoplasia and/or thrombosis of internal carotid artery, poor or absent blood supply of middle and posterior cerebral arteries, and temporal-parietal brain infarction, partially resemble those identified in the present case. On the other hand, Kelly and co-workers, investigating cerebral and retinal infarctions in young hyperhomocysteinemic patients with CBS deficiency, have highlighted the role of carotid intraluminal thrombosis in ischemia pathogenesis. Elevated plasma level of Hcy, secondary to folate-pathway gene variants, can represent the culprit of an abnormal thrombo-coagulative predisposition. The presence of these peculiar mutations, causing functional defects in MTHFR, CBS and other enzymes, lead to vascular thrombophilic damage via hyper-activation of endothelial cells and platelets. These hyperhomocysteinemic effects, reliably arising in our newborn affected by an uncommon double heterozygosity (MTHFR c.677C>T plus CBS c.833T>C/c.844-872ins68bp), could play a crucial role in the pathogenesis of multiple AIS. In fact, the HHcy-related oxidant stress in sub-endothelial spaces may affect the uncoagulable properties of endothelium, giving back basically a more activable surface responsible for these dramatic thromboembolic events. In this apparently asymptomatic newborn, the early detection of ischemic optic neuropathy allowed us promptly to initiate diagnostic testing and therapy. Although Hcy-lowering treatment did not reliably ameliorate the prognosis of cerebral and ocular damages, no other thromboembolic events have occurred during 9-month follow-up. This case supports the rationale for a routine eye-screening program of full-term newborns, indicating both the crucial role of clinical suspicion to correctly address diagnostic iter and the importance of a proper preventive therapy when it is warranted.