Pysden et al.1 describe a female with trisomy 21 and bilateral moyamoya sequence who presented with a presumed perinatal cerebral infarct, detected through hemiparesis at 9 months of age. Because not all cortical strokes present with seizures in the newborn, it is possible that stroke in the Pysden case occurred in early infancy and was not perinatal, but on the other hand it may well have occurred in utero. The history illustrates the need for a comprehensive diagnostic work-up in infants at high risk of arteriopathy. Early recognition of carotid artery stenosis may lead to surgical revascularization to prevent recurrence, as in the case history presented. Interestingly, evidence of persistent foetal eye vasculature may prompt the diagnosis of arteriopathy.
The detection of arterial ischemic stroke (AIS) in the neonatal period relies on accurate brain imaging with serial ultrasonography and with brain magnetic resonance imaging of infants with unexplained seizures. Following detection of a focal brain lesion, a number of conditions that mimic stroke should be considered including border zone infarction, hypoglycaemia, tumour, and vascular anomaly. Further investigations will aim to classify AIS according to whether it is a consequence of trauma, infection, embolism, or other specific aetiologies such as acute blood loss, asphyxia, or extracorporeal membrane oxygenation. In many centres a more or less exhaustive search for prothrombotic tendencies (some genetic, some acquired as demonstrated by the presence of antiphospholipid antibodies) is undertaken. Arteriopathy is an important entity in childhood stroke but is rarely detected in the newborn period, although it is one of the pillars of the Virchow triad of the key features of thrombosis. Virchow noted that once foreign bodies lodged in the pulmonary circulation, there was a triad of adverse consequences, grouped into three categories: (1) phenomena due to irritation of the vessel and its surroundings; (2) phenomena due to blood-coagulation; and (3) phenomena due to interruption of the blood-stream.2 Pysden et al. draw the attention of clinicians to brain arteriopathies (‘phenomena with iritation of vessel and surroundings’) that may extend their presentation to the perinatal period. A perinatal arteriopathy (an ongoing disease of the arterial wall) may be due to a fetal infection with arteritis (rubella, cytomegalovirus, toxoplasmosis), an inborn error of metabolism (hyperhomocysteinaemia, primary hyperoxaluria, galactosialidosis, molybdenum cofactor deficiency, mitochondrial disease), an anomaly of karyotype (Miller–Dieker lissencephaly, trisomy 21), or a syndrome (infantile arterial calcinosis, Aicardi–Goutières syndrome, incontinentia pigmenti).
One might broaden the concept of a primary arterial disorder as a risk factor for stroke to include congenital vessel malformations for which the primary event (absence or atrophy) is often elusive, like carotid artery hypoplasia (which was probably present in the Pysden case). Isolated carotid hypoplasia may be due to drugs, toxins, or infectious agents. Unilateral hydranencephaly may result from unilateral (almost always left) total infarction in the area of the absent internal carotid artery (ICA). Hypoplasia or even aplasia of the ICA canal is invariably found in that context, but the reverse is not true because some persons have no ICA and no brain lesion at all. ICA agenesis or hypoplasia is most often unilateral and rare. Diseases associated with ICA agenesis have included neurofibromatosis I, Klippel–Trenaunay syndrome, Goldenhar syndrome, PHACE (posterior foseu, hemanglome arterial defect, cardiac problems, eye problems) syndrome,3 lobar holoprosencephaly, and apparently trisomy 21. Perfusion of the middle cerebral artery on the affected side may be from a transcavernous collateral arising from the contralateral ICA, from intact parts of the circle of Willis, from anastomoses with the external carotid artery, or through the rete typical of moyamoya sequence as in this case. In fact, six types of cerebral flow have been described.4 The main vascular supply for the brain in patients with congenitally small (hypoplasia) or absent (agenesis or aplasia) ICA is the vertebrobasilar system in bilateral cases. However, the contralateral ICA is the dominant supply for unilateral cases. Other types of arterial malformation than carotid agenesis, with perinatal stroke presentation in some, have been reported for several syndromes: PHACE syndrome, fibromuscular dysplasia, carotid elastin hyperplasia,5 Ehlers–Danlos I syndrome, Stickler syndrome and 22q11 deletion.
Any suspicion of arteriopathy or arterial malformation should warrant a high frequency neck vessel sonogram with Doppler imaging of carotid and vertebral arteries; this may need verification or completion with a computed tomography angiography and bone window sequence or with perfusion magnetic resonance angiography (with contrast). Neck vascular imaging is also useful in some instances of birth trauma (neck traction and rotation) where stroke follows carotid artery dissection.
We are, in the neonatal period, at an early stage of our discovery where arteriopathies are concerned. Genetic conditions underlying an arteriopathy with perinatal presentation are of interest because they may add to our understanding of risk factors for stroke. Apart from case reports like this, we will need prospective imaging studies of healthy newborn infants at different maturational stages, to document the prevalence and importance of congenital vascular anomalies (variations) and progressive arteriopathies in relation to the risk of stroke. Perhaps as important, because of ongoing perinatal remodelling, will be the study of anatomical variation and disease of brain veins and sinus.