Alejandro Fuerte, MD

McCrea N, Fullerton HJ, Ganesan V. Genetic and Environmental Associations With Pediatric Cerebral Arteriopathy: Insights Into Disease Mechanisms. Stroke. 2019;50:257–265.

Childhood arterial ischemic stroke (AIS) occurs by interaction between rare genetic risk factors and common environmental exposures. In this article, McCrea et al. expose these mechanisms relying mainly on the results of the VIPS study (Vascular Effects of Infection in Paediatric Stroke).

Genetic Associations

From a genetic point of view, it is important to highlight moyamoya arteriopathy and Neurofibromatosis type 1 (NF1). Moyamoya is a rare artery disease that consists of a progressive stenosis of the internal carotid artery and its main branches. Children with moyamoya are at risk of AIS, whereas adults are more prone to haemorrhagic stroke. NF1 is an autosomal dominant tumour-suppressor syndrome, caused by mutations in the gene encoding for neurofibromin, a RAS pathway inhibitor (chromosome 17). Children with NF1 have an increased risk of stroke, with odds ratios of 8.1 for haemorrhagic stroke and 3.4 for AIS.

ACTA2 and MYH11 encode proteins that form a major part of the vascular smooth muscle cell contractile apparatus. Heterozygous Arg179 ACTA2 mutations are associated with a distinctive cerebrovascular phenotype with proximal dilatation of carotid arteries and widespread distal occlusive arteriopathy. Specific mutations in MYH11 may cause thoracic aortic aneurysm, aortic dissection, and moyamoya-like occlusive cerebrovascular disease. Both dominantly inherited disorders carry attendant genetic implications for family members and aortic screening.

Mutations affecting vascular basement membranes (COL4A1 and COL4A2) result in variable clinical manifestations, including paediatric cerebral small vessel disease, increasing the risk of both ischemic and haemorrhagic stroke. The diagnosis is useful because although there is no treatment, preventive measures can be taken, like avoiding contact sports and anticoagulation.

Some mutations in the CECR1 gene cause deficiency of adenosine deaminase 2 (ADA2). Deficiency of adenosine deaminase 2 leads to abnormal endothelial and leukocyte development and differentiation. A polyarteritis nodosa-like presentation is common and can cause severe neurological features, such as lacunar and haemorrhagic stroke. Anti-TNF-α therapy is useful in these scenarios.

Environmental Associations

Although genetic disorders may confer susceptibility to paediatric AIS, environmental factors may be important second hits to express the phenotype or to precipitate stroke.

Circulating immune mediators can trigger activation of the coagulation system and platelet aggregation, promoting thrombus formation. This, together with the endothelial injury that usually occurs in this context, does contribute to AIS pathogenesis. The VIPS study showed a distinct pattern of inflammatory biomarkers depending on AIS pathogenesis. This could reflect the varied role of inflammation in AIS, for example, prothrombotic in children with structural heart disease or promoting endothelial injury in arteriopathy.

In the VIPS cohort, infection in the week preceding stroke conferred a 6-fold increased risk of AIS. The infections appeared mostly in the upper respiratory tract and were common across all stroke subtypes. Several viral infections, such as parvovirus, enterovirus, and influenza A, have been reported in the setting of childhood AIS. Varicella zoster virus (VZV) can also cause an arteriopathy and typically affects previously healthy young children, 3 to 4 months after chickenpox infection. It has a characteristic radiological pattern of focal stenosis of the proximal middle cerebral artery and basal ganglia infarction in contrast to VZV vasculitis. VZV DNA or anti-VZV antibodies in CSF aid diagnosis. As for bacteria, meningitis caused mainly by Salmonella species and Streptococcus pneumoniae can be complicated by AIS because of activation of the coagulation cascade, septic emboli, vascular tissue injury, and inflammation.

From the point of view of non-inflammatory factors, significant head trauma (requiring medical) in the previous week conferred an almost 40-fold increased odds of AIS compared with matched controls without trauma exposure in a large population-based study.

At the end of the article, the authors emphasize multifactorial pathogenesis of arteriopathy and the interplay between genetic and environmental factors. Some current therapies and useful methods of prevention, such as vaccination against varicella zoster, are discussed. Finally, it is pointed out that further definition of specific subtypes of artery disease and specific disease targets for trials should be an immediate priority.