David C. Lauzier1, BS; Kristin P. Guilliams1,2,3, MD, MSCI; Akash P. Kansagra1,2,4, MD, MS.
- Mallinckrodt Institute of Radiology, Washington University School of Medicine
- Department of Neurology, Washington University School of Medicine
- Department of Pediatrics, Washington University School of Medicine
- Department of Neurological Surgery, Washington University School of Medicine
Corresponding Author: David C. Lauzier, firstname.lastname@example.org, (828) 578-9926 (ORCID
0000-0003-2825-3360). 510 S Kingshighway Blvd, St. Louis, MO 63110.
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A 10-year-old girl with trisomy 21, epilepsy, and Moyamoya syndrome treated with prior encephaloduroarteriomyosynangiosis (EDAMS) presented to the emergency department following a three-week course of gait instability, short-term memory deficits, and slurred speech accompanied by intermittent left arm weakness and staring spells. Basic metabolic panel and complete blood count values collected upon admission were all within expected ranges. Her neurologic examination demonstrated 5/5 strength in both upper and lower extremities. Her neurological workup included magnetic resonance imaging and cerebral catheter angiography, which revealed imaging findings that are classically found in moyamoya vasculopathy (Figure 1). The patient’s neurologic status remained stable. For prevention of ischemic events related to her moyamoya syndrome, the patient was discharged with low-dose aspirin.
Moyamoya vasculopathy comprises chronic, progressive occlusion of the distal internal carotid artery and proximal anterior and middle cerebral arteries, which results in gradual development of lenticulostriate collateral pathways around the sites of occlusion that produce a characteristic “puff of smoke” appearance. Symptoms can be unilateral or bilateral, with unilateral disease typical of moyamoya syndrome1. Moyamoya vasculopathy in the setting of associated conditions is termed moyamoya syndrome, while moyamoya vasculopathy in the absence of underlying conditions or risk factors is termed moyamoya disease. Moyamoya disease is most common in patients of East Asian descent. Moyamoya syndrome occurs at elevated rates in patients with trisomy 21 (3800/100,000 prevalence)2, 3 and neurofibromatosis 1 (NF1, 600/100,000 prevalence)4 (Table 1). Sickle cell disease (SCD) leads to increased rates of moyamoya vasculopathy and ischemic events, though heterogeneous definitions of vasculopathy employed in past studies have limited precise estimates of the prevalence of moyamoya vasculopathy secondary to SCD5 . Indeed, moyamoya vasculopathy is observed in up to 13-30% of patients with SCD that undergo cerebral angiography1,6,7. In this population, arterial changes consistent with moyamoya are the product of excessive intimal hyperplasia and chronic thrombotic processes, and may be related to severity and duration of anemia7-9. Two recent studies in African populations have found high prevalence rates of over 50% of children with SCD9,10. Thus, the prevalence of moyamoya vasculopathy may be dependent on access to treatment of sickle cell disease early in life. Finally, moyamoya may be driven by SCD severity, as SCD cure via stem cell transplant has been reported to halt progression of vasculopathy11.
Recent research has clarified the biological basis for the associations between several conditions and moyamoya syndrome or disease. The association with trisomy 21 is likely due to chromosome 21 encoding for proteins involved in arterial physiology including superoxide dismutase 1, interferon-γ receptor, cystathionine β-synthase, and the α chains of type IV collagen12,13. Similarly, the association with neurofibromatosis type 1 is thought to result from proximity between the familial moyamoya disease gene (RNF213) mapped to 17q25.2 and the NF1 gene mapped to 17q11.2 14. The increased prevalence of moyamoya disease in East Asian populations is believed to reflect the prevalence of the RNF213 gene mutant allele, an important susceptibility gene of familial moyamoya disease that demonstrates an autosomal dominant pattern of inheritance with low penetrance15. In non-East Asian populations, the DIAPH1 gene has been recently identified as a risk gene for sporadic moyamoya disease16.
There are several additional risk factors for moyamoya vasculopathy. Age is a factor, as moyamoya disease presents with a bimodal age distribution with peaks at approximately 10 and 40 years of age17. Moyamoya disease also occurs at an approximately two-fold higher rate in females than males17. In Caucasian populations, moyamoya disease occurs more frequently in patients with autoimmune diseases18. Prior radiation therapy can also be a predisposing factor19. For example, recent studies have indicated a higher incidence of post-radiation arteriopathy in children following proton beam radiation, with Bhattachayra et al. reporting large vessel arteriopathy in 22% of patients with post-radiation vascular imaging available20. A systematic review identified post-radiation vasculopathy in 5% – 20% of patients that underwent proton and photon radiation, though some observed changes reflective of minor focal arteriopathic changes of the anterior cerebral artery, middle cerebral artery, and internal carotid artery in distinction to true Moyamoya syndrome21,22. Finally, a prospective trial identified radiographic evidence of vessel stenosis after radiation in 36% of patients and need for revascularization procedures in 5% of patients23. Interestingly, half of patients had abnormal screening MRAs prior to therapy, including tumor encasement of vessels, and a pre-radiation vessel abnormality was the strongest predictor of post-radiation vasculopathy.
In children with trisomy 21, careful monitoring of blood pressure may screen for children at risk who warrant further investigation prior to neurologic symptoms, as blood pressure has been noted to rise at routine visits up to a year prior to neurologic presentation in children with trisomy 21 and moyamoya compared to trisomy 21 children without moyamoya24. Children with trisomy 21 and moyamoya have elevated rates of other comorbidities such as congenital heart disease, which may influence presentation and management25. Additional signs of Moyamoya that may prompt workup include ophthalmologic findings including the morning glory disc anomaly26. Clinically, moyamoya vasculopathy is associated with ischemic stroke in the anterior circulation27. Pediatric patients with moyamoya vasculopathy may benefit from indirect vascular bypass procedures, including EDAMS, which confer long-term protection from later ischemic complications28,29. Imaging, including vascular imaging, is an important consideration in children at risk of moyamoya with new neurological deficits. When available, screening with MRI and/or MRA is warranted in populations deemed high-risk for the development of moyamoya vasculopathy30.
Conflict of Interest Statement:
APK is a consultant for Microvention and Penumbra. These relationships are not related to the content of this manuscript.
Designing/planning the manuscript: DCL, KPG, APK. Drafting the manuscript: DCL, KPG, APK. Critically reviewing and editing: KPG, APK. Approving the final version: DCL, KPG, APK.
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Lauzier Imaging and Epidemiology of Moyamoya Vasculopathy Case Report