Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort

Abstract

Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs).

Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country.

Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively).

Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

Keywords: arteriopathy; aspirin; cerebrovascular events; headache; indirect revascularization; moyamoya; stroke; transient ischemic attack.

Figure 1

Clinical data. (A) Clinical phenotype in the total pediatric MMD and MMS cohort at the time of diagnosis (n = 65): incidentally diagnosed MMS in gray, asymptomatic at the time of diagnosis (incMMS) (n = 12) and symptomatic patients with MMD or MMS (symptMMD/MMS, n = 53) in blue shades (single phenotype at the time of diagnosis, n = 36) and green shades (multiple phenotypes at the time of diagnosis, n = 17). Single or multiple phenotypes at the time of diagnosis was categorized according to the presence of one or more than one international consensus “disease types” (2): transient ischemic attack (TIA), recurrent TIA, ischemic stroke, hemorrhagic stroke, headache, epilepsy, and others (see Section “Methods”). (B) First-ever clinical manifestation in 53 patients with MMD or MMS with moyamoya-related symptoms at diagnosis (symptMMD/MMS). Ischemic stroke and TIA were the most frequent clinical manifestations at symptom onset. (C) Frequency of previous or active neurological manifestations in 53 patients with MMD or MMS with moyamoya-related symptoms at diagnosis (symptMMD/MMS). In patients with symptMMD/MMS, at the time of diagnosis 81% had experienced previous or recent cerebrovascular events (TIA, ischemic stroke).

Figure 2

Cerebral MRI and MRA study in an 11-month-old girl with early-onset MMD, presenting with acute ischemic stroke. (A,B) Coronal and axial T2-w image showing left-sided cortical and subcortical infarct; multiple bilateral “flow voids” in the basal ganglia. (C) Magnetic resonance angiography showing typical “puff of smoke”.

Figure 3

mRS at last follow-up in the total cohort of symptomatic MMD (symptMMD) (n = 27), symptomatic MMS (symptMMS) (n = 26), and asymptomatic incidentally diagnosed MMS (incMMS) (n = 12). The proportion of patients with mRS > 2 at last follow-up was significantly higher in symptomatic patients with MMD or MMS (symptMMD/MMS) than in asymptomatic patients diagnosed incidentally (incMMS) (p = 0.021) (see also Table 2).