Brain Pathology Case of the Month - April 2013




The differential diagnosis for the vascular pathology in this case includes a resolving vasculitis or an intimal variant of fibromuscular dysplasia; however, both of these processes should lead to fragmentation of the IEL. Despite the patient's history of hypertension and diabetes mellitus, no atherosclerotic changes were present. This pattern of vascular occlusion, the fibrointimal hyperplasia, attenuated media, and intact undulating IEL are classic for moyamoya disease (5, 7, 8).

Moyamoya disease is a rare cerebrovascular disorder that results in the occlusion of the supraclinoid internal carotid arteries and its branches within the Circle of Willis (5, 7, 8). As a compensatory mechanism, multiple fine collateral vessels form at the base of the brain. These collateral vessels were originally described in Japan by Suzuki and Takaku in 1969 (8), who termed it "moyamoya." This loosely translates into "hazy puff of smoke," describing the cloudy/smoky appearance of the neovascularized network on angiography.

This disease is very rare in patients of non-Asian descent. In the United States, there is an estimated incidence of 0.086 cases per 100,000 (9). Within Europe, the incidence is found to be approximately 10% that of Japan (10). It is much more common in east Asian countries (particularly Japan), where the incidence and prevalence is up to 0.94 and 10.5 cases per 100,000, respectively (1). In these regions it is considered the most common cerebrovascular disease in the pediatric population (7). However, it is found in both children and adults, with a bimodal age distribution peaking at the ages of 5 and 40. It is seen more commonly in women, with a female to male ratio of 1.8 (5). Clinical presentations vary, but usually appear as transient ischemic attacks (TIAs) or overt infarctions. Adults have a tendency to hemorrhage, typically from the fragile collateral vessels at the brain's base (3, 5, 7, 9). Diagnosis is usually made radiographically through angiogram or MRA, according to the guidelines issued by the Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) (2).

While the majority of cases are sporadic, up to 15% of patients show familial inheritance patterns. The pedigrees usually show either a polygenic or autosomal dominant with incomplete penetrance patterns (5). A recent study discovered a founder missense mutation in RNF213 (p.R4859K) which is the first susceptibility gene to be strongly associated with familial Moyamoya disease (4). Other linkage studies have shown possible candidate loci at 3p24-26, 6q25, 8q13-24, 12p12-13, and 17q25 (4). Some pedigrees also suggest that anticipation effect can happen. For example, in one epidemiologic study, there was a subset of eight cases in which both a mother and one of her offspring had moyamoya. In each of these cases, the mother presented as an adult (mean age 31 years) while all the offspring presented in childhood (mean age 7 years) (5).

Treatment for patients with bilateral and symptomatic disease is generally surgical, via vascular bypass. There are multiple possible bypass options, including direct, indirect, and combined procedures (5, 6). The direct bypass involves the anastomosis of the superficial temporal and middle cerebral arteries, which provides rapid revascularization but is associated with an increased risk of hyperperfusion syndrome. Indirect bypass methods use donor tissues such as dura mater, temporal muscle, and galeal tissue to induce spontaneous angiogenesis in the undervascularized cerebral tissue. The most common of these is the encephaloduroarteriosynangiosis (EDAS) procedure, which involves suturing a superficial temporal artery and soft tissue pedicle to a dural incision. While this method has a much lower risk of hyperperfusion syndrome, it often takes up to four months for these new vessels to grow (5). The last option involves a mix of both direct and indirect, offering the benefits of both procedures (5, 6). Though the literature is limited with respect to prospective randomized trials, this latter approach seems to decrease the incidence of TIAs and infarctions (3, 5, 10). In the absence of surgery, patients have a high risk of recurrent infarction and hemorrhage, exceeding 80% for those patients who present with bilateral disease and ischemic symptoms) (3).


  1. Baba T, Houkin K, Kuroda S (2008) Novel epidemiological features of moyamoya disease. J Neurol Neurosurg Psychiatry 79(8): 900-904. Epub 2007 Dec 12.
  2. Fukui, M (1997) Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). Clin Neurol Neurosurg 99(Suppl 2): S238-240.
  3. Hallemeier C L, Rich KM, Grubb RL Jr, Chicoine MR, Moran CJ, Cross DT 3rd, et al (2006) Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke 37(6): 1490-96.
  4. Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kukuchi A, et al (2011) A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 56(1): 34-40.
  5. Kuroda S, Houkin K (2008) Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7: 1056-66.
  6. Rhee JW and Magge SN (2011) Moyamoya disease and surgical intervention. Curr Neurol Neurosci Rep 11(2): 179-186.
  7. Scott RM, Smith ER (2009) Moyamoya disease and moyamoya syndrome. N Engl J Med. 360(12): 1226-1237.
  8. Suzuki J, Takaku A (1969) Cerebrovascular "moyamoya" disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20(3): 288-299.
  9. Uchin K, Johnston SC, Becker KJ, Tirschwell DL (2005) Moyamoya disease in Washington State and California. Neurology 65(6): 956-958.
  10. Yonekawa Y, Ogata N, Kaku Y, Taub E, Imhof HG (1997) Moyamoya disease in Europe, past and present status. Clin Neurol Neurosurg 99(Suppl 2): S58-60.

Contributed by Janna Neltner, MD and Craig Horbinski, MD, PhD

International Society of Neuropathology