11 Adult Moyamoya Disease
Abstract
Moyamoya disease (MMD), a chronic steno-occlusive vasculopathy affecting the vessels at the base of the skull, once thought to only affect the Asian population, has been shown to have increasing incidence worldwide. In this chapter, we review the natural history of MMD, address the controversies associated with this disorder, and present our results based on one of the largest cohorts of treated MMD patients in the western world. Several syndromes and conditions are described as being associated with or causing MMD, and 10 to 15% of MMD cases are familial. We propose screening for MMD in patient subgroups. We also discuss whether treatment is indicated (based on the clinical presentations), and compare the outcome with various management modalities—medical, surgical, or endovascular. A new classification system for MMD is validated, and has clinical implications especially in stratifying pre-operative symptomatology. Prior to undertaking surgical treatment for MMD patients, pertinent workup and investigations (including a formal six-vessel cerebral angiogram, MRI [magnetic resonance imaging] brain, and cerebral perfusion imaging with and without Diamox) were carried out for optimal surgical strategies and patient outcomes. Direct or indirect methods of cerebral revascularization are compared. Generally, indirect bypasses were used for younger patients who have higher angioplasticity with better collateralization compared to older adult patients, repeat revascularization cases to avoid compromising prior bypass grafts from initial procedures, or patients who have internal carotid artery/middle cerebral artery (ICA/MCA) stenosis but still with anterograde ICA/MCA angiographic filling and do not require an immediate increase in blood flow.
Introduction
Moyamoya disease (MMD) refers to a chronic idiopathic occlusive vasculopathy affecting the vessels at the base of the brain. The first report of the disease was published by Takeuchi and Shimizu in 1957, when they described a case of “hypoplasia of the bilateral internal carotid arteries.” The term “moyamoya” was coined by Suzuki and Takaku in 1969 to describe the appearance of the collateral vessels that form in these patients. Although most initial reports of the disease originated in Japan, it has now been established that MMD occurs all over the world. The incidence, however, may differ with geography. For example, the incidence in the United States reported in 2005 was approximately 0.086 per 100,000, vis-à-vis 0.54 per 100,000 in Japan published in 2003. There is also some evidence that the incidence of the disease has been steadily increasing to 0.94/100,000/year in Japan reported in 2006 and to 0.57/100,000/year in the United States (communicated in 2012). MMD has been classically described as having bimodal age distribution, with the first peak occurring in children in the first decade of life and the second peak occurring between the ages of 30 and 50 years.
Major controversies in decision making addressed in this chapter include:
Clinical features and syndromes associated with MMD.
Whom to screen for MMD?
Whether or not treatment is indicated, and how—medical or surgical?
Type of surgery.
Whether to Treat
The natural history of MMD tends to be progressive, with studies showing that patients with unilateral MMD progressed to bilateral disease in 30 to 40% of adult patients within 2 to 3 years ( 1 , 2 in algorithm ). Medical management of MMD includes antiplatelet therapy, blood pressure regulation, and management of underlying associated medical conditions if present. Patients are also instructed to maintain adequate hydration at all times, as dehydration may precipitate transient ischemic attacks (TIAs) or strokes. Antiplatelet therapy (usually 81 mg acetylsalicylic acid) is recommended to prevent the formation of microthrombi at sites of stasis in stenotic intracranial arteries and to maintain patency of extracranial–intracranial (EC-IC) grafts after surgical revascularization. Although the efficacy of antiplatelet therapy in preventing strokes in MMD has never been proven, it appears safe. Anticoagulation is not recommended due to hemorrhagic risk.
The rate of progression of ischemic symptoms or development of a major stroke is as high as 65% over 5 years in medically treated patients. Surgical intervention therefore has become the standard therapy for MMD ( 2–8 in algorithm ). Emerging evidence suggests that surgical revascularization leads to a reduction in stroke and intracranial hemorrhage in symptomatic MMD patients versus medical or conservative management only ( 2, 4 in algorithm ). The recently completed prospective Japanese study randomized 80 patients with hemorrhagic MMD (16–65 years of age) into direct surgical revascularization or medical management arms. At the 5-year follow-up, the rebleed rate was 2.7% per year in the surgical group versus 7.6% per year in the medical group (p = 0.042). The rate of overall morbidity was 3.2% per year in the surgery arm versus 8.2% per year in the medical management arm (p = 0.048) ( 2, 4 in algorithm ).
Whom to Screen
Several syndromes and conditions have been described as being associated with or causing MMD. These cases were formerly termed the MMD or atypical MMD; however, such distinctions are probably no longer relevant. The various conditions associated with MMD include prior radiation therapy to the head and neck or brain, Down′s syndrome, neurofibromatosis 1, tuberous sclerosis, Majewski′s primordial dwarfism, Fanconi′s anemia, sickle cell disease, autoimmune disorders (including Grave′s disease), Marfan′s syndrome, renal artery stenosis, and even infections such as tuberculous, meningitis, and leptospirosis. Patients who have received any of these diagnoses and have symptoms such as chronic fatigue or headache and refractory or unexpected hypertension should undergo noninvasive radiological testing to screen for MMD ( 9 in algorithm ). The RNF213 gene has been identified as being associated with MMD in the Asian population. In Caucasians, ZXDC (p.P562L), a gene involved in major histocompatibility complex (MHC) class II activation, and OBSCN, a gene involved in myofibrillogenesis, were the most enriched. Between 10 and 15% of all cases of MMD are familial, and the disease prevalence is increased in identical twins. Thus, it is reasonable to screen first-degree family members of patients with MMD with magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) if headaches or other unexplained symptoms are present. Patients with primarily unilateral MMD also need to be monitored for progression of disease on the opposite side ( 14 in algorithm ).
Pathophysiology
See Chapter 10: Pediatric Moyamoya.
Classification
Suzuki and colleagues categorized the disease into six stages based on the appearance of the intracranial vessels and moyamoya vessels: stage 1: stenosis of the internal carotid arteries; stage 2: initial appearance of moyamoya vessels; stage 3: increasing internal carotid artery stenosis and further definition of collateral vessels; stage 4: occlusion of the circle of Willis, minimization of collateral vessels; stage 5: further reduction of collateral vessels; and stage 6: disappearance of collateral vessels. However, these purely morphological criteria as assessed by cerebral angiography neither reflect the hemodynamic status adequately nor correlate with clinical symptoms or with surgical outcomes.
The new MMD preoperative symptomatology grading system proposed by the Berlin group incorporates angiographic findings (digital subtraction angiography, DSA) and features of chronic cerebrovascular insufficiency and hemodynamic reserve (diagnosed on perfusion sequences on MRI or xenon computed tomography [CT]). We have validated this system in the Stanford MMD cohort and routinely employ it as an important tool to stratify preoperative hemispheric symptomatology.
Workup
Clinical Evaluation
MMD has been classically described as having either a hemorrhagic or an ischemic presentation ( 1 in algorithm ). Typically, adults present with hemorrhagic disease and children with symptoms of ischemia. However, this pattern varies with ethnicity as well as in non-Asian populations. In adults, nearly 50% presented with intracranial hemorrhage in the Japanese series. In the North American cohort, adult MMD largely presented with cerebral ischemia (about 80%). Analysis of the Stanford series of 658 surgically treated adult MMD patients showed that 59% presented with stroke or TIA and 16% with hemorrhage.
Hemorrhage in patients with MMD can be intracerebral, intraventricular, or subarachnoid. Forty percent of bleeds are within the basal ganglia, 30% are intraventricular, and 15% are thalamic. Given that several patients with MMD have elevated blood pressure and that these are the typical locations for hypertensive hemorrhage, the diagnosis is often missed. In our initial series of 430 patients with MMD (71% adults), we found that female patients were more likely to experience preoperative TIAs and were more likely to have bilateral MMD. No association was observed between sex and risk of preoperative ischemic or hemorrhagic stroke. Females may also be at higher risk of adverse postoperative events despite successful revascularization; however, there appears to be no sex difference in the ultimate neurological outcome. MMD can also present with nonspecific sensory symptoms. Headache is a common presenting feature in both children and adults. Some patients complain only of chronic fatigue and typically receive a diagnosis of MMD late in the course of the disease ( 9 in algorithm ). Patients can present with cognitive dysfunction and progressive memory loss in the absence of other symptoms. Various movement disorders such as chorea and hemiballismus have also been described as presenting symptoms. MMD can present with very nonspecific symptoms and signs and can also mimic other neurological diseases such as multiple sclerosis. This diversity in clinical presentations often leads to delayed diagnosis in patients. The management of these patients depends on the degree of stenosis on angiography ( 10, 11 in algorithm ) and the MRI findings ( 12, 13 in algorithm ).
Patients who are potential candidates for operative cerebral revascularization procedures should undergo a thorough medical, cardiac, and baseline neurological evaluation prior to surgery. In addition, routine preoperative labs and radiological studies should be obtained. Prior to surgery, it is important to measure and record the patient′s mean arterial pressure (MAP). During surgery, the anesthesiologist should be instructed to keep the patient′s MAP at or above the preoperative baseline at all times.
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