Moyamoya Disease

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CHAPTER 207 Moyamoya Disease

An increasingly recognized cause of stroke, including 6% of all strokes in children, moyamoya syndrome is a cerebrovascular disorder characterized by chronic progressive stenosis of the intracranial internal carotid arteries (ICAs), including the proximal anterior cerebral arteries (ACAs) and middle cerebral arteries (MCAs).¹^,² This inexorable occlusion of the anterior circulation occurs simultaneously as characteristic arterial collateral vessels develop at the base of the brain in response to the resultant ischemia. Rarely, in advanced cases, this process can extend to involve the posterior circulation, including the basilar artery and posterior cerebral artery (PCA).

Takeuchi and Shimizu first reported a case of hypoplasia of the bilateral ICAs in 1957, although the term moyamoya (“something hazy, like a puff of smoke”), which describes the characteristic angiographic appearance of abnormally dilated collateral vessels in this condition, was not used until 1969 by Suzuki and Takaku (Fig. 207-1).³^,⁴

FIGURE 207-1 Injection of the internal carotid artery (ICA) demonstrating findings consistent with moyamoya: stenosis of the distal ICA (arrowhead), diminished filling of the middle and anterior cerebral artery branches, and proliferation of collateral vessels, the “puff of smoke” finding.

Individuals with a well-recognized associated condition (see later) are categorized as having moyamoya syndrome, whereas idiopathic cases with no known risk factors have moyamoya disease. To have moyamoya disease, patients must have bilateral stenosis—patients with only unilateral findings have moyamoya syndrome.⁵ The term moyamoya, when used alone without the modifier of disease or syndrome, refers to the distinctive findings on arteriography, independent of etiology.

Epidemiology

First described in Japan, moyamoya has now been identified in patients worldwide.⁶ Although historically considered more prevalent in the Asian population, it affects individuals of many ethnic backgrounds, and there is increasing awareness of this disease in Europe and North America.⁷ In Japan, it is the most common pediatric cerebrovascular disease.¹ In Europe, a recent study cited an incidence of 0.3 patients per center per year, which is approximately a 10th of the incidence in Japan.⁸ In the United States and Korea, reports have corroborated historical claims of a bimodal age distribution of moyamoya, one group in the pediatric age range (around the first decade of life) and a second group of adults in the 30- to 40-year-old range. Females are affected nearly twice as often as males.⁹^–¹¹ In the United States, moyamoya affects individuals differently, depending on ethnicity; when compared with white individuals, Asian Americans are more than four times as likely, African Americans are twice as likely, and Hispanic Americans are half as likely to have moyamoya.¹²

Associated Conditions

Particularly strong associations exist between moyamoya and radiotherapy of the head or neck (especially for optic gliomas, craniopharyngiomas, and pituitary tumors), Down syndrome, neurofibromatosis type 1 (with or without hypothalamic–optic pathway tumors), and sickle cell anemia.^11,¹³^–¹⁵ More tenuous links may exist between moyamoya and other disorders (Table 207-1).¹¹^,¹⁶

TABLE 207-1 Associated Conditions, Risk Factors, or Syndromes

RISK FACTOR	NUMBER
No associated conditions (idiopathic)	66
Neurofibromatosis type 1	16
Asian	16
Cranial therapeutic radiation	15
Hypothalamic–optic system glioma: 8
Craniopharyngioma: 4
Medulloblastoma with Gorlin’s syndrome: 1
Acute lymphocytic leukemia, intrathecal chemotherapy: 2
Down syndrome	10
Congenital cardiac anomaly, previously operated	7
Renal artery stenosis	4
Hemoglobinopathy (2 sickle cell, 1 “Bryn Mawr”)	3
Other hematologic: 1 spherocytosis, 1 ITP	2
Giant cervicofacial hemangiomas	3
Shunted hydrocephalus	3
Idiopathic hypertension requiring medication	3
Hyperthyroidism (one with Graves’ syndrome)	2

Other syndromes, one patient each: Reyes’ (remote), Williams’, Alagille’s, cloacal exstrophy, renal artery fibromuscular dysplasia, and infection with congenital cytomegalic inclusion virus (remote). Two patients had unclassified syndromic manifestations. There were four African Americans, two of whom had sickle cell disease.

ITP, idiopathic thrombocytopenic purpura.

Pathophysiology

The angiographic findings of moyamoya result from a wide range of genetic and acquired conditions. This variety of primary causes predicts distinct moyamoya populations with individual clinical findings and responses to therapeutic interventions. Current research efforts have focused on the mechanisms underlying the shared final common carotid arteriopathy and collateral development.

Pathologic analysis has demonstrated that affected vessels generally do not exhibit arteriosclerotic or inflammatory changes.¹⁷ Rather, vessel occlusion results from a combination of both hyperplasia of smooth muscle cells and luminal thrombosis (Fig. 207-2). The moyamoya collaterals are dilated perforating arteries believed to be a combination of preexisting and newly developed vessels.¹⁸^,¹⁹ A number of growth factors, enzymes, and other peptides have been reported in association with moyamoya, including basic fibroblast growth factor, transforming growth factor-β1, hepatocyte growth factor, vascular endothelial growth factor, matrix metalloproteinases, intracellular adhesion molecules, and hypoxia-inducing factor-1α, among others.¹⁹^–²⁶ At present, it is difficult to discern which of these peptides are pathologic primary causal agents of disease and which are present merely as part of a normal response to ischemia.

FIGURE 207-2 A, Gross pathology of the circle of Willis from a patient with moyamoya. Note the narrowing of the junction of the internal carotid artery (ICA) and middle cerebral artery, particularly on the right (arrowhead). B, Studies of vessels in the ICA distribution demonstrate hyperproliferation (asterisk) of vessel wall components and abundant intraluminal thrombus (>), with resultant narrowing and occlusion of the lumen. The right ICA is particularly narrow, as seen in both the gross specimen and microscopic analysis. The images highlight how the vessel occlusion is a combination of both hyperplasia of smooth muscle cells and luminal thrombosis.

Clues helping to distinguish between these possibilities have come from genetic studies. Associations between moyamoya and loci on chromosomes 3, 6, 8, and 17 (MYMY1, MYMY2, MYMY3), as well as specific HLA haplotypes, have been described.²⁷^–³² The familial incidence of affected first-degree relatives in Japan is 7% to 12%, similar to a rate of 6% reported in a recent U.S. series.^11,³³^–³⁸ However, despite evidence supporting a genetic basis of moyamoya, important caveats remain. Reports exist of identical twins with only one affected sibling.¹¹^,³⁹ These data support the premise that some type of environmental factor must precipitate the syndrome’s clinical emergence in susceptible patients and suggest that the angiographic changes of moyamoya are the result of a complex interplay between genetic predisposition and external stimuli.

Clinical Findings

The clinical features of moyamoya result from either direct cerebral ischemia (e.g., stroke, transient ischemic attack [TIA]) or the deleterious effects of responses to this ischemia (e.g., hemorrhage from fragile collateral vessels, headache as a result of dural irritation from collaterals). Variation in the degree of ischemia and compensatory mechanisms helps explain the range of symptoms seen in practice.

Accounting for approximately 6% of childhood strokes in Western countries, moyamoya affects young children in particular, with 50% of patients identified by 10 years of age.¹^,² Some patients have rare, intermittent ischemic events or even extended periods of clinical stability, whereas other individuals exhibit rapid neurological decline.¹¹^,⁴⁰ Children are usually initially seen with TIAs or strokes, as evidenced in the largest current report of pediatric moyamoya patients (Table 207-2).¹¹ The much higher rate of stroke in children may be related to less developed verbal skills in this age group, thereby leading to delayed recognition of the underlying moyamoya.⁴¹

TABLE 207-2 Symptoms at Initial Evaluation in 143 Patients (Percentage of Patients with Symptoms)

Stroke	97	(67.8%)
Transient ischemic attacks (including drop attacks)	62	(43.4%)
Seizures	9	(6.3%)
Headache	9	(6.3%)
Choreiform movements	6	(4.2%)
Incidental	6	(4.2%)
Intraventricular or intracerebral bleeding	4	(2.8%)

Symptom totals are greater than patient numbers because some patients had multiple symptoms at initial evaluation.

Ischemic Symptoms

The symptoms of cerebral ischemia in moyamoya are generally related to the territory supplied by the ICAs, including the frontal and temporal lobes. Hemiparesis, dysarthria, aphasia, and cognitive impairment are common.¹¹ Seizures occur frequently, and other, more subtle deficits may be present—an issue particularly problematic in younger patients because they may not be able to articulate their experiences as well as adults. These symptoms may be mistaken for psychiatric illness or developmental delay and include visual deficits, syncope, or personality changes.⁴²^–⁴⁴

Once present, the ischemic symptoms may be transient or fixed. TIAs may be precipitated by events particularly common in children, such as hyperventilation with crying or exertion. The cerebral vessels, already maximally dilated in the setting of chronic ischemia, constrict in response to the decrease in PCO₂ and can thus lead to a TIA or stroke.⁴⁵ Dehydration, a problem in children after colds or fevers, may also give rise to ischemic symptoms.

Hemorrhage

Typically, hemorrhage is a hallmark of adult moyamoya, although children can also have this finding initially.¹¹^,⁴⁶ Hemorrhage can be intraventricular, intraparenchymal (frequently in the region of the basal ganglia), or subarachnoid. Bleeding has historically been attributed to rupture of fragile collateral vessels unable to contain the increased flow shunted from progressive ICA stenosis.⁴⁷^,⁴⁸ In addition to these friable vessels, studies have revealed that aneurysms in the circle of Willis may form in response to altered circulatory patterns, thus providing another potential cause of hemorrhage.⁴⁹^,⁵⁰

Headache and Other Symptoms

Children with moyamoya will often complain of headache. Although the etiology is unclear, a recent review has speculated that dilation of meningeal and leptomeningeal collateral vessels may stimulate dural nociceptors.⁵¹ Typically, the headache is migraine-like in quality and refractory to medical therapies; although it may improve after surgical treatment of the moyamoya, often concordant with regression of the collateral vessels, it often persists as a troublesome symptom years after other symptoms remit.

Collateral vessels in the basal ganglia have also been implicated in the development of choreiform movements in individuals with advanced moyamoya.¹¹^,⁵² Similar to headache, these symptoms may regress after revascularization of the affected hemisphere.

Natural History and Prognosis

It is difficult to predict the natural history of moyamoya in a given patient. As discussed in the section “Clinical Findings,” patients can have isolated problems with lengthy periods of relative health or can exhibit fulminant deterioration in a very short time.¹¹^,⁴⁰ However, moyamoya syndrome, in terms of both arteriopathy and clinical symptoms, inevitably progresses in untreated patients.⁴^,⁵³ A recent study revealed that the rate of disease progression is high even in asymptomatic patients and that medical therapy alone is of limited use.⁵⁴ It has been estimated that two thirds of patients with moyamoya have symptomatic progression with poor outcomes if left untreated.⁵⁵^–⁵⁷ This number contrasts strikingly with an estimated rate of symptomatic progression of just 2.6% after surgical treatment in a recent meta-analysis of more than 1000 patients.⁵⁸ In general, neurological status at time of treatment, more so than age of the patient, predicts long-term outcome.^11,^59,⁶⁰ The unpredictable but relentless course of this disease, coupled with the irreversible nature of deficits once present, dictates a need for early diagnosis whenever possible and prompt treatment once moyamoya is identified.

Diagnosis

Any child with new symptoms of cerebral ischemia should be considered as a possible moyamoya patient until proved otherwise. The evaluation of moyamoya usually proceeds through several stages, with the initial studies identical to those performed in any individual suspected of having a stroke or hemorrhage.

Computed Tomography

In most patients with suspected stroke or intracranial hemorrhage, the evaluation typically begins with computed tomography (CT) of the head. In patients with moyamoya, hemorrhage or small areas of hypodensity suggestive of stroke are commonly observed in the cortical watershed zones, basal ganglia, deep white matter, or periventricular regions.⁶¹^,⁶²

Magnetic Resonance Imaging

In recent years, magnetic resonance imaging (MRI) has become more widely available, which has led to substantial increases in its use as primary diagnostic modality for patients suspected of having a stroke—including patients undergoing evaluation for moyamoya.⁶³^–⁶⁸ Acute infarction is best seen with diffusion-weighted imaging, whereas chronic infarction is better demonstrated on T1- and T2-weighted images (Fig. 207-3). Diminished cortical blood flow secondary to moyamoya can be inferred from fluid-attenuated inversion recovery (FLAIR) sequences, which demonstrate linear high signal following a sulcal pattern, the so-called ivy sign (Fig. 207-3).⁶⁹^–⁷² Reduced flow voids in the ICA, MCA, and ACA, coupled with prominent flow voids from the basal ganglia and thalamic collateral vessels, are considered by many to be essentially diagnostic of moyamoya.^62,^63,⁷³^–⁷⁶ However, it is important to note that although MRI can often establish a diagnosis of moyamoya, it remains limited with regard to helping identify specific collateral networks and areas of marked stenosis—data frequently critical for successful surgical planning.

FIGURE 207-3 Typical magnetic resonance images of moyamoya. T1-weighted (A) and T2-weighted (B) studies reveal cortical atrophy, old infarcts, and flow void signals resulting from basal collaterals (arrowheads). C, Fluid-attenuated inversion recovery image demonstrates the “ivy sign” (arrowhead) consistent with bilateral ischemia.

Angiography

Angiography provides crucial surgical planning data and should be performed in all moyamoya patients if possible. In a study of 190 angiograms, the complication rate from angiography in patients with moyamoya syndrome was no higher than that in non–moyamoya-affected populations with other forms of cerebrovascular disease.⁷⁷ Studies should include all four vessels and external carotid artery (ECA) injections.

The diagnosis of moyamoya is defined by angiography and is characterized by bilateral stenosis of the distal intracranial ICA extending to the proximal ACA, MCA, and PCA, with disease severity classified into six progressive stages by Suzuki and Takaku (see Fig. 207-1).⁴

Other Diagnostic Techniques

Electroencephalography (EEG) and cerebral blood flow studies may be helpful in the evaluation of patients with moyamoya. Specific findings on EEG, usually in pediatric patients, include posterior or centrotemporal slowing, a hyperventilation-induced diffuse pattern of monophasic slow waves (i.e., build-up), and a characteristic “re–build-up” phenomenon ⁷⁸ (maneuver not recommended in a patient with known moyamoya; see later).

Cerebral blood flow studies include techniques such as transcranial Doppler, perfusion CT, xenon-enhanced CT, positron emission tomography, MR perfusion imaging,⁷⁹^–⁸¹ and single-photon emission CT with acetazolamide challenge. These studies can help quantify blood flow, information that some clinicians incorporate into treatment algorithms for children with moyamoya.⁸²^–⁹⁰

Treatment

Current treatments are designed to prevent strokes by improving blood flow to the affected cerebral hemisphere, not to reverse the primary disease process. Reduction of ischemia can protect against future strokes, effect a concurrent reduction in the number and size of collateral vessels, and improve symptoms, but it does not arrest the underlying carotid arteriopathy.

Medical Therapy

When an individual is considered a poor operative risk or has relatively mild disease, medical therapy has occasionally been used for the treatment of moyamoya. However, there are few data demonstrating either short-term or long-term efficacy of this approach. Antiplatelet agents have been used in individuals whose ischemic symptoms seem to arise as a result of emboli from the formation of microthrombi at sites of arterial stenosis and have been administered routinely in all patients in many operative series.^11,^40,^91,⁹² Anticoagulants such as warfarin are rarely used, although there has been some experience with low-molecular-weight heparin.⁹³ The other type of medication helpful in the management of moyamoya is calcium channel blockers.⁹¹ This class of drugs is particularly useful in ameliorating the symptoms of intractable headache or migraine, commonly seen in moyamoya patients, and also seems to be effective in reducing both the frequency and severity of refractory TIA. The use of calcium channel blockers is generally limited to patients with these symptoms, but caution needs to be exercised to avoid hypotension.

Published reports directly comparing outcomes between medical and surgical therapy for moyamoya are limited in number. A large survey from Japan in 1997 found no significant differences in outcome between medically and surgically treated moyamoya patients in the short term, although a more recent review revealed that 38% of 651 moyamoya patients who were initially treated medically subsequently required surgery as a result of progressive symptoms.⁵^,⁹⁴

Surgery

The curious fact that the arteriopathy of moyamoya involves the ICA while sparing the ECA provides the foundation underlying the surgical treatment of moyamoya, which is predicated on using the ECA to provide arterial supply to the ischemic hemisphere. Two general methods are used: direct and indirect. In direct revascularization, a branch of the ECA (usually the superficial temporal artery [STA]) is divided and anastomosed to a cortical artery (usually a distal branch of the MCA)—an STA-MCA bypass. In contrast, indirect techniques involve mobilizing vascularized tissue supplied by the ECA (dura, muscle, pedicles of the STA) and placing it in contact with the brain to facilitate ingrowth of new vessels to the cortex.

Traditionally, direct procedures have been used in adults, with immediate restoration of blood supply being cited as a major benefit. Protection from ischemia is delayed for several weeks with indirect techniques while new vessel ingrowth is established. However, direct bypass is often technically difficult to perform in children because of the small size of donor and recipient vessels, thus making indirect techniques appealing in pediatric populations. Nonetheless, direct operations have been successful in children, as have indirect procedures in adults.⁹⁵^–⁹⁷ Considerable debate exists regarding the relative merits and shortcomings of the two approaches, with some centers advocating combinations of both.^94,⁹⁷^–¹⁰⁰

Numerous variations of indirect revascularization procedures exist, including encephaloduroarteriosynangiosis, encephalomyoarteriosynangiosis, and simply drilling bur holes without vessel synangiosis.^99,¹⁰¹^–¹⁰⁵ A modification termed pial synangiosis has been used with encouraging results in both adults and children (Fig. 207-4).¹¹ A review of 143 patients treated by pial synangiosis demonstrated marked reductions in stroke frequency after surgery. Sixty-seven percent had strokes before treatment, 7.7% had strokes in the perioperative period, and just 3.2% had strokes after at least 1 year of follow-up. The long-term stroke rate was 4.3% in individuals with a minimum of 5 years of follow-up.¹¹

FIGURE 207-4 Operative sequence for pial synangiosis. A, First, the course of the superficial temporal artery (STA) is mapped with Doppler ultrasound. B, The STA is dissected free from surrounding tissue, with a pedicle of areolar tissue and galea left on its undersurface. C, A craniotomy is performed with a stellate dural opening. D, The arachnoid is opened widely and the STA is affixed to the cortex with interrupted 10-0 nylon suture.

Given the poor response to medical therapy, the relentless course of the disease, and the excellent response to surgery, operative indications for revascularization in moyamoya are broad.⁵⁸ Two large studies with long-term follow-up demonstrated a good safety profile for surgical treatment of moyamoya (approximately 4% risk for stroke within 30 days of surgery per hemisphere), with a 96% probability of remaining stroke free over a 5-year follow-up period.¹¹^,⁵⁵ A recent meta-analysis of 1156 moyamoya patients treated surgically concluded that 87% derived symptomatic benefit from surgical revascularization, with indirect and direct/combined techniques demonstrating equal effectiveness.⁵⁸ In general, all patients with documented moyamoya should be considered operative candidates.

Anesthetic Management

Proper anesthetic management of moyamoya patients, regardless of technique, is critical for operative success. Premedication adequate to avoid hyperventilation and crying in children is essential, and patients undergo typical craniotomy monitoring, including arterial lines and bladder catheterization. Intraoperative EEG monitoring with a full array of scalp electrodes (except directly at the operative site) is performed on all patients in whom bilateral surgery during the same course of anesthesia is contemplated. If any significant changes on EEG occur as the initial side is operated on, surgery on the contralateral hemisphere is postponed.

There is no evidence that one anesthetic agent or technique is superior in patients with moyamoya syndrome. Muscular blockade is established with a nondepolarizing muscle relaxant before intubation. Any fluid deficits are partially replaced with intravenous crystalloid without glucose (10 mL/kg) over a 15-minute period after induction. Anesthesia is maintained with low-dose isoflurane and a balanced nitrous oxide/oxygen mixture with fentanyl. The rationale for the use of these agents is that isoflurane is a cerebral vasodilator and may even provide a protective effect against ischemia. However, any anesthetic technique that will maximize the balance between cerebral blood flow and oxygen consumption is probably reasonable. End-tidal CO₂ is maintained between 36 and 42 mm Hg. We avoid the use of hyperventilation or any anesthetic technique that would cause cerebral vasoconstriction because hyperventilation in a child with compromised cerebral circulation could precipitate further ischemic sequelae. Normotension, appropriate for age, is maintained. Diuretics such as mannitol and furosemide (Lasix) are unnecessary and possibly risky in this patient population because of the possibility of dehydration leading to hypotension.

Perioperative Care

Moyamoya patients are at additional risk for ischemic events during the perioperative period. Potential complications of surgery for moyamoya include stroke, infection, and intracranial hemorrhage. Crying and hyperventilation can lower PaCO₂ and induce ischemia secondary to cerebral vasoconstriction. Any techniques to reduce pain—including the use of perioperative sedation, painless wound-dressing techniques, and closure of the wound with absorbable suture—may reduce the likelihood of stroke and shorten the hospitalization.¹⁰⁶ Similarly, it is important to avoid hypotension, hypovolemia, hyperthermia, and hypocapnia both intraoperatively and perioperatively.¹¹ Postoperatively, patients should be given intravenous fluids at 1.25 to 1.5 times the normal maintenance rate for 48 to 72 hours.¹⁰⁶

Acute Symptoms

In addition to providing surgical therapy for patients with moyamoya, there is often a need to ameliorate acute symptoms. Rapid institution of measures capable of increasing cerebral blood flow and oxygenation can reduce the likelihood of a TIA progressing to a completed stroke. The initial steps are similar to perioperative management and should include intravenous hydration with isotonic fluids (usually at 1 to 1.5 times maintenance), avoidance of hypotension, and administration of supplemental oxygen.^11,^106,¹⁰⁷ Hyperventilation is to be avoided. Serum electrolyte and glucose levels should be normalized. Seizure activity, if present, should be treated with appropriate pharmacologic agents.

Emergency imaging can ascertain whether ischemia or hemorrhage is the cause of the new symptoms. Although commonly evaluated with CT, MRI with diffusion-weighted images can be helpful in the identification of completed stroke. In the absence of hemorrhage, antiplatelet agents have been used on the assumption that emboli from microthrombus formation at sites of arterial stenosis may contribute to the symptoms.^11,^40,^91,⁹² Aspirin is used at many institutions: 325 mg for adults and 81 mg (or less) for preteen children.

Follow-up

Several reports suggest that periodic clinical and radiographic re-examination of patients with moyamoya disease may be helpful in some clinical settings.⁵^,⁵⁸ Recent studies have demonstrated that bilateral involvement eventually develops in approximately a third of patients with unilateral moyamoya.¹⁰⁸^,¹⁰⁹ There is also evidence that progression of the disease is more likely to occur rapidly and more frequently in younger patients.¹⁰⁸^,¹⁰⁹ Of patients who underwent surgery (for either bilateral or unilateral disease), reoperation because of refractory disease was necessary in 1.8% to 18% of patients.⁹⁴ Many institutions perform angiography 1 year postoperatively, followed by annual MRI studies for several years thereafter (Fig. 207-5).