Moyamoya disease in children

Transcription

1 Childs Nerv Syst (2010) 26: DOI /s SPECIAL ANNUAL ISSUE Moyamoya disease in children David M. Ibrahimi & Rafael J. Tamargo & Edward S. Ahn Received: 8 June 2010 /Accepted: 12 June 2010 /Published online: 4 July 2010 # Springer-Verlag 2010 Abstract Purpose Moyamoya disease, a rare cause of pediatric stroke, is a cerebrovascular occlusive disorder resulting from progressive stenosis of the distal intracranial carotid arteries and their proximal branches. In response to brain ischemia, there is the development of basal collateral vessels, which give rise to the characteristic angiographic appearance of moyamoya. If left untreated, the disease can result in overwhelming permanent neurological and cognitive deficits. Methods Whereas moyamoya disease refers to the idiopathic form, moyamoya syndrome refers to the condition in which children with moyamoya also have a recognized clinical disorder. As opposed to adults who typically present in the setting of intracranial hemorrhage, the classic pediatric presentation is recurrent transient ischemic attacks and/or completed ischemic strokes. Results Surgical revascularization, including direct and indirect techniques, remains the mainstay of treatment, and has been shown to improve long-term outcome in children with moyamoya. Conclusion The authors discuss the diagnosis and treatment of moyamoya disease in the pediatric population. D. M. Ibrahimi : R. J. Tamargo : E. S. Ahn Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA D. M. Ibrahimi Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA E. S. Ahn (*) Division of Pediatric Neurosurgery, The Johns Hopkins Hospital, 600 N. Wolfe St., Harvey 811, Baltimore, MD 21287, USA eahn4@jhmi.edu Keywords Moyamoya disease. Stroke. Cerebral revascularization. Pial synangiosis. Pediatric Introduction Moyamoya disease is a cerebrovascular arteriopathy of unknown origin characterized by progressive stenosis and, ultimately, occlusion of the distal intracranial internal carotid arteries (ICA) and the proximal branches of the anterior and middle cerebral arteries. To perfuse the ischemic brain distal to the occlusion, there is parallel development of collateral vessels from the leptomeninges as well as both the external and intracranial ICAs. It is the dilated basal collateral vessels arising from the intracranial ICAs, which normally supply the optic nerves, pituitary gland, anterior perforated substance, dura, and other skull base structures [1], that lead to the characteristic angiographic appearance likened to a puff of smoke. Moyamoya disease was first described in the Japanese literature in 1957 by Takeuchi and Shimizu [2] as a case of hypoplasia of the bilateral internal carotid arteries. However, it was not until 1969 when Suzuki and Takaku [3] coined the term moyamoya signifying something hazy, like a puff of cigarette smoke to describe the angiographic appearance that would both describe and define the illness. Epidemiology Though initial descriptions and studies initially centered on Japanese populations, presently, moyamoya disease is observed throughout the world, affecting children and adults of various ethnic backgrounds [4, 5]. With this observation, moyamoya disease is becoming more widely

2 1298 Childs Nerv Syst (2010) 26: recognized, and currently accounts for approximately 6% of all causes of pediatric ischemic stroke [6, 7]. There are striking differences between the incidences of moyamoya disease among pediatric populations based upon ethnic and geographic background. For example, moyamoya remains the most common cause of pediatric cerebrovascular events in Japan, and in a recent European study by Yonekawa et al. [7 9], the incidence of moyamoya disease in Europe was 0.3 patients per center per year, nearly one tenth that of the incidence found in Japan. The reported incidence in the USA is approximately per 100,000 patients, as compared to 0.35 per 100,000 found in the Japanese literature [10, 11]. In the past, moyamoya disease was an under-recognized cause of pediatric stroke within the USA, as evidenced by a review published by Numaguchi et al. [12] that showed there were only 46 definitive and 52 presumptive cases of moyamoya disease published in the American literature prior to More recently, there have been considerably more reports on both cases of and surgical treatment for moyamoya disease in the USA, as it is now considered in the differential diagnosis for any child with ischemic cerebrovascular disease [13, 14]. There is a bimodal age distribution of moyamoya disease, with the first peak occurring in the pediatric population, typically in the first decade of life, and a second peak between 30 and 40 years of age [8]. Moyamoya is found in both females and males; however, there is a clear female preponderance, with affected females outnumbering males nearly 2:1 [15]. Lastly, familial occurrence has been reported in Japan to range from 7% to 12%, and similarly, approximately 6% in the USA [1, 16, 17]. Clinical presentation There are a multitude of symptoms associated with moyamoya disease, including TIAs, ischemic strokes, intracranial hemorrhages, seizures, headaches, choreiform movements, and cognitive deficits. In contrast to adults who often present within the setting of intracranial hemorrhage ( 46%) [18], children affected with moyamoya disease typically exhibit signs and symptoms of cerebral ischemia secondary to TIAs and/or cerebral infarctions. Ischemia to the frontal, parietal, and temporal lobes are associated with hemiplegia or paresis, sensory loss or parasthesias, aphasia, and/or cognitive impairments [19]. Following a TIA, children have a much higher rate of completed infarcts when compared to their adult counterparts. This tendency is likely due to immature verbal skills in younger children making it difficult to communicate symptoms associated with TIAs, delaying the diagnosis of moyamoya and increasing likelihood of completed stroke upon presentation [20]. Moyamoya disease should be suspected in children who present with ischemic symptoms prompted by common childhood behaviors including, hyperventilation, crying, coughing, or blowing. Ischemia in the setting of these activities results from hypocapniainduced cerebral vasoconstriction of already maximally dilated cerebral blood vessels (in the face of chronic ischemia), further reducing cerebral blood flow and prompting worsening ischemia [21]. Though rare, visual symptoms related to posterior circulation stenosis and ischemia have been well documented and include temporary and permanent blindness, visual field deficits, homonymous hemianopsia, quadrantanopsia, scintillating scotomata, blurred vision, and amaurosis fuguax [22]. Disturbances in the visual pathway are more likely to occur in children as opposed to adults. For example, in a study by Miyamoto et al. [22], visual abnormalities attributed to moyamoya disease were found in 43 of 178 patients reviewed, and 79.1% of these cases were in children. Intracranial hemorrhage associated with moyamoya is infrequently encountered in the pediatric population. More commonly seen in adults, the hemorrhage can be located within the intracerebral, intraventricular, and/or subarachnoid spaces. Specifically, 40% are within the basal ganglia, 30% are intraventricular, and 15% are thalamic with intraventricular extension [23]. Traditionally, hemorrhage associated with moyamoya disease has been attributed to rupture of the fragile intracranial ICA collaterals that develop to perfuse the ischemic brain distal to the occluded vessels [19]. However, more recently, there have been reports of intracerebral and subarachnoid hemorrhage related to moyamoya-induced aneurysms and arteriovenous malformations [24 26]. Aneurysms associated with moyamoya are likely induced from the increased flow and subsequent shear stress on the fragile basal collateral vessels, and are likely to be found at the basilar apex and posterior communicating artery [25, 26]. It is also thought that the hyperangiogenic state of moyamoya induces the formation of arteriovenous shunts that mimic traditional arteriovenous malformations [27]. There has even been a case report of a non-traumatic subdural hematoma resulting from spontaneous rupture of a transdural collateral vessel [8]. Headache is a common presenting symptom of moyamoya, although its etiology remains unclear. It is postulated that headaches arise from hypoperfusion-induced activation of pain-sensitive structures such as both intracranial and extracranial vasculature, dura, orbital contents, and mucous membranes of the oral and nasal cavities [28]. Concomitantly, other mechanisms such as dilation of the meningeal collaterals stimulating dural nociceptors and ischemia induced lowering of the migraine threshold have also been suggested [8, 29]. Seizures, both focal and generalized, have been associated with moyamoya and are likely related

3 Childs Nerv Syst (2010) 26: to hypoperfusion. Choreiform movements have been associated with moyamoya disease, occurring in 3 6% of patients, and are attributed to any dysfunction of the basal ganglia-thalamocortical circuits, including infarctions and mechanical compression by traversing dilated collateral vessels [30]. Moyamoya disease refers to the idiopathic variant, whereas moyamoya syndrome refers a condition in which children with a recognized clinical disorder also have moyamoya. There are multiple documented clinical syndromes and conditions that have been associated with moyamoya. These entities include: prior radiotherapy to the head or neck for tumors, including craniopharyngiomas, pituitary tumors, optic gliomas; genetic disorders including Down syndrome, neurofibromatosis type 1 (with or without hypothalamic-optic pathway tumors), tuberous sclerosis, primordial dwarfism, large facial hemangiomas, Fanconi s anemia, sickle cell disease, and other hemoglobinopathies; autoimmune disorders including Grave s disease; collagen vascular disorders including Marfan s syndrome; congenital cardiac anomalies; renal artery stenosis; infections including tuberculous meningitis and leptospirosis; and fibromuscular dysplasia [15, 19]. These clinical associations and syndromes represent a risk factor for both the development and progression of moyamoya. Natural history and progression The natural history of untreated moyamoya ranges from a slow progression with intermittent events, to rapid neurological and cognitive decline, with overall mortality rates in the Japanese literature as high as 4.3% [1]. The long-term outcome of moyamoya disease is poor, as inevitable progression occurs in the majority of patients, with up to 66% having symptomatic progression over a 5-year period following diagnosis [19, 31]. However, various studies have shown a significant impact on longterm outcome in those patients undergoing surgical revascularization. Fung et al. [70] conducted a literature review of all cases of reported pediatric moyamoya from 1966 to 2004, and found a total of 1,156 symptomatic patients treated surgically. Post-operatively, 592 (51.2%) were completely asymptomatic, 411 (35.5%) had definitive improvement (defined as decreased frequency and/or severity of symptoms), and 122 (10.5%) remained static. Only 31 (2.7%) of 1,156 patients had definitive deterioration following surgical revascularization. As far as clinical indicators for favorable long-term prognosis in children undergoing surgical revascularization, it is apparent that neurological status at the time of surgery holds the most prognostic value (as opposed to age at time of surgery) [19]. There have been several reports of children presenting with unilateral moyamoya, and the obvious concern in these cases becomes contralateral progression of disease. The rate of progression of contralateral disease is variable. For example, Smith and Scott [8] report that of 16 children with unilateral disease, nine developed contralateral stenosis over a 6-month to 4-year follow-up period, whereas the remainder of children were disease free up to 7 years after initial angiogram. In a single-center review of 157 patients by Kelly et al. [32], there were 28 patients with unilateral moyamoya, 18 of which had clinical follow up of greater than 5 months. Seven went on to develop contralateral findings of moyamoya, and the authors noted that equivocal or mild stenosis in the contralateral hemisphere was a good predictor for the development of contralateral moyamoya. Mean time to development of contralateral disease varies by study, and has been reported as 12.7 months (range of 5-22 months) to 3.1 years (0.5-7 years) [32, 33]. Pathology and pathophysiology Pathologically, the stenosis associated with moyamoya arises in the supraclinoid ICA, extends distally to the bifurcation, and in the latter stages, involves the proximal branches of both the anterior and middle cerebral arteries. In rare cases, stenosis has also been observed in vessels of the posterior circulation, most commonly affecting the proximal portion of the posterior cerebral arteries or the basilar artery [22]. Histologically, vascular changes involve endothelial hyperplasia, fibrocellular thickening of the intima, and torturosity and duplication of the internal elastic lamina [15, 19, 34, 35]. There is neither evidence of an inflammatory infiltrate nor atheromatous plaque within the vascular walls [34]. Rather, occlusion results from progressive narrowing of vessel diameter from a combination of smooth muscle cell hyperplasia and the formation of an intraluminal thrombus [19, 35]. Collateral vessels form in moyamoya disease in response to brain ischemia distal to the ICA stenosis. They originate from various perforating vessels including the lateral and medial lenticulostriate, anterior and posterior choroidal, thalamoperforating, and thalamogeniculate arteries [22, 36]. In the latter stages of moyamoya, transdural collaterals derived from the external carotid arteries (ECA) including the middle meningeal, superficial temporal, occipital, and internal maxillary arteries, and from the ophthalmic arteries including the anterior and posterior ethmoid, recurrent meningeal, and anterior falx arteries are noted [36]. Histological study of postmortem collateral vessel specimens reveal overall thinned walls, atrophy of the media secondary to damaged smooth muscle cells and increased matrix deposition with cellular debris, and torturosity,

4 1300 Childs Nerv Syst (2010) 26: fragmentation, and thinning of the internal elastic lamina [37]. Microaneurysm formation within the weakened moyamoya vessels are a potential source of intracranial hemorrhage, and have been found on both the anterior and posterior choroidal arteries [15]. Exact pathogenesis and etiology of moyamoya disease are currently unknown; however, several studies have shown both environmental and genetic associations. Environmentally, moyamoya disease has been diagnosed in children who underwent prior head and neck irradiation for neoplastic disease. Vascular stenosis is a documented finding after radiation therapy. In addition, moyamoya disease has been found in children with prior skull base infections, including tuberculosis meningitis. Finally, in the series from Boston Children s Hospital, there were two sets of identical twin, each with only one affected sibling, indicating an environmental influence [1]. Moyamoya is most highly associated with Japanese populations where a familial occurrence has been reported to range from 7% to 12%, with a slightly lower occurrence in the USA, suggesting a genetic linkage [1, 16, 17]. Furthermore, moyamoya has been associated with certain genetic disorders including Down s syndrome, neurofibromatosis one, and sickle cell disease [1, 15, 19, 38]. Similar histological changes in the extracranial vasculature, including pulmonary, renal, and pancreatic arteries, have been documented in patients with moyamoya disease [35]. There have been linkages between moyamoya and genetic markers/foci on chromosomes 3p, 6q, 8q, and 17q [39 41]. Chromosome 3p includes a locus for the Von-Hippel- Lindau tumor suppressor gene as well as a locus for Marfan s syndrome. Though a gene product has not been discovered from the 3p locus as of yet, in light of its linkage to both Von-Hippel-Lindau and Marfan s, it is likely involved in the formation and maintenance of normal vessel walls [15]. Several studies have investigated the molecular basis of moyamoya disease, and even though a direct genetic abnormality has not been recognized, multiple cellular aspects of the disease have been elucidated. Basic fibroblast growth factor (bfgf), an angiogenic substance, has been studied in moyamoya disease. Hoshumaru et al. [39] using immunohistochemistry examined two sections of superficial temporal artery (STA) and four samples of dura in the postmortem study of four patients with moyamoya disease. The vascular and meningeal cells exhibited more intense staining for bfgf than controls, and multiple associations were postulated [39]. First, intimal thickening, the underlying histology of moyamoya, may be caused by the migration and activation of smooth muscle cells containing abnormally large amounts of bfgf. Secondly, endogenous production of bfgf is required for movement of vascular endothelial cells during neovascularization. Larger amounts of bfgf within the STA and dura may play a role in the development of collateral moyamoya vessels. Furthermore, Malek et al. [40] found elevations of bfgf in the cerebrospinal fluid of children with moyamoya when compared to matched samples in patients with hydrocephalus and controls, further signifying the role of bfgf in moyamoya disease. A further link to the genetic basis of moyamoya was revealed in a study by Minehaura et al. [41] were a major locus for the autosomal dominant form of moyamoya was found in the telomeric region of 17q25. Four candidate genes were selected from this locus based on their biological properties, including BAIAP2, which interacts with BAI1 (brain angiogenesis inhibitor-1), which is an inhibitor of bfgf [41]. Overall, further studies need to be performed to elucidate both the genetic and environmental roles in the development of moyamoya disease. Diagnosis Moyamoya disease should be taken into consideration and worked up in any child presenting with ischemic symptoms, especially in the setting of hyperventilation, crying, and/or physical exertion. A suspected diagnosis of moyamoya disease is confirmed with radiological studies. Head computed tomography Workup of a child with moyamoya disease typically begins with a head computed tomography (CT) to assess for more common pathology including tumors and/or hydrocephalus. Classically, findings on a head CT in pediatric patients with moyamoya include hypodensities suggestive of prior infarctions in watershed areas (especially in the distribution of the middle cerebral artery), basal ganglia, deep white mater, and periventricular regions [8, 15, 19]. Although rare in the pediatric population, head CT imaging will also reveal hemorrhagic pathology, including intracerebral, intraventricular, subarachnoid, and subdural hemorrhages [8, 24 27]. Depending upon the severity of prior infarctions, cerebral atrophy and encephalomalacia may also be detected. Recent advances in the field of CT angiography has led to its use in both the diagnosis of moyamoya disease and to evaluate neovascularization after surgical bypass [42]. Magnetic resonance imaging/angiography Magnetic resonance imaging (MRI) has become a reliable diagnostic modality in moyamoya disease. Acute cerebral infarctions are easily recognized on diffusion-weighted imaging, with chronic infarcts delineated by both T1- and

5 Childs Nerv Syst (2010) 26: T2-weighted imaging [43]. Fluid attenuated inversionrecovery MRI which demonstrates linear high signal intensity following a sulcal pattern (ivy sign) has been used to infer cortical ischemia and is felt to represent slow flow in the poorly perfused cortical circulation in children with moyamoya [19, 44]. Magnetic resonance angiography (MRA) has been used to accurately characterize both the stenosis and basal collateral formation associated with moyamoya disease [45]. The MR findings most suggestive of moyamoya disease remains diminished flow voids in the ICA, ACA, and MCA bilaterally, with concurrent large flow voids in the basal ganglia and thalamus representing collateral moyamoya vessel formation [45, 46]. Recently, MRI/MRA has been suggested as a reliable alternative to conventional angiography for diagnosis of moyamoya, based on the ease and fewer procedural associated risks in the pediatric population (Fig. 1). In studies by Yamada et al. [45, 46], compared to conventional angiography, stenosis was accurately diagnosed via MRA in 88%, 83%, and 88% of ICA, ACA, and MCA vessels, respectively. An overall sensitivity and specificity for accurate diagnosis of vascular stenosis was 100%, 93% and 100%, 77%, respectively, for MRA and MRI. In addition, 75% of moyamoya collateral vessels diagnosed on MRA corroborated with angiographic findings, concluding that MRA is beneficial in diagnosing larger basal ICA, leptomeningeal, and transdural collaterals, whereas smaller collateral remain underestimated. Of note, the average age of the patient population in these studies was older, likely leading to better quality imaging without motion artifact. The authors concluded that when MRA and MRI imaging are performed in tandem, a more complete diagnosis and evaluation of moyamoya disease is obtained. Although MRA and MRI are not the gold standard, they are sensitive and specific enough for reliable diagnosis without invasive testing when moyamoya is suspected in a child, reserving conventional angiography for pre-operative planning. Conventional angiography Conventional angiography remains the gold standard for both the diagnosis and surgical planning for patients with suspected moyamoya disease. A five- or six-vessel study should be performed, including imaging of the bilateral ECA, ICA, and one or two vertebral injections. Angiographic imaging of the bilateral external carotid arteries is of utmost importance for pre-operative planning to prevent disruption of these collaterals during the surgical revascularization. Classical findings on angiogram include stenosis of the supraclinoid ICA, proximal ACA and MCA, associated with basal ICA, leptomeningeal, and transdural collaterals giving rise to the classic puff of smoke appearance [3] (Fig. 2). Furthermore, angiography is functional in both the detection and anatomical descriptions of aneurysms and AVM associated with moyamoya disease [24 27]. Angiographic appearance of moyamoya disease progresses through one of six stages as originally defined by Suzuki and Takaku [4] in 1969: (1) carotid stenosis without the presence of moyamoya collaterals; (2) initial appearance of basal collateral vessels; (3) progressive stenosis of the distal ICA, with increasing prominence of the basal collaterals; (4) severe stenosis or occlusion of the anterior circulation with the formation of ECA collaterals; (5) prominence of the ECA collaterals, reduction, and stenosis of the basal moyamoya collaterals; and (6) complete occlusion of the ICA, disappearance of the basal moyamoya collaterals, with cortical blood supply solely provided though ECA collaterals. Angiography can play an important role in post-operative imaging after surgical bypass as it is frequently used in addition to MRI/A as a Fig. 1 T2-weighted axial MR images in a child with moyamoya disease showing incomplete flow voids in bilateral suprasellar cisterns indicating severe stenosis of the supraclinoid ICAs (left, white arrows). There are multiple small flow voids throughout the bilateral basal ganglia which represent moyamoya collateral vessels (right, black arrows) and periventricular ischemic changes

6 1302 Childs Nerv Syst (2010) 26: found to be present in greater than 50% of children with diagnosed moyamoya. Additional imaging studies have been used to monitor cerebral blood flow in children diagnosed with moyamoya, both as a pre-operative measure and following surgical bypass to assess neovascularization induced cortical perfusion. These studies include transcranial Doppler ultrasonography, CT and MR perfusion imaging, xenon enhanced CT, positron-emission tomography, and single-photon-emission CT [49 52]. Treatment options Fig. 2 ICA injection in a conventional cerebral angiogram in a child with moyamoya disease revealing stenosis of the supraclinoid ICA (white arrow) with formation of an extensive network of collateral vessels means of assessing neovascularization and cortical perfusion. A grading scheme has been developed to assess synangiosis-induced collateral formations by Matsushima et al. [47], with grade A representing synangiosis-induced filling of greater than two thirds of the MCA circulation, grade B between one third and two thirds, and grade C signifying less than one third filling. Electroencephalography and cerebral blood flow studies Electroencephalography (EEG) is a diagnostic tool used in the evaluation of moyamoya, as specific alterations are found in children affected with this condition. Characteristic findings include posterior and/or centrotemporal slowing, and a re-buildup phenomenon after the end of hyperventilation [48]. In all children, hyperventilation induces a diffuse pattern of high voltage, monophasic slow waves, referred to as build up, that terminate after hyperventilation has ceased. In pediatric patients with moyamoya, there is a return of the high voltage, monophasic slow waves following the end of hyperventilation, termed re-buildup, which is thought to represent a diminished cerebral perfusion reserve [8, 15, 19, 48]. Essentially, hyperventilation induces cerebral vasoconstriction, and upon its cessation, cerebrovascular dilation (buildup). In children with moyamoya, re-buildup occurs as a steal phenomenon as blood is diverted from the dilated cortical vessels to the moyamoya-associated collaterals, creating a cortical ischemic state, represented as the reappearance of the high voltage, monophasic slow waves on the EEG [21, 48]. Over time, re-buildup resolves and the EEG returns to baseline. Re-buildup has been After a significant stroke or intracerebral hemorrhage, the pediatric patient with moyamoya is often left with devastating permanent neurological and cognitive impairments [1, 15, 53 55]. Neurological status at the time of surgical interventions remains the most significant prognostic indicator for long term outcome [19]. Therefore, early diagnosis and prompt surgical treatment provide the best chances to improve neurological outcome. Medical treatment Currently, there is no definitive medical treatment to reverse or stabilize the course of moyamoya disease. There are two classes of medications that play an adjuvant role in the treatment of moyamoya; antiplatelet agents and calcium channel blockers [53 55]. A proportion of the ischemic symptoms associated with moyamoya disease have been attributed to microthrombus formation due to emboli arising from sites of arterial stenosis [8, 15, 19]. Daily, lifelong aspirin use is prescribed to prevent the ischemia associated with this embolic phenomenon. Patients less than 6 years of age receive 81 mg/day, with the dose gradually increased into adolescence and adjusted appropriately if there are any signs of the known side effects, including easy bruising and bleeding [15]. Anticoagulants, such as warfarin (Coumadin), are rarely used in the pediatric population due to the difficultly in maintaining steady therapeutic levels, though there have been some successes in the use of low-molecular weight heparin (Lovenox) for select children [8, 19]. The second class of medications used in moyamoya disease is calcium channel blockers, and evidence exists to support their use in the treatment of persistent postoperative TIAs and intractable headaches [8, 15, 19]. The mechanism of action remains unknown, but calcium channel blockers are shown to reduce the frequency and severity of refractory TIAs, with a low side-effect profile in children [8, 15, 19].

7 Childs Nerv Syst (2010) 26: Surgical treatment Results from several published studies have shown a favorable response to surgical intervention in moyamoya disease, especially in the reduction of ischemic events [56, 57]. Although there is no published prospective randomized controlled clinical trial to define a superior surgical procedure in children with moyamoya, there have been several reported successes using a variety of the surgical revascularization procedures. Revascularization can be divided into two groups, direct and indirect types. Direct bypass provides rapid, instant increases in cerebral perfusion, whereas indirect procedures rely on delayed neovascularization through a variety of processes. The most common direct and indirect revascularization procedures will be discussed, as well as the surgical outcomes from the two largest published pediatric series, in addition to the data from our institution. Superficial temporal artery-to-middle cerebral artery bypass (STA-MCA) Yasargil and Donaghy were the first to perform direct extracranial-to-intracranial bypass in 1967 for the treatment of cerebral ischemia, and Yasargil then performed the first reported case of direct superficial temporal artery-to-middle cerebral artery bypass (STA-MCA) bypass in a child with moyamoya [57, 58]. Surgical technique begins with the identification and dissection of the frontal and/or parietal branches of the STA [59, 60]. A frontotemporal craniotomy is carried out over the Sylvian fissure, dura is opened, and a suitable M3 or M4 recipient vessel is identified. The recipient vessel is clamped proximally and distally to the site of anastomosis, as well as distal clamping of the donor STA. An end-to-side anastomosis is performed. The temporary clips are removed, and the patency and hemostasis of the bypass is assessed. Dura, bone flap, and skin closure are then carried out with care taken to avoid compression of the donor STA. In a study by Schick et al. [61], long-term patency of STA-MCA bypass, irregardless of clinical indication, was 91% at a 5.6 year follow up period. STA-MCA bypass remains the most common direct revascularization procedure for childhood moyamoya, though occipital artery-to-middle cerebral artery bypass has been used in cases where the STA does not provide a suitable donor [62]. The use of STA-MCA bypass in combination with indirect procedures, including EMA and EDAMS, has also encountered success as reported in the literature. The major advantage of the direct bypass procedure is an immediate increase in blood flow to the ischemic brain. Disadvantages include technical difficulty due in part to the small diameter of the donor and recipient vessels in the pediatric population. In addition, direct bypass procedures may result in transient hypervascular edema of the revascularized hemisphere, which typically resolves with no sequelae. While the treatment addresses the MCA distribution, there is no direct effect upon ACA or PCA territories. Temporary clipping of the MCA, which may interfere with already present leptomeningeal and transdural collaterals, can lead to peri-operative stroke. Furthermore, the STA-MCA bypass provides only a limited amount of meaningful blood flow to the entire MCA distribution, thus placing the child at risk for refractory ischemic events [8, 15]. Encephalomyosynangiosis Indirect procedures were developed as an alternative to bypass due to the difficulties encountered in the pediatric population with direct STA-MCA anastomosis. Indirect procedures tend to be less invasive, are technically easier and result in a shorter operative time, do not restrict treatment to solely the MCA distribution, and most importantly, do not involve clamping of recipient vessels [8, 15, 19, 59]. Encephalomyosynangiosis (EMS) was first used in the treatment of moyamoya disease in the late 1970s, and involves a frontotemporal craniotomy, dural opening, followed by the removal of the arachnoid over the region to be treated [63]. The temporalis muscle is placed over the exposed pia and the dura approximated over the muscle. Care must be taken to avoid disruption of the temporalis blood supply both during opening and closing. Angiogenesis occurs over several weeks to months due to the rich blood supply of the temporalis muscle by the deep temporal artery [63, 64]. Even though EMS is a less invasive procedure, there are distinct disadvantages, including the necessity of a larger craniotomy and dural opening, cosmetic deformation, and more importantly, post-operative complications such as seizure, brain edema, and symptomatic mass effect associated with the large space-occupying muscle [59, 63]. Encephaloduroarteriosynangiosis Encephaloduroarteriosynangiosis (EDAS) was introduced as a surgical alternative for the treatment of moyamoya disease in 1980 [65]. In this technique, the intact donor STA (parietal branch) is dissected free, a craniotomy flap is turned, and the STA is sutured by its adventitia/galeal cuff to a linear opening in the dura [8, 15, 59]. The donor STA is left intact, as opposed to its sacrifice in the STA-MCA bypass. In modified variants, the dura near the middle meningeal artery is either inverted onto the cortical surface, or it is split into both an outer and inner layer with the heavily vascular outer layer placed in direct contact with

8 1304 Childs Nerv Syst (2010) 26: the cortex [8, 59]. This modification derives from the finding that the vascular dura near the middle meningeal artery has been shown to be more inclined to form vascular collaterals in patients with moyamoya disease [66]. A further modification, encephalomyoarteriosynangiosis (EMAS) consists of a combination of both EMS and EDAS. In this procedure, the temporalis muscle along with a superficial branch of the STA is placed in contact with the cerebral cortex. Besides the typical disadvantages of the indirect procedure, failure of EDAS and EMAS (in addition to EDAMS and pial synangiosis) typically render the STA ineffective for use in future direct bypass procedures. Pial synangiosis Scott [1, 8], first introduced pial synangiosis as a modification to the EDAS procedure. This technical modification was derived from the thought that the arachnoid layer served as a preventative barrier to vascular in-growth in the standard EDAS procedure [59]. The technique involves the following steps [8]: (1) a suitable donor vessel, typically the parietal branch of the STA, is dissected from distal to proximal along with a galeal cuff and surrounding soft tissue; (2) a large craniotomy is turned in the region adjacent to the donor vessel; (3) the dura is opened in a stellate fashion into a minimum of six flaps to increase the surface area of dural to pial contact, and avoiding disruption of potential meningeal collateral vessels; (4) the arachnoid is opened widely and removed in the area exposed by the dural opening; (5) the intact donor artery is sutured through its adventitia, using four to six interrupted 10-0 nylon sutures, to the pial surface; and (6) the bone flap is replaced over a Gelfoam cover of dura, the temporalis muscle and skin are closed paying close attention to avoid compression of the donor vessel. Despite opening the arachnoid widely and no dural closure, risk of CSF leak remains extremely low [1]. Encephaloduroarteriomyosynangiosis Encephaloduroarteriomyosynangiosis (EDAMS) was introduced in 1984 as a combination of multiple indirect procedures to provide the greatest chance for neovascularization. The technique involves the following procedures [67]: (1) dissection and isolation of a branch of the STA with a galeal cuff, (2) a large craniotomy and dural opening into multiple leaflets avoiding disruption of the middle meningeal artery, (3) opening of the arachnoid overlying the entire craniotomy, (4) the outer surface of the dural leaflets are folded inward to contact the pial surface and sutured in place, (5) the STA and galeal cuff are laid onto the pial surface and affixed to the dural margin, and (6) the temporalis muscle is stretched to cover the brain and sutured to the dural edges. This procedure provides multiple sources for the development of collateralization, including the highly vascular outer dural layer, the STA and its galeal cuff, and the temporalis muscle via the deep temporal artery. In one study, EDAS was compared to EDAMS, and EDAMS with STA-MCA bypass both clinically and radiographically. EDAMS, regardless of the combined STA-MCA anastomosis, was more effective in achieving angiographic revascularization and reduction of pre-operative ischemic symptoms compared to EDAS alone [68]. Omental transplantation Omental transplantation is a rarely used technique used to treat pediatric moyamoya disease, and is classically reserved for cases in which both direct and indirect revascularization procedures have failed. Omental transplantation was first introduced in 1973 as a treatment for cerebral ischemia as studies in a canine model showed neovascularization between the omentum and underlying neural tissue; several years later it became a viable option for the treatment of moyamoya disease [69]. In this procedure, either an intact omental flap is tunneled from the abdomen, thru the chest and neck, and placed on the cortical surface, or a free flap is anastomosed via the gastroepiploic artery and vein to the superficial temporal artery and vein, respectively [15]. The patency rate for omental grafts have been reported to be as high as 70% and neovascularization is attributed to lipid factors in the omentum that may have intrinsic angiogenic properties [59]. Cranial bur holes Multiple cranial bur holes have been used as adjuncts to other revascularization procedures, including STA-MCA bypass, EMS, EDAMS, and pial synangiosis [1]. Typically, the bur holes are placed, the underlying dura, arachnoid, and pia are opened, and a pericranial flap is placed in contact with the cortex. In a study by Sainte-Rose et al. [71], 14 children underwent placement of bur holes per hemisphere. Follow-up MR perfusion and correlation with conventional angiography, in the five most recent cases showed excellent revascularization of the ischemic cortex by ECA collaterals, with no postoperative ischemic events in these children. Peri-and postoperative considerations Regardless of surgical procedure, there are specific perioperative risks for children undergoing revascularization for moyamoya. The risk of stroke is highest in the first 30 days following surgery. Then, the risk decreases noticeably after the first month with a 96% probability of remaining stroke-

9 Childs Nerv Syst (2010) 26: Table 1 Children treated with moyamoya at the Johns Hopkins Children s Center Variables Johns Hopkins Hospital No. of pediatric patients (age 14 ( years) range at time of surgery) No. of surgical procedures Pial synangiosis EDAMS 7 3. Combined STA-MCA and 3 EDAMS Moyamoya type 1. Disease 8 2. Syndrome 6 (sickle cell disease 3, Down s syndrome 2, NF1 1) Presenting symptoms 1. Ischemic (TIA & CVA) 12 (85.8%) 2. Seizure 1 (7.1%) 3. Headache 0 (0%) 4. Hemorrhage 0 (0%) 5. Incidental 1 (7.1%) Postoperative complications 3 1. TIA 2 2. Pseudomeningocele 1 (non-operative) free over the subsequent 5-year period [8]. Focus has concentrated on preventing ischemic events in the initial 30 days following surgery. Methods to reduce pain, crying, and hyperventilation induced cerebral vasoconstriction include effective pain control with peri-operative sedation and the use of painless wound dressings and absorbable sutures [8, 19]. Intra-operatively, hypotension, hypovolemia, hyperthermia, hypercapnia, and hypocapnia should be avoided. The use of intra-operative scalp EEG to detect ischemic events during the induction and maintenance of general anesthesia has also been employed [8]. Additionally, the use of aspirin in both the peri-operative period and long-term has become routine care. Surgical outcome data To date, there have been two large published series in the English language dealing with the surgical treatment of moyamoya in the pediatric population. Each has documented success with surgical revascularization, one via the indirect method, and one via the direct. The largest series is reported by Scott et al. from The Children s Hospital, Boston in which 143 patients underwent 271 revascularization procedures (96 in whom both hemispheres were treated in the same sitting), all with pial synangiosis [1]. Preoperative stroke and TIAs occurred in 67.8% and 43.4% Table 2 Children treated with moyamoya at three different hospitals Variables The Children s Hospital, Boston, Massachusetts Stanford University, California Johns Hopkins Hospital, Maryland No. of patients (age range at time of 143 ( years) 96 ( years) 14 ( years) surgery) No. of surgical procedures Direct 0% 76.2% 0% 2. Indirect 100% 23.8% 87% 3. Combined 0% 0% 13% Moyamoya type 1. Disease Syndrome Presenting symptoms 1. Ischemic 67.8% stroke, 51% 85.7% 43.4% TIA 2. Hemorrhagic 2.8% 2.1% 0% 3. Headache 6.3% 44% 0% 4. Seizure 6.3% NR 8.3% 5. Choreiform movements 4.2% NR 0% 6. Incidental 4.2% NR 8.3% Immediate postoperative complications (<30 days) CVA TIA (severe) Hemorrhage 0 1 0

10 1306 Childs Nerv Syst (2010) 26: of children, respectively, with only 11 episodes of stroke and three severe TIAs in the immediate 30 day postoperative period. The success of pial synangiosis is evident by the fact that in 126 patients followed for more than 1 year, there were only seven late-onset complications: four suffered a late-onset stroke, one experienced a severe, but completely resolved TIA, and two with persistent TIAs. Of the 46 patients with the sole presentation of stroke followed for more than 5 years, only two developed new strokes in this follow-up period. The second largest series dealing with the surgical treatment of pediatric moyamoya has been published by Steinberg et al. [38] from Stanford University Medical Center. In this series (which included both adult and pediatric patients for a total of 450 revascularization procedures), there were 96 children undergoing 168 procedures, of which, 76.2% were direct bypass with STA-MCA anastomosis, and 23.8% with various indirect measures including EDAS. Within the immediate 30 day post-operative period, there were only three reported events in the pediatric population: two documented strokes and one hemorrhage with complete neurological recovery. TIAs which were documented to occur between post-operative day 3-7 and last until day 14, were all associated with a complete recovery. Of note, it was found that in children presenting with stroke, there was a trend towards a higher rate of post-operative complications, with those treated with indirect revascularization being 2.5-fold more likely to suffer postoperative stroke then those treated with STA- MCA bypass. From October 1999 to October 2009, we have treated 14 children (age ranging from 0.1 to years) with moyamoya at the Johns Hopkins Children s Center. Twenty three procedures have been performed, including 13 for pial synangiosis, seven for encephaloduroarteriomyosynangiosis, and three for a combination of STA-MCA bypass with EDAMS. The idiopathic form was present in eight children and six children had the moyamoya syndrome (three with sickle cell disease, two with Down s syndrome, and one with neurofibromatosis-1 with bilateral optic nerve gliomas). Presenting symptoms in the majority of cases was ischemic disease (12 of 14), with one case associated with seizures, and one as an incidental finding. Within the immediate 30 days post-operative period, there were only two events, both TIAs with complete resolution. There was no evidence of CSF leak, but one case of a pseudomeningocele managed conservatively (Tables 1, 2). Conclusions Despite being relatively uncommon, moyamoya disease is becoming more widely recognized worldwide as a cause of pediatric cerebrovascular events, and should be considered in any child who presents with symptoms of cerebral ischemia. Rapid diagnosis of the pediatric patient with moyamoya is disease is essential, as neurological status at the time of treatment is more predictive of long-term outcome then age. Diagnosis is confirmed by MR and conventional angiographic imaging. Associated clinical conditions and syndromes should be assessed for, as they are a risk for both the development of moyamoya and its progression. If left untreated, moyamoya disease progresses, and frequently results in permanent neurological and cognitive deficits. Although there is no curative medical treatment for moyamoya, numerous studies have shown long-term improvement in children undergoing surgical revascularization procedures. 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