Factors Associated with the Presentation of Moyamoya in Childhood

Factors Associated with the Presentation of Moyamoya in Childhood Catherine Amlie-Lefond, MD,* and Richard G. Ellenbogen, MD†

Background: Moyamoya accounts for approximately one fifth of cerebral arteriopathies in children presenting with acute stroke; however, often is not diagnosed until stroke occurs, even in higher risk populations and often despite a history of transient ischemic attacks (TIAs). This study was undertaken to better define which groups of children are at risk for moyamoya and how they present. Methods: With institutional review board approval, the charts of all patients with a diagnosis of moyamoya were reviewed. Results: Fifty-four patients were identified. Mean age at presentation was 7.5 years; 56% were female; 32 (59%) had predisposing medical conditions associated with moyamoya; and 17 (31%) were of Asian descent. Only 11 children (20%) had no underlying predisposing condition identified, of whom, 4 had underlying conditions not previously reported in association with moyamoya. Eight patients (15%) were Native American; 38 (70%) had a history of TIAs; and 26 (48%) presented with acute stroke, of whom, three fourth had left and one fourth had right hemisphere strokes. Fifty-two percent had a history of headache. Conclusions: Most children with moyamoya in this series had an underlying predisposing condition, compared with other US series, where almost half had no predisposing condition identified. In this series, fewer children (48% versus 68%) presented with stroke, many (70% versus 43%) had a history of TIAs, and many (52% versus 22%) had a history of headaches than in previous reports. In addition, the Native American population may be at higher risk of moyamoya than previously recognized. Key Words: Moyamoya—stroke—transient ischemic attack—childhood. Ó 2015 by National Stroke Association

Cerebral arteriopathy is increasingly recognized as a significant risk factor for primary and recurrent stroke in childhood.1,2 Moyamoya represents one of the most

From the *Department of Neurology; and †Department of Neurosurgery, Seattle Children’s Hospital, University of Washington, Seattle, Washington. Received September 29, 2014; revision received January 5, 2015; accepted January 9, 2015. There is no grant support for this article. The authors have no disclosures or conflicts of interest. C.A.-L. performed data collection and analysis of the data, and C.A.-L. and R.G.E. wrote the article. C.A.-L. had full access to all the data and takes responsibility for the integrity of the data and accuracy of the data analysis. Address correspondence to Catherine Amlie-Lefond, MD, Seattle Children’s Hospital, University of Washington, MB 7.420, 4800 Sand point Way NE, Seattle, WA 98105. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.018

1204

severe arteriopathies and accounts for approximately one fifth of identified cerebral arteriopathies in children presenting with acute stroke.3 Moyamoya is often not diagnosed until stroke occurs and acute stroke heralds the diagnosis of moyamoya in 39%-69% of children,4-6 despite a history of transient ischemic attacks (TIAs) in many patients. In addition, TIAs are most difficult to detect particularly in very young children who are mostly at risk. Moyamoya can have an aggressive course in young children who are more likely to have more infarcts at baseline, have recurrent stroke while awaiting revascularization surgery, and have poor clinical outcomes and persistent neurocognitive impairment in adulthood.5,7,8 Moyamoya disease is a chronic progressive occlusive cerebrovascular disorder characterized by progressive bilateral stenosis of distal internal carotid arteries circulation resulting in chronic and acute ischemia. Compensatory enlargement of the perforating vessels at the base

Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 6 (June), 2015: pp 1204-1210

MOYAMOYA IN CHILDHOOD

of the brain leads to the development of collaterals that appear to appear like a ‘‘puff of smoke,’’ thus, the Japanese term ‘‘moyamoya.’’9 Moyamoya disease may be idiopathic (‘‘moyamoya disease’’) or occur in association with other syndromes (‘‘moyamoya syndrome’’), such as sickle cell disease, neurofibromatosis, postradiation, and trisomy 21. The term ‘‘moyamoya disease’’ is often used to include both.6 Moyamoya can occur unilaterally or asymmetrically, particularly, when associated with an underlying syndrome. In addition, presenting signs and symptoms may not correlate with radiographic stage. Moyamoya has a bimodal incidence with a peak at 5 years, with a smaller peak in the fourth decade. Most children present with ischemic symptoms or headache. However, the adult presentation is different with intracranial hemorrhage as the most common presentation. Moyamoya disease often involves a progressive radiologic and clinical process, particularly in children. Children with moyamoya may present with headache and TIAs. TIAs frequently precede a sentinel stroke, which is confirmed by imaging. Signs of anterior circulation ischemia including aphasia, dysarthria, hemiparesis, and seizures are often seen, but less common presentations such as syncope, visual changes, and chorea can occur. Symptoms are often provoked by hyperventilation because of hypocarbia-induced vasoconstriction. Provocative activities include crying, yelling, breath holding, exercise, or tussive maneuvers. Much of the literature on childhood moyamoya is derived from neurosurgical registries. There are robust data on the diagnosis, surgical management, and outcome after surgery, but limited information on the signs and symptoms preceding diagnosis. This study was undertaken to better define which children are at risk for underlying moyamoya disease/ syndrome and how they present in the Northwest region of the United States. Detecting early symptoms of moyamoya is critical as neurologic status at the time of treatment predicts long-term functional outcome.

Methods The charts of all patients with a diagnosis of moyamoya cared for at Seattle Children’s Hospital between January 1, 1997, and July 27, 2014, were reviewed. The Seattle Children’s Hospital is the only freestanding pediatric hospital in the WWAMI states (Washington, Wyoming, Alaska, Montana, and Idaho), which is 27% of the land mass of the United States. The Seattle Children’s Hospital, thus, cares for most, but not all, of the children referred for treatment of moyamoya in this region. Institutional review board approval was obtained, including waiver of consent. A total of 60 patients were identified and charts were reviewed. Three patients did not have moya-

1205

moya, and 3 had no clinical information available. The charts of the remaining 54 patients were reviewed in detail.

Results The mean age at presentation was 7.5 years, with a range of .5-18.4 years (Table 1). In all, 30 of 54 (56%) were female; 32 of 54 (59 %) had predisposing medical conditions associated with moyamoya. Seventeen (31%) were of Asian descent. Only 11 children (20%) had no underlying predisposing condition identified. Of these, 4 had underlying conditions not previously reported in association with moyamoya: Raynaud and fibromyalgia; FLNA (filamin A) mutation; a history of viral meningitis; and autism and mental retardation. Eight patients (15%) were Native American, of whom 4 were Alaska native and 3 were of partial Native American descent; 4 (7%) patients were of partial Hawaiian/Pacific Islander descent. Demographic information from the past 2 years shows that 1.3% of all children seen at our institution considered themselves American Indian or Alaska Native, compared with 15% of the patients with moyamoya (P , .001). In addition, .8% of patients at Seattle Children’s Hospital consider themselves Native Hawaiian or other Pacific Islander, compared with 7% (4 of 54) of patients with moyamoya in this series (P 5 .001). Thirty-eight patients (70%) had a history of TIA, in whom, 35 had lateralized TIA symptoms. Twenty children had symptoms lateralized to the left hemisphere, 14 to the right hemisphere, and 1 to both hemispheres. Duration of TIAs could only be ascertained in 34 patients among whom the mean age was 1.2 years. In all, 26 patients (48%) presented with acute stroke, of whom, 19 (73%) had involvement of the left hemisphere, 6 (23%) had involvement of the right hemisphere, and 1 had bilateral strokes. Twenty-eight patients had signs of remote asymptomatic ischemia on neuroimaging at presentation, and most (45 of 54 or 83%) patients had acute and/or remote ischemic findings at presentation. Twenty-eight patients had a history of headache at presentation, 6 of whom had been diagnosed with migraine headaches including 1 patient diagnosed with hemiplegic migraine.

Discussion Moyamoya is more common in the Asian population and is associated with many underlying conditions.10 Predisposing conditions associated with moyamoya include sickle cell disease, neurofibromatosis type 1, cranial irradiation, trisomy 21, cardiac anomalies such as pulmonary artery hypertension/stenosis, renal artery stenosis, hypertension, hyperthyroidism, William syndrome, and Alagille syndrome.6,11-22 Other less commonly

Age at presentation/sex Hemisphere

Race/ethnicity

Underlying predisposing condition

Caucasian

None

None

1.2/F 1.3/M

B R

Caucasian Caucasian/Hispanic

Pulmonary hypertension Autism, mental retardation

Unknown None

2.3/M

B

Caucasian

None

2.6/F

B

Caucasian/Hispanic

Pulmonary stenosis; MDR3 homozygous mutations Trisomy 21

2.6/F

B

Alaska native

2.8/F 3.6/M 3.7/M

B B B

African American Caucasian Caucasian

3.8/F 4.0/M 4.3/M

B B R

4.7/M 5.0/M 5.2/F 5.4/M

B L B B

Caucasian Chinese 1/2 Native American, 1/2 Caucasian Korean Caucasian Korean Caucasian

5.5/F 5.5/M 5.7/F 5.8/F 5.8/M 6.0/F

B B B B L B

Korean Korean 1/4 Japanese Caucasian African American 1/2 Hawaiian

6.3/F

L

Caucasian

6.4/M 6.4/F

B B

African American Caucasian

6.6/F

B

Korean

6.7/F

R

Alaska Native

Neurofibromatosis type 1; radiation therapy 15 mo earlier for optic glioma Sickle cell disease Noonan syndrome, coarctation of the aorta B accessory renal arteries; renal artery stenosis Tuberculous meningitis age 2 y

None None None Over 3-d period before presentation R hemiparesis, tingling, aphasia; L hemiparesis R hemiparesis (seizures also) R hemiparesis with crying None L arm numbness and dysarthria 10 d of stuttering weakness and headache R hemiparesis, ‘‘collapse’’ None mentioned R hemiparesis especially with scolding Yes, including ‘‘hemiplegic migraine’’ L hemiparesis None Unknown Dizziness, TIA described as seizure with L-sided weakness L hemiparesis

Acute stroke: R hemiplegia; R-sided seizures for 4 mo Acute bilateral strokes Acute stroke: L hemiplegia, L-sided seizures Acute stroke: R hemiplegia Acute stroke: R hemiplegia, seizures Developmental regression, hypertonicity Acute stroke: R hemiplegia Acute stroke: L hemiplegia

Seizures None

Acute stroke: R hemiplegia Acute stroke: R hemiplegia

Acute stroke: R hemiparesis Acute stroke: L hemiplegia

Unknown R hemiparesis

Acute stroke: R hemiplegia

R hemiparesis with R-sided migraine

Acute stroke: R hemiplegia

R leg numbness

Optic nerve pallor

C. AMLIE-LEFOND AND R.G. ELLENBOGEN

B

None Herpes zoster 4 mo previously None Alagille syndrome, pulmonary artery stenosis None 6p25 deletion None Trisomy 21; ventricular septal defect Sickle cell disease Noonan syndrome, pulmonary stenosis

Other symptoms at diagnosis

Transient ischemic attacks

.5/F

Probable neurofibromatosis type 1; autoimmune disease Sickle cell disease Possible Noonan syndrome Partial duplication of FLNA (filamin A, alpha); aortic insufficiency Neurofibromatosis type 1 None Neurofibromatosis type 1

1206

Table 1. Presenting features of patients with moyamoya

B

7.3/F 7.4/F 7.8/F

B B B

7.8/F 7.9/M 8.4/M 8.8/F

B B B B

8.8/F 8.9/M

B B

9.2/M 9.3/F

B B

9.4/F

L

10.0/M 10.2/F 10.6/F

1/2 Bangladesh, 1/2 Caucasian African American African American 1/2 Vietnamese, 1/2 Caucasian Korean Caucasian Alaska Native Caucasian/African American Caucasian Korean

Neurofibromatosis type 1

R hemiparesis, staggering

Acute stroke: R hemiplegia

Sickle cell disease Sickle cell disease None

R hemiparesis and slurred speech R hemiparesis R hemiparesis (diagnosed as ‘‘seizures’’)

Acute stroke: R hemiplegia Acute stroke: R hemiplegia ‘‘Seizures’’

Hyperthyroidism Raynaud syndrome, fibromyalgia None Deletion 6pter / 6p23; pulmonary stenosis None None

R face and hand numbness L hemiparesis L hemiparesis Unclear

Perinatal HIV None

B B B

Caucasian Asian/Hawaiian Pacific Islander African American/Indian/ Hawaiian Pacific Islander Caucasian Caucasian/Hispanic Unknown

11.0/F 11.0/F

B B

‘‘Asian’’ Alaska Native

11.2/M 11.2/M

B B

12.1/M 13.2/F 13.5/M

B R B

Caucasian Filipino; Native American, Japanese 1/2 Japanese Caucasian Native American

None Neurofibromatosis type 1; acute myeloid leukemia at presentation None Hypertension

15.2/M 15.9/M 18.0/F

B B B

Korean 1/2 Tongan Caucasian/Hispanic

18.4/F

R

Unknown

Radiation therapy 3 y 9 mo earlier for maxillary tumor None Viral meningitis at 3-4 mo of age None

None None Neurofibromatosis type 1; renal artery stenosis; hypertension None Trisomy 21 Radiation therapy 5 y earlier for craniopharyngioma Neurofibromatosis type 1; radiation therapy for optic glioma

Acute stroke: L hemiplegia TIA versus seizure 1 mo earlier, regression

MOYAMOYA IN CHILDHOOD

6.7/M

R hemiparesis and sensory loss L-sided hemiparesis numbness, tingling, dysarthria R hemiparesis, aphasia, and L hemiparesis L-sided numbness R hemiparesis and aphasia R-sided numbness and aphasia Syncope, R-sided twitching for 1 y R hemiparesis with speech difficulties, suspected seizures L hemiparesis headache for 4 1/2 y R hemiparesis with aphasia L-sided numbness L arm weakness and tingling

Acute stroke: R hemiparesis

Acute stroke: R hemiparesis Acute stroke: R hemiparesis; suspected seizures Acute stroke: R hemiparesis

Acute stroke: L hemiparesis; L-sided seizures

R arm numbness and tingling, syncope L hemiparesis None reported

Acute stroke: R hemiplegia

None None L hemiparesis, ‘‘collapse’’

Acute stroke: R hemiplegia Acute stroke: L hemiplegia

L hemiparesis with aphasia, dizzy spells

Regression

Abbreviations: B, bilateral; F, female; HIV, human immunodeficiency virus; L, left; M, male; R, right; TIA, transient ischemic attack. 1207

1208

associated syndromes include human immunodeficiency virus,23 varicella,24 terminal 6p deletion,25 tuberculosis meningitis,26 primordial dwarfism, glycogen storage disorder type 1A, Russell-Silver syndrome, and Hurler syndrome.27 In 2 large US series totaling 239 cases of childhood moyamoya, almost half had no predisposing condition identified.6,27 In contrast, most children with moyamoya in this series have an underlying predisposing condition. Frequently associated conditions often represented arteriopathies: heart disease (pulmonary stenosis and pulmonary hypertension), renal artery stenosis, and hypertension. The high incidence of moyamoya among Native Americans has not been previously reported. Because of small numbers, the incidence of moyamoya among Native Americans could not be determined in a recent study of moyamoya among all ages in Washington and California.10 In the Nationwide Inpatient Sample, 1.4% of patients admitted with moyamoya were Native American.28 Nevertheless, Native American populations including the Alaska native population have genetic similarity with eastern Asians, and this population may need to be considered as being at higher risk of developing moyamoya. The higher incidence of moyamoya among Native Hawaiian or other Pacific Islander populations may be explained by the hypothesis that the Polynesian population and eastern Asian population are genetically similar. Although a report of patients with moyamoya in Hawaii found that non-Japanese Asians and Pacific Islanders did not have a statistically significant higher incidence of moyamoya than Caucasians, only 21 patients, of whom only 4 were children, were included in this study.29 The demographic comparison data in this study is limited in that it is self-reported and 15.7% of families chose not to disclose racial and ethnic information; however, is consistent with the overall catchment population. In this series, 48% of patients presented with acute stroke, consistent with 39%-69% previously reported.4-6 Scant literature exists regarding the types and duration of preceding TIAs. In a series of 143 children presenting with moyamoya, 43.4% had a history of TIAs, although the frequency with which TIAs preceded a stroke is unknown.6 Among 16 children aged 1.5-16 years presenting with moyamoya, the 10 who presented with stroke were described as having had ‘‘months of TIAs.’’4 In this series, TIAs were present in 70% of patients, usually with hemimotor or hemisensory dysfunction. TIAs in moyamoya may be mistakenly ascribed to focal onset seizures with postictal hemiparesis. Focal onset seizures were reported in this series and are not uncommon in children with moyamoya, likely associated with unrecognized ischemic injury. They may coexist with TIAs. In addition, it may be challenging to distinguish hemiparesis from a TIA versus postictal hemiparesis and limb shaking TIA from a focal seizure.

C. AMLIE-LEFOND AND R.G. ELLENBOGEN

It is difficult based solely on literature review to distinguish the age at symptom onset in childhood moyamoya as preferentially the age of surgical intervention is most frequently reported. The mean age of 7.5 years in this series is consistent with previously reported mean ages ranging from 4.5 to 10 years.5,6,27,30-35 Progressive severe headaches were frequently seen in this series, not infrequently with ominous features such as night time waking or developmental regression. The co-occurrence of headache and transient lateralized neurologic dysfunction was common, and 1 child was diagnosed with hemiplegic migraine, which has been previously reported in moyamoya.36 Hemiplegic migraine is very rare in childhood; however, with a mean age of onset of familial hemiplegic migraine of 16 years in males and 21 years in females. Seol et al37 found that 44 of 204 (22%) children diagnosed with moyamoya had significant headaches at presentation, with a mean duration of 21 months. Although stroke is the most common event leading to diagnosis of moyamoya in children, this study shows that most children with moyamoya have preceding signs and symptoms suggestive of the clinical diagnosis of moyamoya. In this series, 80% of children who presented with moyamoya had a predisposing condition, and 70% described a history of lateralized transient neurologic dysfunction consistent with TIA. Consideration of moyamoya in children presenting with transient focal neurologic dysfunction, particularly, among populations at increased risk for moyamoya, is necessary so that definitive neurosurgical intervention can occur before the development of a stroke. Despite the lack of level I evidence such as randomized studies, level II evidence such as cohort or case–control outcome studies support the role of revascularization in moyamoya, particularly in symptomatic and young children.38-40 Moyamoya should be suspected in any child presenting with transient lateralized neurologic dysfunction. Our experience with the increased incidence in the Native American population warrants further study and more meticulous surveillance. This cautious approach is reasonable in all populations, when a child exhibits other risk factors for moyamoya or a history of headache or focal seizures. This is particularly true among very young children in whom detection of transient neurologic dysfunction is most challenging, but in whom the risk of recurrent stroke and poor neurologic outcome is highest. Acknowledgment: The authors thank Dr Sidney Gospe for his review and suggestions.

References 1. Fullerton HJ, Wu YW, Sidney S, et al. Risk of recurrent childhood arterial ischemic stroke in a population-based

MOYAMOYA IN CHILDHOOD

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

cohort: the importance of cerebrovascular imaging. Pediatrics 2007;119:495-501. Mackay MT, Wiznitzer M, Benedict SL, et al. Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. Ann Neurol 2011;69:130-140. Amlie-Lefond C, Bernard TJ, Sebire G, et al. Predictors of cerebral arteriopathy in children with arterial ischemic stroke: results of the International Pediatric Stroke Study. Circulation 2009;119:1417-1423. Darwish B, Besser M. Long term outcome in children with Moyamoya disease: experience with 16 patients. J Clin Neurosci 2005;12:873-877. Kim SK, Cho BK, Phi JH, et al. Pediatric moyamoya disease: an analysis of 410 consecutive cases. Ann Neurol 2010;68:92-101. Scott RM, Smith JL, Robertson RL, et al. Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg 2004;100(2 Suppl P):142-149. Karzmark P, Zeifert PD, Bell-Stephens TE, et al. Neurocognitive impairment in adults with moyamoya disease without stroke. Neurosurgery 2012;70:634-638. Kim SK, Seol HJ, Cho BK, et al. Moyamoya disease among young patients: its aggressive clinical course and the role of active surgical treatment. Neurosurgery 2004;54:840-844. discussion 4-6. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 1997;99(Suppl 2):S238-S240. Uchino K, Johnston SC, Becker KJ, et al. Moyamoya disease in Washington State and California. Neurology 2005;65:956-958. Koshy M, Thomas C, Goodwin J. Vascular lesions in the central nervous system in sickle cell disease (neuropathology). J Assoc Acad Minor Phys 1990;1:71-78. Choi Y, Kang BC, Kim KJ, et al. Renovascular hypertension in children with moyamoya disease. J Pediatr 1997; 131:258-263. Ellison PH, Largent JA, Popp AJ. Moya-moya disease associated with renal artery stenosis. Arch Neurol 1981; 38:467. Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 2004;109:1354-1358. Kuwayama F, Hamasaki Y, Shinagawa T, et al. Moyamoya disease complicated with renal artery stenosis and nephrotic syndrome: reversal of nephrotic syndrome after nephrectomy. J Pediatr 2001;138:418-420. van der Vliet JA, Zeilstra DJ, Van Roye SF, et al. Renal artery stenosis in moyamoya syndrome. J Cardiovasc Surg (Torino) 1994;35:441-443. Yamada I, Himeno Y, Matsushima Y, et al. Renal artery lesions in patients with moyamoya disease: angiographic findings. Stroke 2000;31:733-737. Koss M, Scott RM, Irons MB, et al. Moyamoya syndrome associated with neurofibromatosis Type 1: perioperative and long-term outcome after surgical revascularization. J Neurosurg Pediatr 2013;11:417-425. Limaye CS, Khude S, Pednekar SJ. Moyamoya disease with hypertension in a young adult. J Assoc Physicians India 2011;59:124-126. Woolfenden AR, Albers GW, Steinberg GK, et al. Moyamoya syndrome in children with Alagille syndrome:

1209

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

additional evidence of a vasculopathy. Pediatrics 1999; 103:505-508. Ou P, Dupont P, Bonnet D. Fibromuscular dysplasia as the substrate for systemic and pulmonary hypertension in the setting of Moya-Moya disease. Cardiol Young 2006;16:495-497. Tokunaga K, Hishikawa T, Sugiu K, et al. Fatal outcomes of pediatric patients with moyamoya disease associated with pulmonary arterial hypertension. Report of two cases. Clin Neurol Neurosurg 2013;115:335-338. Hsiung GY, Sotero de Menezes M. Moyamoya syndrome in a patient with congenital human immunodeficiency virus infection. J Child Neurol 1999;14: 268-270. Ueno M, Oka A, Koeda T, et al. Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection. Brain Dev 2002;24:106-108. Rosenberg RE, Egan M, Rodgers S, et al. Complex chromosome rearrangement of 6p25.3-.p23 and 12q24.32-.qter in a child with moyamoya. Pediatrics 2013;131:e1996-e2001. Misch M, Thomale UW, Keitzer R, et al. Prevention of secondary ischemic events by superficial temporal artery-middle cerebral artery bypass surgery after tuberculosis-induced vasculopathy in a 5-year-old child. J Neurosurg Pediatr 2010;6:69-72. Guzman R, Lee M, Achrol A, et al. Clinical outcome after 450 revascularization procedures for moyamoya disease. J Neurosurg 2009;111:927-935. Lee DJ, Liebeskind DS. Characterization of inpatient moyamoya in the United States: 1988-2004. Front Neurol 2011;2:43. Graham JF, Matoba A. A survey of moyamoya disease in Hawaii. Clin Neurol Neurosurg 1997;99(Suppl 2): S31-S35. Ezura M, Yoshimoto T, Fujiwara S, et al. Clinical and angiographic follow-up of childhood-onset moyamoya disease. Childs Nerv Syst 1995;11:591-594. Fukuyama Y, Umezu R. Clinical and cerebral angiographic evolutions of idiopathic progressive occlusive disease of the circle of Willis (‘‘moyamoya’’ disease) in children. Brain Dev 1985;7:21-37. Han DH, Kwon OK, Byun BJ, et al. A co-operative study: clinical characteristics of 334 Korean patients with moyamoya disease treated at neurosurgical institutes (1976-1994). The Korean Society for Cerebrovascular Disease. Acta Neurochir (Wien) 2000;142:1263-1273. discussion 73-4. Khan N, Schuknecht B, Boltshauser E, et al. Moyamoya disease and Moyamoya syndrome: experience in Europe; choice of revascularisation procedures. Acta Neurochir (Wien) 2003;145:1061-1071. discussion 71. Kim DS, Kang SG, Yoo DS, et al. Surgical results in pediatric moyamoya disease: angiographic revascularization and the clinical results. Clin Neurol Neurosurg 2007;109: 125-131. Yun TJ, Cheon JE, Na DG, et al. Childhood moyamoya disease: quantitative evaluation of perfusion MR imaging–correlation with clinical outcome after revascularization surgery. Radiology 2009;251:216-223. Siddiqui MR, Khan SU, Hoque MA, et al. Moyamoya disease presented as a case of hemiplegic migraine. BMJ Case Rep 2010;2010. Seol HJ, Wang KC, Kim SK, et al. Headache in pediatric moyamoya disease: review of 204 consecutive cases. J Neurosurg 2005;103(5 Suppl):439-442.

1210 38. Smith ER, McClain CD, Heeney M, et al. Pial synangiosis in patients with moyamoya syndrome and sickle cell anemia: perioperative management and surgical outcome. Neurosurg Focus 2009;26:E10. 39. Hankinson TC, Bohman LE, Heyer G, et al. Surgical treatment of moyamoya syndrome in patients with sickle cell

C. AMLIE-LEFOND AND R.G. ELLENBOGEN anemia: outcome following encephaloduroarteriosynangiosis. J Neurosurg Pediatr 2008;1:211-216. 40. Sekhar LN, Natarajan SK, Ellenbogen RG, et al. Cerebral revascularization for ischemia, aneurysms, and cranial base tumors. Neurosurgery 2008;62(6 Suppl 3):1373-1408. discussion 408-10.