Cerebral Angiopathies as a Cause of Ischemic Stroke in Children
Differential Diagnosis and Treatment Options
; ; ;
Background: Ischemic stroke in children can present with an epileptic seizure or be initially asymptomatic. The median time to diagnosis is 24 hours.
Methods: This review is based on a selective literature search, with additional consideration of published guidelines and the authors’ personal experience.
Results: In Europe and the USA, the combined incidence of ischemic and hemorrhagic stroke in childhood is 2.5 to 10 per 100 000 children per year. 40% of ischemic strokes in childhood occur after an infectious illness or in association with a congenital heart defect, sickle-cell anemia, or a coagulopathy. Arterial dissection and chronic, progressive cerebral arteriopathies, particularly moyamoya disease, each account for up to 10% of childhood strokes. Magnetic resonance imaging can be used to demonstrate infarcts and to display the perfusion of ischemic areas and the surrounding brain tissue; arterial and venous occlusions can be defined more precisely. Children with arterial dissection, vasculitis, and para-infectious cerebral ischemia should be treated empirically, with medications and supportive care, according to the treatment plans developed for adults. For patients with moyamoya disease, surgical revascularization with extra-intracranial bypass techniques is recommended.
Discussion: The current data provide an inadequate evidence base for the treatment of stroke in children. Potential revascularization or thrombolysis must be discussed individually in each case. For the treatment of temporary, para-infectious cerebral ischemia, hemodynamic optimization is an available option. Better evidence is needed regarding the surgical treatment of moyamoya disease.
On average, an ischemic stroke in a child is not diagnosed until 24 hours after the event (1). Epileptic seizures are the most common clinical manifestation of cerebral ischemia in neonates and small children. For early intervention to be effective, referral to a specialized treatment center within a few hours of the event is essential (2). Current studies show that the incidence of stroke in children and adolescents in Western countries is as high as 10 per 100 000 persons per year (3, 4); 50% to 70% of these events are ischemic, and the remainder hemorrhagic (5). These current figures are more than twice as high as those from earlier decades. It must be assumed, however, that many cases never enter into the statistics, for a number of reasons: the manifestations of stroke in small children can be hard to detect, rich arterial collateralization can limit infarct size, and the high plasticity of the immature brain can enable functional compensation (6). Despite good collateralization and high plasticity, 90% of children who have sustained a stroke suffer from late sequelae including epileptic seizures and motor and cognitive impairment (7, 8). Many children who have sustained a stroke have a constellation of risk factors that can lead to recurrent infarcts if they are not detected in timely fashion and then definitively treated. In this article, we present the current concept of the evaluation and treatment of ischemic cerebral arteriopathies in children. This analysis is based on a PubMed search on the terms “pediatric” and “stroke,” with special consideration of the relevant guidelines of the American Heart Association (9).
The differential diagnosis of ischemic stroke in children
Cerebral ischemia in children is classified by etiology as cardioembolic, arterioembolic (due to diseases of the cervical arteries), or arteriopathic (due to diseases of the intracranial arteries) (8, 10–13) (Tables 1 gif ppt and 2 gif ppt). Coagulopathies and heart disease are each present in 25% of children who sustain ischemic strokes (11, 14–16). Infection, the most frequent risk factor, is present in 40% of cases (14). The presumed mechanism is an infection-associated arteriopathy. No cause can be found in 10% to 20% of cases, and multiple risk factors are present in 20% to 30%, e.g., coagulopathy combined with infection.
Up to one-fourth of all children with heart disease will suffer an ischemic stroke (17). Children with complicated cyanotic congenital heart defects are particularly at risk (18), though stroke can occasionally occur as a consequence of acquired disease of the myocardium or the heart valves.
Perinatal ischemic stroke due to arterial hypoperfusion (occurring in the first week after birth) is usually due to infection and perinatal asphyxia; other causes include fertility treatments, chorioamnionitis, early rupture of the amniotic sac, and preeclampsia (5, 11, 19). In the neonatal period, both venous and arterial strokes are often characterized by focal epileptic seizures. Convulsions due to ischemia account for roughly 10% of epileptic seizures in infants born at full term.
The initial treatment and prognosis of ischemic stroke in children
When ischemic stroke is suspected, the diagnostic evaluation depends on the age of the patient, as well as on the available methods of examination. Cranial ultrasound is widely available but insufficiently sensitive to detect many cases of ischemia. Computerized tomography (CT) is a relatively quick and sensitive way to detect hemorrhage but can easily miss venous thrombosis and early arterial ischemia. Magnetic resonance imaging (MRI) can display zones of infarction, precisely define arterial and venous occlusions, and demonstrate the degree of reserve perfusion in the surrounding area. Catheter angiography is recommended in children only when there is a prospect of performing a therapeutic endovascular procedure (9).
It is recommended that all stroke patients be monitored and treated in an intensive care unit (9). In most cases, the treatment is conservative. Overall, children have a better prognosis after stroke than adults, and the risks of various therapeutic interventions in children, particularly thrombolysis, are insufficiently known. Treatment decisions are to be made on a case-by-case basis. 90% of the affected children suffer in the long term from cognitive impairment, spastic paresis, or epilepsy (8). Cognitive impairment without any other deficit is seen in up to 60% of patients. In children who have suffered a stroke because of arterial hypoperfusion, the average risk of recurrent stroke is roughly 15%; the risk of recurrent stroke in the individual case is largely a function of the constellation of causative factors that produced the initial stroke. In multiple large-scale studies, the risk of recurrent stroke was found to be highest in patients who carry a marker for a thrombotic tendency, e.g., a protein C deficit, in combination with a vascular disease, such as moyamoya (9, 16). Patients in whom a thrombotic tendency has been demonstrated should be treated, according to the current recommendations, with an inhibitor of platelet aggregation or with an anticoagulant drug (9, 20).
Secondary and transient cerebral arteriopathies
Infection is the most common risk factor for stroke in both neonates and older children (9) (Table 1). Pathophysiologically, stroke in such cases is usually due to involvement of the vasculature by local bacterial infection, e.g., meningitis or a local infection in the neck. Other infectious causes of stroke include septic embolization (e.g., in bacterial endocarditis), viral infection of an artery (e.g., with varicella-zoster virus [VZV]), and para-infectious vasculopathy (which may also be due to VZV). Vasculitis accompanies most types of intracranial infection; it is seen, for example, in tuberculous meningitis and in the aftermath of VZV infection. VZV can also cause necrotizing arterial infection: in such cases, transient intracranial vasculopathy may arise weeks or months after an uncomplicated episode of chickenpox. Transient vasospastic angiopathy has been described with increasing frequency in recent years (21) and can be caused by a variety of infections. VZV infection, in particular, seems to be a common trigger of transient, unilateral intracranial arteriopathy in childhood. As many as 30% of cases of purulent meningitis are complicated by ischemic stroke. Uni- or bilateral occlusion of the internal carotid artery can be caused by necrotizing fasciitis in the parapharyngeal space. Fungal infection, which is more common in immunocompromised persons, can cause arteritis, aneurysms, thromboses, and cerebral infarction. Stroke has also been described as a consequence of various other infections of the central nervous system, including aspergillosis, Mycoplasma pneumoniae infection, Coxsackie 9 viral infection, California encephalitis, mumps, paramyxovirus infection, borreliosis, cat-scratch disease, brucellosis, and malaria (9). Transient angiopathy that has caused a stroke or transient ischemic attack (TIA) generally has a favorable prognosis for its further course, even without treatment. Anti-inflammatory medication is recommended in the acute phase (21). There is, however, a continuum of disease states ranging from transient angiopathy to necrotizing arteriopathy. Even non-necrotizing angiopathy, if hemodynamically significant, can cause progressive cerebral infarction. The advisability of therapeutic anticoagulation or inhibition of platelet aggregation for four weeks is currently under discussion (7, 14, 20, 22).
Autoimmune vasculitis in childhood
Primary central nervous system (CNS) vasculitis is rarer in childhood than in adulthood. This entity is a granulomatous, necrotizing disease of blood vessels (23). It is difficult to diagnose because the systemic inflammatory and autoimmune parameters are often not very informative. Cerebrospinal fluid examination can reveal a high protein concentration (an inconstant finding) and lymphocytic pleocytosis. The MRI findings are abnormal in more than 90% of cases, yet they are often nonspecific and thus diagnostically unhelpful. Meningeal biopsy can be considered when the diagnosis remains in doubt. Primary CNS vasculitis takes a variable clinical course: some children reach a stable condition without any specific treatment, while others have progressive disease and must be treated with immune suppression (24).
Systemic diseases, such as lupus erythematosus, that more commonly affect adults are occasionally seen in children. Takayasu’s arteritis sometimes affects adolescent girls (9).
Cervicocephalic arterial dissections in children and adolescents
Acute cervicocephalic arterial dissection is an important cause of stroke in children and is probably underdiagnosed (25). It is estimated that up to 10% of ischemic strokes in childhood are due to dissection. Most dissections occur in the extracranial portion of the internal carotid artery, often as the result of blunt trauma (Figure 1 gif ppt). Intracranial dissection is rarer and usually spontaneous; its causes include fibromuscular dysplasia (FMD), Ehlers-Danlos syndrome, Marfan syndrome, aortic isthmus stenosis, polycystic kidney disease (e.g., MIM 173910, 173900), osteogenesis imperfecta, atherosclerosis, and moyamoya. Intracranial dissection manifests itself clinically either by ischemia or by subarachnoid hemorrhage. The angiographic criteria for dissection include the so-called pearl and string sign (a dilated vessel segment adjacent to a stenosis), a double lumen, and vascular occlusion with a pointed contour. High-resolution MRI can also reveal dissections; their detection by duplex ultrasonography is problematic, although this technique is often useful for follow-up of the lesion after it has been diagnosed. The affected artery becomes recanalized in about 60% of children, while the probability of a recurrent stroke or TIA is about 10%. The main goal of treatment in cervicocephalic arterial dissection is to prevent further thromboembolic strokes until the vessel is healed. The treatment of children and adolescents is based on that of adults with this condition and consists of immediate anticoagulation with intravenous heparin or a low-molecular-weight heparinoid drug, followed by 3 to 6 months of oral anticoagulation with a target International Normalized Ratio (INR) of 2. Anticoagulation should be given to a patient with an intracranial dissection only after subarachnoid hemorrhage has been excluded (9).
Moyamoya disease and moyamoya syndrome
Moyamoya disease is characterized by chronic progressive stenosis of the distal intracranial portion of the internal carotid artery; less commonly, there is additional involvement of the proximal portion of the middle cerebral artery, the anterior cerebral artery, the basilar artery, or the peripheral arteries of the brain (9, e1). Moyamoya is a Japanese word meaning “cloudy, like a puff of smoke.” This is a description of the typically nebulous angiographic appearance of the collateral arterial network that develops as a secondary feature of the disease (Figure 2 gif ppt). Traditionally, the condition is called moyamoya syndrome when it appears in association with some other disease, e.g., sickle-cell anemia or Down syndrome, and moyamoya disease when it is unaccompanied by any known risk factor. Moyamoya is rare in Western countries, with an estimated incidence of 0.1 per 100 000 persons per year, but it is ten times more common in Japan. It is presumed that many cases do not enter into the epidemiological statistics, because progressive stenosis of the basal arteries of the brain can also be clinically silent (e2). The diagnosis is made on the basis of radiological criteria (1): most often, there is stenosis of the distal portion of the internal carotid arteries on both sides of the brain and possibly also of the proximal portions of the middle and/or anterior cerebral arteries (2), combined with extensive arterial collateralization around the base of the brain (3) and bilateral abnormalities (e3). If angiographic abnormalities are found only on one side, the diagnosis is considered probable. Moyamoya disease accounts for about 10% of all strokes in children in Western countries and seems to be caused largely by genetic factors (e4, e5). Marked familial clustering has been observed; the disease is associated with the HLA B40 haplotype in children under age 10 and with the HLA B52 haplotype in older children. Moyamoya has also been linked to the AW24, BW46, B51-DR4, and BW54 antigens.
A Korean research team estimates that 50% to 70% of children with moyamoya disease who are treated conservatively go on to develop progressive neurological impairment and a poor clinical outcome (e6), while the rate of stroke in surgically treated children is 2.6% per year, according to a recent meta-analysis that involved a total of 1156 patients (e7). The prognosis of patients with moyamoya is a function of the rapidity and extent of vascular narrowing, the extent of neurological deficits, the presence or absence of effective collateral circulation, age, and the size of the infarct as seen by MRI (e8). Some authors consider the long-term outcome to depend mainly on the patient’s neurological condition at the time of treatment, rather than on the patient’s age (e9).
Many patients with moyamoya are treated with surgical revascularization, particularly patients with cognitive impairment or recurrent or progressive clinical manifestations (e10, e11). Revascularization can involve either a direct anastomosis, usually of a superficial scalp artery to a cerebral artery (Figure 3 gif ppt), or an indirect technique such as encephalo-duro-arteriosynangiosis or encephalo-myo-arterio-synangiosis. Procedures of the latter type are often preferable in children because the donor arteries of the scalp are of small caliber (e7, e12). They involve laying the temporalis muscle or the dural vessels directly onto the surface of the brain, so that arteries can sprout from these tissues and supply the brain with blood.
A number of authors have addressed the question of postoperative improvement of the prognosis after direct and indirect revascularization (e13–e15). A recent meta-analysis of children with moyamoya revealed that most patients benefit from treatment in terms of their clinical manifestations (e7). The meta-analysis included data on a total of 1448 patients from 57 studies. 73% underwent indirect revascularization, and 23% underwent indirect revascularization combined with direct anastomosis. In the perioperative period, 4.4% of patients had a stroke and 6.1% had a TIA. 87% of these children had a complete, or at least partial, reduction in new ischemic events; no difference in effectiveness was seen in this respect between direct and indirekt techniques. For adult patients, in contrast, direct techniques were found to be much more effective.
Interestingly, surgical revascularization is performed in moyamoya disease not only when the patients present with ischemic stroke, but also when they present with intracranial hemorrhage. Its purpose in such cases is to prevent the further development of fragile collateral arteries at the base of the brain (e14–e17). The effectiveness of such procedures in preventing hemorrhage is less well documented than their effectiveness in preventing ischemic stroke.
Only a few studies have compared medical and surgical treatments for moyamoya. One study revealed that, among 651 moyamoya patients who were initially not operated upon, 38.4% went on to be treated with platelet aggregation inhibitors because of progressively severe clinical manifestations (e14). Anti-platelet preparations have been used mainly to treat patients whose ischemic manifestations are thought to be due, at least in part, to thromboembolism. Coumarin derivatives have been used only rarely in children, but low-dose heparinoids have been used along with calcium-channel blockers as an empirical treatment for recurrent TIAs.
Other vascular diseases
Fibromuscular dysplasia (FMD) is a non-arteriosclerotic, segmental, non-inflammatory disease of blood vessels that usually affects the renal arteries and the extracranial segment of the internal carotid artery (e18, e19). Most persons with FMD are adult women, but cases of FMD in children and adolescents have been reported (e18–e21). Some 20% to 30% of FMD patients have cerebrovascular involvement, which is usually asymptomatic. Ischemic stroke can arise through stenosis or dissection of an affected artery, or through embolism. Intracranial aneurysms are found in about 7% of patients, but only a few cases of aneurysms in children with FMD have been reported. Surgical revascularization is recommended for symptomatic stenosis of the arteries supplying the brain (e22).
The precise significance of migraine for stroke in children remains unknown. Migraine with aura seems to increase the danger of ischemic stroke in adolescents, particularly in girls taking oral contraceptives (e23). Migraine alone hardly ever causes ischemic stroke, but there is greater cause for concern when migraine with aura is combined with other risk factors such as cigarette smoking, pregnancy, or oral contraception. It is recommended that patients with migraine who have a stroke should be investigated for the presence of other risk factors, e.g., dissection, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), moyamoya, and mitochondrial encephalopathy with lactic acidosis and episodic strokes (MELAS) (e24).
Isoforms of three genes have been identified that are associated with familial hemiplegic migraine, and one of these genes encodes an ion-channel subunit (e25). Some children with familial hemiplegic migraine develop permanent neurological deficits; thus, children with this type of migraine seem to be at greater risk than children with other types. In view of the additional risk conferred by oral contraceptives, women with migraine who have suffered a stroke are advised to use another method of birth control instead (9). It is unknown whether triptans increase the risk of stroke in children, yet it seems prudent to avoid using these drugs in children with hemiplegic migraine, basilar migraine, known vascular risk factors, or previous episodes of cerebral or cardiac ischemia (e26). Options for prophylactic treatment include amitriptyline, valproate, cyproheptadine, verapamil and other calcium-channel blockers, and aspirin (e26–e28). There is as yet no specific treatment for patients with CADASIL; platelet inhibitors can be considered for this indication (9).
Ischemic stroke does occur in children, though less commonly than in adults. It is often diagnosed only after a delay, particularly in small children. Recent decades have seen a number of diagnostic and therapeutic advances in the area of acute stroke, but children have benefited from these advances to a lesser extent than adults, because the existing data do not permit the formulation of any definitive pediatric recommendations. For moyamoya disease, which causes chronic, progressive cerebral ischemia in childhood, surgical revascularization is now accepted as the treatment of choice, although better validation of this is needed.
Conflict of interest statement
The authors declare that they have no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.
Manuscript submitted on 23 July 2009, revised version accepted on 22 December 2009.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Hans-Jakob Steiger
40225 Düsseldorf, Germany
@For eReferences please refer to:
Bereich Neuropädiatrie, Klinik für Allgemeine Pädiatrie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf: PD Dr. med. Assmann
Neuroradiologische Abteilung, Institut für Radiologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf: PD Dr. med. Turowski
|1.||Rafay MF, Pontigon AM, Chiang J, et al.: Delay to diagnosis in acute pediatric arterial ischemic stroke. Stroke 2009; 40: 58–64. MEDLINE|
|2.||Liebeskind DS: Reperfusion for acute ischemic stroke: arterial revascularization and collateral therapeutics. Curr Opin Neurol 2010; 23: 36–45. MEDLINE|
|3.||Giroud M, Lemesle M, Gouyon JB, Nivelon JL, Milan C, Dumas R: Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993. J Clin Epidemiol 1995; 48: 1343–8. MEDLINE|
|4.||DeVeber G, Roach ES, Riela AR, Wiznitzer M: Stroke in children: recognition, treatment, and future directions. Semin Pediatr Neurol 2000; 7: 309–17. MEDLINE|
|5.||Roach ES: Etiology of stroke in children. Semin Pediatr Neurol 2000; 7: 244–60. MEDLINE|
|6.||Giroud M, Lemesle M, Madinier G, Manceau E, Osseby GV, Dumas R: Stroke in children under 16 years of age. Clinical and etiological difference with adults. Acta Neurol Scand 1997; 96: 401–6. MEDLINE|
|7.||Bernard TJ, Goldenberg NA, Tripputi M, Manco-Johnson MJ, Niederstadt T, Nowak-Gottl U: Anticoagulation in childhood-onset arterial ischemic stroke with non-moyamoya arteriopathy. Findings from the Colorado and German (COAG) collaboration. Stroke 2009; 40: 2869–71. MEDLINE|
|8.||Steinlin M, Roellin K, Schroth G: Long-term follow-up after stroke in childhood. Eur J Pediatr 2004; 163: 245–50. MEDLINE|
|9.||Roach ES, Golomb MR, Adams R, et al.: Management of stroke in infants and children: a scientific statement from a special writing group of the American heart association stroke council and the council on cardiovascular disease in the young. Stroke 2008; 39: 2644–91. MEDLINE|
|10.||Williams LS, Garg BP, Cohen M, Fleck JD, Biller J: Subtypes of ischemic stroke in children and young adults. Neurology 1997; 49: 1541–5. MEDLINE|
|11.||Steinlin M, Pfister I, Pavlovic J, et al.: The first three years of the Swiss neuropaediatric stroke registry (SNPSR): a population-based study of incidence, symptoms and risk factors. Neuropediatrics 2005; 36: 90–7. MEDLINE|
|12.||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: 1417–23. MEDLINE|
|13.||Bernard TJ, Goldenberg NA, Armstrong-Wells J, Amlie-Lefond C, Fullerton HJ: Treatment of childhood arterial ischemic stroke. Ann Neurol 2008; 63: 679–96. MEDLINE|
|14.||Del Balzo F, Spalice A, Ruggieri M, Greco F, Properzi E, Iannetti P: Stroke in children: inherited and acquired factors and age-related variations in the presentation of 48 paediatric patients. Acta Paediatr 2009; 98: 1130–6. MEDLINE|
|15.||Nowak-Gottl U, Gunther G, Kurnik K, Strater R, Kirkham F: Arterial ischemic stroke in neonates, infants, and children: an overview of underlying conditions, imaging methods, and treatment modalities. Semin Thromb Hemost 2003; 29: 405–14. MEDLINE|
|16.||Strater R, Becker S, von Echardstein A, et al. Prospective assessment of risk factors for recurrent stroke during childhood–a 5-year follow-up study. Lancet 2002; 360: 1540–5. MEDLINE|
|17.||Kumar K: Neurological complications of congenital heart disease. Indian J Pediatr 2000; 67: 287–91. MEDLINE|
|18.||Cottrill CM, Kaplan S: Cerebral vascular accidents in cyanotic congenital heart disease. Am J Dis Child 1973; 125: 484–7. MEDLINE|
|19.||Dickerhoff R, Genzel-Boroviczeny O, Kohne E: Haemoglobinopathies and newborn haemoglobinopathy screening in Germany. J Clin Pathol 2009; 62: 34. MEDLINE|
|20.||Strater R, Kurnik K, Heller C, Schobess R, Luigs P, Nowak-Gottl U: Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study. Stroke 2001; 32: 2554–8. MEDLINE|
|21.||Braun KP, Bulder MM, Chabrier S, et al.: The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke. Brain 2009; 132: 544–57. MEDLINE|
|22.||Goldenberg NA, Bernard TJ, Fullerton HJ, Gordon A, DeVeber G: Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol 2009; 8: 1120–7. MEDLINE|
|23.||Benseler SM, Silverman E, Aviv RI, et al.: Primary central nervous system vasculitis in children. Arthritis Rheum 2006; 54: 1291–7. MEDLINE|
|24.||Danchaivijitr N, Cox TC, Saunders DE, Ganesan V.: Evolution of cerebral arteriopathies in childhood arterial ischemic stroke. Ann Neurol 2006; 59: 620–6. MEDLINE|
|25.||Fullerton HJ, Johnston SC, Smith WS: Arterial dissection and stroke in children. Neurology 2001; 57: 1155–60. MEDLINE|
|e1.||Scott RM, Smith ER: Moyamoya disease and moyamoya syndrome. N Engl J Med 2009; 360: 1226–37. MEDLINE|
|e2.||Khan N, Yonekawa Y: Moyamoya angiopathy in Europe. Acta Neurochir 2005; 94(Suppl): 149–52. MEDLINE|
|e3.||Sunaga Y, Fujinaga T, Ohtsuka T: [MRI findings of moyamoya disease in children]. No To Hattatsu 1992; 24: 375–9. MEDLINE|
|e4.||Inoue TK, Ikezaki K, Sasazuki T, et al.: DNA typing of HLA in the patients with moyamoya disease. Jpn J Hum Genet 1997; 42: 507–15. MEDLINE|
|e5.||Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M: Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 2000; 15: 179–82. MEDLINE|
|e6.||Choi JU, Kim DS, Kim EY, Lee KC: Natural history of moyamoya disease: comparison of activity of daily living in surgery and non surgery groups. Clin Neurol Neurosurg 1997; 99(Suppl): S11–8. MEDLINE|
|e7.||Fung LW, Thompson D, Ganesan V: Revascularisation surgery for paediatric moyamoya: a review of the literature. Childs Nerv Syst 2005; 21: 358–64. MEDLINE|
|e8.||Scott RM: Moyamoya syndrome: a surgically treatable cause of stroke in the pediatric patient. Clin Neurosurg 2000; 47: 378–84. MEDLINE|
|e9.||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. MEDLINE|
|e10.||Hanggi D, Mehrkens JH, Schmid-Elsaesser R, Steiger HJ: Results of direct and indirect revascularisation for adult European patients with Moyamoya angiopathy. Acta Neurochir 2008; 103(Suppl): 119–22. MEDLINE|
|e11.||Gururaj A, Hardy D, Al-Gazali LI, Sztriha L, Roos A, Nork M: Are the strokes in moyamoya syndrome associated with Down syndrome due to protein C deficiency? Brain Dev 2002; 24: 719–22. MEDLINE|
|e12.||Golby AJ, Marks MP, Thompson RC, Steinberg GK: Direct and combined revascularization in pediatric moyamoya disease. Neurosurgery 1999; 45: 50–8. MEDLINE|
|e13.||Matsushima T, Fujiwara S, Nagata S, et al. Surgical treatment for paediatric patients with moyamoya disease by indirect revascularization procedures (EDAS, EMS, EMAS). Acta Neurochir (Wien) 1989; 98: 135–40. MEDLINE|
|e14.||Ikezaki K: Rational approach to treatment of moyamoya disease in childhood. J Child Neurol 2000; 15: 350–6. MEDLINE|
|e15.||Guzman R, Lee M, Achrol A, et al.: Clinical outcome after 450 revascularization procedures for moyamoya disease. J Neurosurg 2009; 111: 927–35. MEDLINE|
|e16.||Yoshida Y, Yoshimoto T, Shirane R, Sakurai Y: Clinical course, surgical management, and long-term outcome of moyamoya patients with rebleeding after an episode of intracerebral hemorrhage: An extensive follow-up study. Stroke 1999; 30: 2272–6. MEDLINE|
|e17.||Kawaguchi S, Sakaki T, Kakizaki T, Kamada K, Shimomura T, Iwanaga H: Clinical features of the haemorrhage type moyamoya disease based on 31 cases. Acta Neurochir (Wien) 1996; 138: 1200–10. MEDLINE|
|e18.||Lemahieu SF, Marchau MM: Intracranial fibromuscular dysplasia and stroke in children. Neuroradiology 1979; 18: 99–102. MEDLINE|
|e19.||Osborn AG, Anderson RE: Angiographic spectrum of cervical and intracranial fibromuscular dysplasia. Stroke 1977; 8: 617–26. MEDLINE|
|e20.||DiFazio M, Hinds SR, Depper M, Tom B, Davis R: Intracranial fibromuscular dysplasia in a six-year-old child: a rare cause of childhood stroke. J Child Neurol 2000; 15: 559–62. MEDLINE|
|e21.||Zurin AA, Houkin K, Asano T, Ishikawa T, Abe H: Childhood ischemic stroke caused by fibromuscular dysplasia of the intracranial artery–case report. Neurol Med Chir (Tokyo) 1997; 37: 542–5. MEDLINE|
|e22.||Chiche L, Bahnini A, Koskas F, Kieffer E: Occlusive fibromuscular disease of arteries supplying the brain: results of surgical treatment. Ann Vasc Surg 1997; 11: 496–504. MEDLINE|
|e23.||Ebinger F, Boor R, Gawehn J, Reitter B: Ischemic stroke and migraine in childhood: coincidence or causal relation? J Child Neurol 1999; 14: 451–5. MEDLINE|
|e24.||Zeiler K, Wessely P, Holzner F: [The cerebral angiogram in patients with complicated migraine]. Wien Klin Wochenschr 1985; 97: 667–72. MEDLINE|
|e25.||van de Ven RC, Kaja S, Plomp JJ, Frants RR, van den Maagdenberg AM, Ferrari MD: Genetic models of migraine. Arch Neurol 2007; 64: 643–6. MEDLINE|
|e26.||Pakalnis A: Current therapies in childhood and adolescent migraine. J Child Neurol 2007; 22: 1288–92. MEDLINE|
|e27.||Silberstein SD: Pharmacological profile and clinical characteristics of frovatriptan in the acute treatment of migraine: introduction. Headache 2002; 42(Suppl): S45–6. MEDLINE|
|e28.||Silberstein SD, Dodick D, Freitag F, et al.: Pharmacological approaches to managing migraine and associated comorbidities–clinical considerations for monotherapy versus polytherapy. Headache 2007; 47: 585–99. MEDLINE|
|e29.||Lee J, Croen LA, Lindan C, et al.: Predictors of outcome in perinatal arterial stroke: a population-based study. Ann Neurol 2005; 58: 303–8. MEDLINE|
|e30.||Barnes C, Newall F, Harvey AS, Monagle P: Thrombophilia interpretation in childhood stroke: a cautionary tale. J Child Neurol 2004; 19: 218–9. MEDLINE|
|e31.||Barnes C, DeVeber G: Prothrombotic abnormalities in childhood ischaemic stroke. Thromb Res 2006; 118: 67–74. MEDLINE|
|e32.||Ohene-Frempong K, Weiner SJ, Sleeper LA, et al.: Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91: 288–94. MEDLINE|
|e33.||Moser FG, Miller ST, Bello JA, et al.: The spectrum of brain MR abnormalities in sickle-cell disease: a report from the Cooperative Study of Sickle Cell Disease. Am J Neuroradiol 1996; 17: 965–72. MEDLINE|