Child’s Nerv Syst (1997) 13: 595–600 © Springer-Verlag 1997 Eric Manceau Maurice Giroud Raymond Dumas Received: 2 April 1997 E. Manceau (½) · M. Giroud · R. Dumas Consultation de Neurologie Infantile, Service de Neurologie, Centre Hospitalier Universitaire, 3, Rue du Faubourg Raines, F-21033 Dijon Cedex, France ORIGINAL PAPER Moyamoya disease in children A review of the clinical and radiological features and current treatment Abstract Two cases of moyamoya disease observed in two children are reported. The two cases recall the frequency of ischemic strokes, transient ischemic attacks, and seizures revealing the disease. Diagnosis is made by cerebral arteriography showing carotid stenosis and the dense deep arterial collateral as seen in these two cases. Magnetic resonance imaging makes it possible to identify this vascular disease as it reveals vascular varicosities in the basal ganglia, as in case 1. Strokes can Introduction Moyamoya means ‘‘spirals of smoke’’ in Japanese. This term was used to name a cerebrovascular disease characterized by a particular angiographical appearance of the cerebral collateral network that it causes. This condition consists in progressive stenosis of both terminal internal carotid arteries in their supraclinoid part, with the development of a network of cerebral collaterals, which are what define the condition as a specific pathologic entity. Starting with two neuropediatric cases, we give a theoretical summary of this disease, describe information contributed by recent radiological techniques, and suggest some pathophysiological hypotheses. Case reports Case 1 This girl is an adopted child of Korean origin, whose natural parents are first cousins. Her first years of life passed without incident, with normal food, motor and sphincter development, but a slight language sometimes be prevented by constructing an anastomosis between the superficial temporal artery and the middle cerebral artery, as demonstrated in case 1. Thus, the diagnosis of moyamoya disease has been improved by magnetic resonance imaging and there is now a surgical treatment to prevent ischemic stroke. Key words Moyamoya disease · Carotid stenosis · Deep arterial collaterals delay was noted, in contrast with apparently good comprehension. When she was 3 years old her adoptive parents were surprised to note that she was starting to have repeated brief episodes of confusion, mainly on waking. When she was 4 years old, she was admitted to hospital following several generalized tonic-clonic epileptic fits, followed by a partial clonic motor fit affecting the left arm, which was complicated by a homolateral hemiparesis that recovered in 45 min. Waking and sleeping electro-encephalograms (EEG) and CT scan with and without injection of contrast medium did not show any specific features. However, T2-weighted magnetic resonance imaging (MRI) gave a picture with a right frontal hyposignal and two nodules with a hypersignal in the white matter of the right lobe. It was decided just to monitor these abnormalities, since there were no signs of a spaceoccupying lesion. At 5 years old, the child started having sudden weakness in the legs and to complain of migraine-like headaches. In view of severe episodes of hyperactivity, normothymic anticonvulsant treatment with carbamazepine (CBZ) was begun. At that time, she developed a state of neglect of the right side, which forced her to become left-handed. She continued to have atonic fits which made her fall down, whose posticteric phase seemed to get longer and longer. The EEG showed a slowing of the background rhythm associated with large slow bifrontal waves, predominantly on the left, which suggested that the lesion was progressing. When she was 6 years old, she was readmitted to hospital for investigation, because she woke up with right faciobrachial hemiplegia, which disappeared totally in 1 month. A second cerebral MRI scan showed diffuse heterogeneous hypersignal, associated with posterior cortical and subcortical ischemic plaques with thinning of the 596 Fig. 1 Case 1: T1-weighted MRI with horizontal view: posterior cortical and subcortical hypersignal, associated with deep arterial varicosities within basal ganglia Fig. 2 Case 1: T1-weighted MRI with frontal view showing the deep arterial varicosities ehanced by gadolinium Fig. 4 Case 2: arteriography showing the terminal carotid artery stenosis with deep arterial collaterals characteristic of moyamoya disease Fig. 3 Case 1: arteriography showing the terminal carotid artery stenosis with deep arterial collaterals characteristic of moyamoya disease cortical layer in the same area, and in particular tortuous images which were similar to arterial varicosities of the central gray nuclei (Figs. 1, 2). This typical radiological appearance, together with the clinical picture, allowed the diagnosis of moyamoya disease to be made, which was confirmed by a cervico-cerebral angiogram (Fig. 3). The internal carotid arteries had a classic appearance as far as the supraclinoid part, where they ended as a narrow stenosis, before giving off narrow anterior and middle cerebral arteries; there was also markedly abnormal development of the basal ganglia perforating arteries. A left temporo-sylvian artery anastomosis was performed on the left by angio-myo-duro-synangiogenesis, followed 6 months later by the same procedure on the right. Since then, the patient, now 7 years old, has had no more migraine or epileptic fits; she shows good psychomotor development and has only slight underusage of her right hand, which remains apraxo-astereognosic. A control angiogram showed perfect collateral formation by the external carotid network of the autograft, although the internal carotid abnormality continued to progress insidiously to a late stage, without causing the child any harm. Case 2 The birth of this child of western Caucasian origin was uncomplicatd and his parents do not have a history of any particular hereditary diseases. When he was 3 months old his parents noted that he was greatly agitated during the night, with a clonic epileptic fit involving the right leg and causing his head and gaze to turn to the left. When the fit had finished he had right hemiparesis, predominantly 597 facio-brachial, associated with axial hypotonia. There was no fever or increased pressure at the fontanel. Retinal examination and lumbar puncture were normal, but the EEG showed permanent low voltage of the left hemisphere. A cerebral CT scan showed a large hypodense area in the left fronto temporoparietal region, demonstrating a massive sylvian and left anterior cerebral ischemic cerebrovascular stroke. A left carotid angiogram showed there was a narrow stenosis of the presylvian internal carotid, as well as an abnormal view of a lenticulo-striated collateral network at the level of the basal ganglia (Fig. 4) allowing the diagnosis of moyamoya disease. When the boy was 4 months old psychomotor retardation was noted, with the absence of spontaneous grasping associated with alternating convulsions. CT scan revealed generalised cerebral atrophy, predominantly in the left hemisphere, associated with severe bilateral ventricular dilatation. A right carotid angiogram revealed that there was also partial stenosis of the right carotid siphon. When he was 1 year old, paresis of the left arm and axial hypotonus persisted with microcephaly. His waking seemed to be better, and his psychomotor developmental age was estimated as equivalent to 6 months. The EEG showed a focus of left-sided frontorolandic spikes, and an overall angiographic examination (supra-aortic vessels, coronaries and renal arteries) was asked for in view of the recent discovery of associated labile hypertension with systolic blood pressure of 170 mmHg and diastolic blood pressure of 100 mmHg. These tests were all normal, as were a temporal artery biopsy and the renal function. It was decided that this patient was not suitable for any neurosurgical operation using a temporo-sylvian shunt, in view of the length of time he had had the symptoms, their severity, and the fact that a slight psychomotor improvement had been seen. Nevertheless, the outcome has been marked by mental retardation and drug-resistant frontal epilepsy. Discussion Moyamoya (MM) is a rare occlusive arterial condition, which causes ischemic strokes in young people, for which precise classification was only made possible by the advent of cerebral angiography, and which was long considered as an exclusively Japanese disease. This disease was first described in Japan [18], characterized by progressive stenosis of both supra-clinoid internal carotids on cerebral arteriography, associated with abnormal collateral circulation within the basal ganglia. Then, more than 100 cases from all over the world were collected [12]. In France, Picard et al. [16] appears to have described the largest European series with his 24 cases. By 1979, it had become a real public health problem in Japan, needing an official definition in an annual research report commissioned by the Ministry of Health: “Occlusive disease of the vessels at the basal ganglia characterized by the association of an angiographic picture of bilateral stenosis of the supraclinoid carotid arteries and/or their main terminal branches, and abnormal development of a collateral network around the circle of Willis.” In 1989, Kitamura et al. [12] stressed that a primary form existed with an ethnic preference, and that this form could be called moyamoya disease, and that there were also secondary forms, which he excluded from the definition. This distinction seems to us to be fundamental, even though overall, the clinical features, evolution and the principles of treatment are similar. Our patient in the first case is a child of Korean origin. In Korea, the annual incidence of the disease has been studied over a period of 18 years and seems to be half that in Japan [20] [0.08 (0.072–0.129) per 100,000 population], with no regional preference. Around 150 new cases per year are seen by the Japanese, compared with fewer than 3 in France. Yonekawa also noted that Africans were overrepresented amongst Western patients and also have a large predominance of secondary forms compared with the Oriental cases. Our second patient continues to be the youngest case in the world, and was described by Israel et al. in 1982 [8], when he was only 2 years old. The regular reports from the Japanese Ministry of Health and the numerous publications or theses show that there are two age peaks for the time of diagnosis, viz the 1st and 4th decades of life. The most frequent age at which the condition comes to light is 6 years old. The number of secondary forms increases in proportion to age, but cases described after 50 years of age are rare, and to our knowledge none have been described after the age of 60. The sex ratio shows a slight female predominance (60%). Only 7% of cases are familial, but the risk is 40 times greater in children with a first-degree relative affected by the disease. It should be recalled that the natural parents of our first patient were first cousins, although we do not have any more information on their family histories. It seems to us to be important to look for any factors responsible for occlusion of the vasa vasorum (e.g. drepanocytosis or thalassemia) [17], for enveloping fibrosis of the vessels at the basal ganglia (pachymeningitis, tumors of the brain stem or, especially, cerebral irradiation) and conditions affecting the arterial wall (systemic elastorrhexis, fibromuscular dysphasia, glycogenesis or homocystinuria), as these may be secondary, potentially curable, forms. Our second patient later also developed Raynaud disease and unexplained early hypertension, which are without doubt part of a multisystem vascular condition. Whatever the causative disease is, close and long-term monitoring seems to be advisable, even if a specific treatment seems to have been spectacularly effective, because a relapse is always possible [10]. Apart from these supposedly secondary forms, the great majority seem to be primary, as in our first case. This would explain the ethnic predilection, the increased risk when a family history is present, the forms that are associated with genetically determined diseases, such as phakomatosis, trisomy 21, Turner syndrome, Fanconi disease or multiple malformation syndromes (congenital cataract, transposition of the great vessels, coarctation of the aorta, polycystic renal disease, or fibromuscular dysplasia of the renal arteries). The presence of primary moyamoya disease is revealed mostly by ischemic strokes or by their immediate or late complications. Since there is progressive bilateral stenosis, sometimes asymmetrical at the onset, of the end of the carotids with secondary development of a collateral network through perforating and choroid arteries and also through the transcortical and transdural networks, it is easy 598 to understand, from a time-scale point of view, why it is particularly transient ischemic attacks (TIAs) that reveal moyamoya disease in children [14], and hemorrhagic strokes in adults. Repeated TIAs, sometimes alternating, in particular during exercise, are the classic way that the disease starts [4]. All types of segmental motor deficit have been seen, as have several descriptions of abnormal movements, according to Suzuki et al. [18] (dyskinesia of the limbs, chorea and hemiballismus). As in our two cases, the disease may be revealed by epileptic fits, which are mainly partial but may later become generalized. Moyamoya represents 12% of pediatric cases and may of course initially be confused with idiopathic or benign epilepsy and treated as such [12]. We also see it as important to insist on the fact that symptoms such as severe headaches that appear to be migrainous, like those our first patient complained of, are undoubtedly the result of rapid cerebral hemodynamic alterations with their many associated symptoms, such as slowing down of mental function or irritability, as her parents had noted [6, 9]. Finally, as with all causes of chronic ischemia during childhood development, the absence of curative treatment unavoidably leads to progressive mental deterioration, as in case 2. More than half of these children will have at least three strokes during their lives, bearing in mind that ischemic attacks in childhood generally herald hemorrhagic strokes in adulthood. These strokes should in theory be less serious than other types of intracranial hemorrhage, since they are caused by rupture of pseudo-aneurysms that have developed on small vessels, but in fact they are the main cause of mortality. Thus, any subarachnoid hemorrhage occurring in this context requires a search for an associated true aneurysm. More than 50% of the patients remain independent in their daily lives; 25% have a greater or lesser degree of residual functional disability, but the complications may cause disabilities or may lead to true encephalopathy by way of chronic ischemia and its complications. Apart the disease manifesting itself by epileptic fits, Kodama et al. [13] described the characteristics of the EEG with long slow waves indicating a subcortical origin, which were often posterior, that is in the areas where the blood flow was spared, disappeared when the eyes were opened and were greatly reduced during sleep, when the spindles had a low voltage. On hyperventilation testing, the slow waves persisted abnormally for 20–60 s after the end of hyperventilation, sometimes accompanied by mental confusion. This pattern is only found in around 80% of pediatric forms; it has not been found in any adult cases. Kodama et al. [13] tried to explain the EEG abnormalities and studied its progression with time in a prospective study on 25 children who were followed up for 72 months from the start of their symptoms. Thanks to this study, we now know that it takes 10 months for the large wide posterior waves to appear, 20 months for them to be found also in the centrotemporal areas and to be less reactive, and 56 months for there to be diffuse low-amplitude activity. The natural progres- sion of the disease can thus be assessed indirectly, because the posterior slow waves correspond to the expression of deeper activity in a healthy cortical area, whereas their disappearance is due to the degree of ischemia becoming too severe and/or to a superadded deep lesion. As for hyperventilation, this produces hypocapnia, which causes widespread vasoconstriction, and this naturally affects small vessels first of all, so involving the network of telangiectases in the brainstem. This could explain the repeated confusional states and the paroxysmal deficits of the lower limbs by vasoconstriction of the anterior cerebral arteries during physical exertion or crying, as described in our two cases. Fujiwara et al. [4], thanks to EEG recordings on ten patients with simultaneous assessment of their arterial blood gases, recently proved that administration of O2 soon after hyperventilation makes it possible to avoid the rebuild-up phenomenon and, especially, its accompanying symptoms which according to him, may go as far as producing TIAs. Iwama et al. [9], investigating a series of 124 children, have also just proved the importance of maintaining normocapnia and normal blood pressure during the whole of the perioperative period. TIAs are, for them, an index of an intracranial hemodynamic lesion and of potential peri- or postoperative complications. Moyamoya owes its definition and its classification to the development of angiographic techniques. It is a progressive condition, as our two cases show, which has radiological features that are now well known and which allowed Suzuki et al. [18] to classify it into six successive stages as early as 1966. In any case, the radiological features recognized as diagnostic criteria remain: the presence of stenoses or occlusions of the two intracranial internal carotid arteries and/or of the start of the sylvian or anterior cerebral arteries, the presence of a network of abnormally dilated, anastomotic perforating arteries, the presence of collaterals from the arteries of the external carotid network in place of the supraclinoid internal carotid vessels, thanks to abnormally developed transdural anastomoses, and finally transcortical collaterals with arteries from the vertebro-basilar network. It is important to note that primary moyamoya disease always presents with an asymmetrical stenosis, but that the unilateral forms (1/3 of cases) become bilateral later. Handa et al. [5] described four possible sites for these stenoses: these are, distal to the ophthalmic artery, between the anterior choroid and the posterior communicating arteries, beyond the anterior choroid artery, and lastly between the A1 segment of the anterior cerebral artery and M1 of the sylvian artery. In addition, the basal ganglia perforating arteries can be separated into anterior (lenticular) and posterior (thalamic) arteries at three different levels, according to their location with respect to the basal ganglia. MRI is a recent technique, which has made it possible for more to be known about the radiological features of moyamoya disease. It provides very good precision for detection of small strokes not seen on CT scan, whether ischemic or hemorrhagic, and for the assessment of the brain stem network 599 [3]. Neuroradiologists recognize the tortuous appearance devoid of a signal with T1 weighting and the moth-eaten appearance of the brain stem nuclei, showing the presence of telangiectases of the moyamoya network. ARM (angiography by magnetic resonance) not only allows a carotid stenosis to be seen, but transdural anastomoses can also be identified by trained radiologists with good-quality equipment. Doppler examinations are particularly used for functional assessment after treatment, bearing in mind that before treatment, they notably reveal an acceleration in blood flow in the ophthalmic arteries and in the vertebral axes, with a reduction of blood flow in the carotid network. Functional cerebral imaging, which is currently being developed, also provides good quality peri- and postoperative assessment, as Touho et al. [19] showed in a series of 25 patients. SPECT shows an antero-posterior gradient in these patients, which is increased with hyperventilation, and preferential posterior perfusion, as well as better perfusion in the gray nuclei. PET scanning also demonstrates a reduction in local O2 metabolism in the ischemic areas, with an increased O2 extraction coefficient in the cortex, but not in the basal ganglia. Moyamoya was treated symptomatically for many years, and has always had a very poor prognosis for function and survival. It was not until 1977 that Yonekawa and Yasargil [20] performed the first temporo-sylvian anastomosis, using a neurosurgical operation that consisted of bypassing the stenosis at the brain stem by creating a transdural anastomosis, using a vessel from the external carotid network. He also made an end-to-side anastomosis between the branches of the superficial temporal artery and the sylvian artery on the same side for anterior moyamoya. Since then, other authors have proposed the same sort of operation, but between the occipital artery and the calcarin artery, for the forms with posterior progression of the disease. Many indirect methods have followed on from these direct methods, whose main disadvantage lies in the small size of the sylvian artery for anastomosis. Some of these methods consist of occipito-gastro-epiploic anastomoses by omental transplantation into the cortex. Others move the temporal muscle inside the skull, which has the advantage of being possible in patients at any age, although it has many disadvantages (postoperative epilepsy from compressive irritation, loss of muscle trophicity in the medium term, a large hole with an unsightly appearance). Inspired by this encephalo-myo-synangiogenesis (EMS) described by Karasawa et al. in 1978 [11], Matsushima et al. [14] perfected a simple technique in which a piece of epicranial aponeurosis is moved inside the skull onto the dura mater, together with its branch of the temporal artery. In our first case, the patient benefited from a bilateral transdural angiogenesis (TDA), with a spectacularly successful result. This type of operation is quick and causes minimal damage, and remains at present the easiest and most frequently performed in children, with an angiographic efficacy that was first recognized in 1986 and has been confirmed more recently both by EEG and by functional imaging techniques [15]. Direct anastomoses are still very widely performed, with an equally good result in most cases. The neurosurgical contraindications are rare, the main ones being early onset of the symptoms, a high frequency of stroke, and the finding of a poor transdural network.. These three criteria were present in our second case, which is why we did not perform a curative surgical operation for this patient. At present, moyamoya seems to us to be the only acceptable surgical indication for treatment to prevent strokes, in particular in children. Even if the mechanism responsible for the development of basal ganglia collaterals is unanimously recognized as the result of any type of recent intracranial stenosis, the exact pathophysiology of the stenosing process in primary moyamoya as yet remains unclear. A malformation hypothesis has easily been refuted, because the lesions are progressive, as proved by repeated angiograms performed on the different patients and pathological examination of these areas. The histological description is in fact more or less that of an atherosclerosed vessel in hypertension, with hyperplasia of the intima, made up of smooth muscle fibers and elastic fibers, and the media, which has few fibrocytes and separates it by an external elastic layer that has splits in several layers or is simply jagged. No parietal inflammatory reaction has ever been seen on these stenosed arterial walls, which excludes a form of arteritis. Fibrocellular hyperplasia of the intima seems to be the essential lesion, and Aoyagi et al. [1, 2] and later Hoshimaru et al. [7] suggested that the cause might be a defect in the synthesis of PDGF (platelet-derived growth factor) receptors, when the FGF (fibroblast growth factor) receptors are saturated, possibly as a result of ischemia. In view of these recent observations and the fact that Kitamura et al. [12], as early as 1991, described the stigmata of fibromuscular hyperplasia in all the systemic vessels, and even in the smaller vessels, we can honestly integrate primary moyamoya into the larger group of genetically induced angiodysphasia, through the growth factors of the small muscle fiber. 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