Moyamoya disease and syndrome: a review / Doença e síndrome de moyamoya: uma revisão

Abstract Moyamoya disease is a chronic occlusive cerebrovascular disease that is non-inflammatory and non-atherosclerotic. It is characterized by endothelial hyperplasia and fibrosis of the intracranial portion of the carotid artery and its proximal branches, leading to progressive stenosis and occlusion, often clinically manifesting as ischemic or hemorrhagic stroke with high rates of morbidity and mortality. On cerebral angiography, the formation of collateral vessels has the appearance of a puff of smoke (moyamoya in Japanese), which became more conspicuous with the refinement of modern imaging techniques. When there is associated disease, it is known as moyamoya syndrome. Treatments are currently limited, although surgical revascularization may prevent ischemic events and preserve quality of life. In this review, we summarize recent advances in moyamoya disease, covering aspects of epidemiology, etiology, presentation, imaging, and treatment strategies.

RESUMO A doença de moyamoya, ou doença cerebrovascular oclusiva crônica, é uma afecção não inflamatória e não aterosclerótica, caracterizada por hiperplasia endotelial e fibrose dos segmentos intracranianos das artérias carótidas internas e da porção proximal de seus ramos. Isso provoca estenose progressiva e oclusão, frequentemente manifestada clinicamente como isquemia cerebral ou hemorragia intracraniana, com alta morbimortalidade. A formação compensatória de vasos colaterais produz, na angiografia encefálica, um aspecto de nuvem de fumaça (moyamoya, em japonês). Quando existe doença subjacente que possa estar relacionada, a doença recebe o nome de síndrome de moyamoya. Embora a incidência esteja aumentando graças aos novos métodos diagnósticos, as estratégias terapêuticas ainda são limitadas. O diagnóstico precoce permite cirurgias de revascularização cerebral que podem evitar novos acidentes vasculares e melhorar a qualidade de vida. Nesta revisão são apresentados os avanços recentes sobre a doença de moyamoya, citando aspectos de epidemiologia, etiologia, apresentação, exames diagnósticos e tratamento.

Intracranial arterial dolichoectasia and cerebral small vessel disease / 国际脑血管病杂志

Intracranial arterial dolichoectasia (IADE), also known as dilated cerebral artery disease, is a kind of disease in which the diseased arteries are lengthened, enlarged, and tortuous due to various reasons. Cerebral small vessel disease (CSVD) refers to a series of clinical, imaging and pathological syndromes caused by various etiologies affecting cerebral arterioles, venules and capillaries. Its main imaging manifestations include lacunar infarction, cerebral microbleeds, enlargement of perivascular space, white matter hyperintensities, and brain atrophy. In recent years, more and more studies have shown that IADE is closely associated with the occurrence and development of CSVD. This article reviews the correlation between IADE and CSVD.

Intracranial arterial dolichoectasia and cerebral small vessel disease / 国际脑血管病杂志

Intracranial arterial dolichoectasia, also known as dilated cerebral artery disease, is characterized by an increase in the length and diameter of at least one intracranial artery, and the involved intracranial arteries enlarge and dilate. Cerebral small vessel disease mainly refers to diseases caused by small vessel lesions in the brain. It is usually used to describe a series of imaging changes of white matter and subcortical gray matter, including recent subcortical small infarction, lacuna, white matter hyperintensity, enlarged perivascular space, cerebral microhemorrhage, and cerebral atrophy. Recently, more and more studies have shown that there is a certain correlation between intracranial arterial dolichoectasia and cerebral small vessel diseases.

Analysis of clinical, imaging and genetic mutations of 37 cases of cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy from 19 pedigrees / 中华神经科杂志

Objective To analyze the clinical, imaging characteristics and NOTCH3 mutations of cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy (CADASIL) in Henan, China.Methods CADASIL patients diagnosed by gene or biopsy in People′s Hospital of Zhengzhou University between 2012-2016 were recruited.Clinical and imaging features of these patients were analyzed retrospectively.The distribution of NOTCH3 gene mutations hotspots was described in Henan region at the same time.Results There were 37 patients from 19 families who were diagnosed as CADASIL by genetic testing or biopsy, 27 of whom had symptoms of CADASIL.Two families were confirmed by pathological examination and 17 by genetic testing.Of these 17 families, 13 mutations were found.Mutations in exon 11 were found in eight families, in exon 4 were detected in four families, and in exon 13 were found in two families.Mutation in exons 3, 8 and 20 was detected in one family respectively.Most patients presented with stroke and several presented with cognitive decline.Twelve patients had been attacked by risk factors.Magnetic resonance imaging (MRI) was performed on 22 patients.White-matter lesions were distributed in brain stem, basal ganglia, subcortical, temporal pole, external capsule.There were 19 patients with white-matter lesions in temporal pole and seven in capsula externa, showed as a high signal in T2WI.Conclusions CADASIL patients can be associated with risk factors.T2WI hyperintensities in the anterior temporal lobe were more common than that in the capsular external.Exon 11 and exon 4 were the hotspots for the NOTCH3 mutation in Henan patients.

Transcranial Doppler ultrasonographic evaluation of vertebral artery hypoplasia and focal artery stenosis / 国际脑血管病杂志

Objective To investigate the diagnostic values of transcranial Doppler ultrasonography (TCD) for vertebral artery hypoplasia (VAH) and focal vertebral artery stenosis (fVAS) with CT angiography (CTA) finding as a standard.Methods Consecutive patient who underwent TCD and CTA were included.According to the findings of CTA,they were divided into 3 groups:a normal group,a VAH group,and a fVAS group.The TCD parameters included the mean flow velocity (MFV),peak systolic velocity (PSV),pulsatility index (PI),resistance index (RI) and asymmetry index (AI),and they were compared among the groups,respectively.The receiver operator characteristic (ROC) curves were used to evaluate the sensitivity and specificity of TCD parameters for diagnosis of VAH and fVAS.Results A total of 405 patients were enrolled,including 278 (68.6％) in the normal group,75 (18.5％) in the VAH group,and 52 (12.8％) in the fVAS group.There were significant differences in MFV,PSV,PI,and RI on the affected sides among different groups (the affected side in the normal group was defined as the right side).The blood flow velocity in the VAH group was the slowest,and that in the fVAS group was the fastest.Other parameters had the same trend.There were significant differences in MFV and PSV on the unaffected side among different groups.The blood flow velocity in the VAH group was significantly faster,the fVAS group was slightly faster,and the fVAS group was less than the VAH group.There were significant differences in AI among different groups,and it could be used as an indicator for diagnosis of VAH (the area under the curve 0.78,95％ confidence interval 0.72-0.84;P＜0.001).With the AI ＞33.7％ as a cut-off value,the sensitivity and specificity of VAH diagnosis were 74.7％ and 68.7％.Conclusions Attention should be paid to identifying VAH and fVAS when using TCD for evaluation of vertebral artery.AI ＞33.7％ can be used as a reference index for diagnosis of VAH.

Arteritis de Takayasu: Etiolog¡a inhabitual de infarto cerebral. Reporte de un caso / Takayasu arteritis: an unusual etiology of ischemic stroke. A case report

La arteritis de Takayasu (AT) es una vasculitis crónica de grandes vasos que afecta a la aorta y a sus principales ramas. La presentación clínica inicial generalmente se manifiesta con síntomas constitucionales inespecíficos, perode forma ocasional puede debutar con isquemia de un órgano determinado. Presentamos el caso de una mujer de 31años de edad sin ascendencia japonesa, sin factores de riesgo vasculares, que presentó de forma súbita déficit motoren hemicuerpo derecho y alteración del lenguaje. Al examen físico se encontró ausencia de pulso en una arteriadistal y una diferencia en la presión arterial en los miembros superiores. La angiografía por sustracción digital mostró oclusión de la arteria subclavia y carótida común izquierda, así como estenosis severa de la arteria subclavia derecha en su parte media.Se diagnosticó AT de acuerdo a los criterios diagnósticos del Colegio Americano de Reumatólogos de 1990 ylos Criterios modificados de Ishikawa. La paciente recibió tratamiento médico y de la rehabilitación con buena respuesta. La AT debe considerarse como posibilidad etiológica en todos los pacientes jóvenes que presenten uninfarto cerebral. Su diagnóstico precoz es crucial, ya que esta patología es sensible al tratamiento médico y se asociacon buenos resultados clínicos.

Takayasu arteritis (TA) is a chronic large vessel vasculitis that affects the aorta and its main branches. The initialclinical presentation is generally with non-specific constitutional symptoms, but occasionally it may debut with aparticular organ ischemia. We report the case of a 31-year-old woman, who presented suddenly a motor deficit inthe right hemibody and language impairment. Physical examination revealed the lack of a pulse in a distal artery and the difference in blood pressure between upper limbs. Digital subtraction angiography showed occlusion of the left subclavian artery and left common carotid artery and severe stenosis of the right subclavian artery in the middle portion. AT was diagnosed according to the diagnostic criteria of the American College of Rheumatologists, 1990. The patient received medical treatment and rehabilitation with good response. AT as an etiologic possibility should be considered in all young patients who have a stroke. Early diagnosis is crucial because this pathology is sensitive to medical treatment and it is associated with good clinical results.

RNF213 gene polymorphisms and susceptibility of intracranial vascular stenosis disease: a meta-analysis / 国际脑血管病杂志

Objective To investigate the correlation between RNF213 gene polymorphisms (rs112735431,rs138130613,and rs148731719) and the susceptibility of intracranial vascular stenosis disease.Methods The literature of studies on the correlation between RNF213 gene polymorphisms and intracranial vascular stenosis disease was collected according to the related databases.Using the Stata 12.0 software and selecting suitable genetic model,the heterogeneity was analyzed and the pooled odds ratio (OR) and its 95％ confidence interval (CI) were calculated.Results A total of 12 articles were included after screening.The result of meta-analysis showed that the rs112735431 polymorphism had a significant correlation with the susceptibility of moyamoya disease (MMD) in all genetic models,especially the most significant dominant model (AA + GA genotype vs.GG genotype:OR 101.46,95％ CI 59.41-173.27;P ＜0.001),at the same time,the polymorphism of this site also had significant correlation with the nonMMD intracranial large artery stenosis/occlusion (AA + GA genotype vs.GG genotype:OR 13.82,95％ CI 4.48-42.61;P＜ 0.001);the rs138130613 polymorphism had significant correlation with the susceptibility of MMD in Chinese population (OR 5.01,95％ CI 1.57-15.98;P=0.006);and no correlation between the rs148731719 polymorphism and the susceptibility of MMD was observed.Conclusions The RNF213 gene rs112735431 polymorphism is a susceptible factor of MMD,at the same time,the polymorphism of this site is also associated with the formation of non-MMD intracranial large artery stenosis.Systematic study on the molecular function of RNF213 may have important significance for diagnosis and treatment of such vascular stenosis diseases.

Arteria trigeminal persistente: reporte de tres casos / Persistent trigeminal artery: three case reports

La persistencia de la arteria trigeminal es una alteración vascular infrecuente y representa la permanencia, después del nacimiento, de la comunicación entre el sistema carotideo y el sistema vertebro-basilar. Esta persistencia se ha asociado a la existencia de otras alteraciones de la morfología vascular cerebral y a condiciones clínicas variadas. Reportamos tres casos de persistencia de la arteria trigeminal, dos como hallazgo incidental en pacientes con sintomatología transitoria y uno en un cuadro de hemorragia subaracnoidea, identificados mediante reconstrucción tridimensional de imágenes obtenidas por angiotomografía.

Persistent trigeminal artery is a rare vascular disorder and represents the permanence of the communication between the carotid system and vertebrobasilar system after birth. This persistence has been associated with the existence of other alterations of brain vascular morphology and different clinical conditions. We report three cases of persistent trigeminal artery, two incidental findings in patients with transient symptoms and one in a patient with subarachnoid hemorrhage, identified by three-dimensional reconstruction of images obtained by angiotomography.

Prognostic value of fluid-attenuated inversion recovery imaging vascular hyperintensity in intravenous thrombolysis of acute ischemic stroke / 中华神经科杂志

Objective To explore the prognostic effect of fluid-attenuated inversion recovery imaging vascular hyperintensity (FVH)on intravenous thrombolysis of acute ischemic stroke.Methods We retrospectively reviewed the clinical and imaging data of intravenous thrombolytic patients with acute anterior circulation infarction admitted from May 2009 to December 2013.The presence of FVH was evaluated,and its associations with reperfusion and clinical outcome after thrombolysis were assessed.Results Ninety-three patients were analyzed.FVH was detectable in 55 (59.1％) cases.Patients with FVH had higher NIHSS scores (11.8 ± 6.0 vs 7.2 ± 4.5,P ＜ 0.01),larger initial DWI lesions (5.5 ml vs 2.0 ml,Z =-3.030,P=0.002) and perfusion lesions (42.0 ml vs 3.0 ml,Z=-6.104,P =0.005),compared with those without FVH.The history of hyperlipidemia (OR =0.264,95％ CI 0.07-0.90,P =0.048) and proximal large vessel occlusion(OR =48.874,95％ CI 11.6-205.924,P ＜ 0.01) were independently associated with the presence of FVH.The presence of FVH independently predicted the poor neurological outcome at 3 months (OR =4.143,95 ％ CI 1.440-11.919,P =0.008).However,early reperfusion was associated with favorable outcome in patients with FVH after intravenous thrombolysis (OR =8.500,95％ CI 1.964-36.790,P =0.004).Conclusions The presence of FVH is associated with proximal large vessel occlusion,which predicts poor outcome in patients with intravenous thrombolysis.However,early reperfusion among patients with FVH can improve the outcome.

Advances in vertebrobasilar dolichoectasia / 国际脑血管病杂志

This article reviews and summarizes the research data about vertebrobasilar dolichoectasia in recent years from the aspects of epidemiology,pathogeny,pathology,diagnosis,clinical manifestations,as well as its mechanism and treatment.

Novel mutation of HTRA1 gene causes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy: one case / 中华神经科杂志

ObjectiveTo report a novel HTRA1 gene mutation caused cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) with migraine,urinary retention and constipation.MethodsThe patient was a 34-year-old woman who suffered from myalgia with cramp for 16 years,lumbago for 5 years,migraine and mild alopecia for 3 years,right hemiparesis for 5 months,and urinary retention and constipation for 1 month.Vertebral MRI showed degeneration of vertebral bodies with disc herniations.Brain MRI revealed diffuse white matter lesions and lacunar infarcts.Sural nerve and skin biopsies were performed in the patient. HTRA1 gene analysis was performed in patient,her parents and 2 brothers,and Notch3 gene analysis in the patient.ResultsThe sural biopsy demonstrated discontinuous of elastica internal with thickness of intima of arterioles.The capillary basement membranes were thickness with mini granular changes.A homozygous T to A transition at position 524( c.524T ＞ A) was found in HTRA1 gene.The heterozygous c.524T ＞ A mutation appeared in the parents and 2 brothers,but not in the controls.Notch3 mutations were not found in the patient. Conclusion CARASIL caused by novel homozygous c.524T ＞ A mutation of HTRA1 gene can present with migraine,urinary retention and constipation.

Imaging features of acute small subcortical infarcts: comparison of large artery atherosclerotic and small artery disease stroke / 国际脑血管病杂志

Objective To investigate the differences in neuroimaging between large artery atherosclerosis and small subcortical infarction (SSI). Methods The consecutive hospitalized patients with acute SSI were divided into large atherosclerotic stroke group and small-artery occlusive stroke group according to the evidence-based etiolologic classification of ischemic stroke (the SSS-TOAST criteria). The neuroimaging features between the two groups were compared.Results A total of 118 patients with SSI were recruited. Seven patients with cardiogenic cerebral embolism were excluded from the study. Three were stroke of other determined etiology and 7 were cryptogenic stroke. Twenty-six patients in the large artery atherosclerotic stroke group had new infarcts (3.69 ± 5. 79), 50％ of them were multiple lesions, mainly a half oval in the center (P ＜0. 01); 75 patients in the small-artery occlusive stroke group had new infarcts (1.08 ±0. 51), only 3 (3.7％) were mltiple lesions, and they were in the different artery territories.Compared to the large atherosclerotic stroke group, the white matter lesions was more severe in the small-artery occlusive stroke group (P =0. 04), and most of them were accompanied by silent infarction (P =0. 012). Conclusions The large atherosclerotic SSI was mostly multiple infarcts in a half oval in the center, while the small artery occlusive SSI was mostly single infarct, and was usually accompanied by severe white matter lesions and silent infarction.

Arterial ischemic stroke in children / 国际脑血管病杂志

Stroke is an important cause for childhood disability and death.Its risk factors and pathophysiological processes have significant differences with the adult patients.The common risk factors for pediatric arterial ischemic stroke (AIS) include cerebral arteriopathy,cardiac diseases,blood system and metabolic diseases,infection,and genetic factors.The clinical manifestations of AIS are different because of the age,underlying cause,and location of stroke.After a full examination,some risk factors or precipitating factors can be identified in more than 90％ of children with AIS,and thus emphasizing the importance of comprehensive diagnosis and evaluation.Although a number of clinical guidelines for pediatric stroke have been published,its evidence base is rather weak.Therefore,the present treatment mainly bases upon the expert consensus and the conclusions from the adult stroke studies.This article reviews the epidemiology,risk factors,clinical evaluation,managment and outcome of pediatric AIS.

Reversible cerebral vasoconstriction syndrome / Síndrome de vasoconstricción cerebral reversible

Background: Reversible cerebral vasoconstriction syndrome is characterized by thunderclap headache associated with multifocal vasoconstriction of cerebral arteries in patients without aneurysmal subarachnoid hemorrhage (SAH). The vasoconstriction reverts within three months. We report a 44-year-old man who had a thunderclap headache during sexual intercourse. A similar episode occurred at rest 36 hours later. The patient had already experienced a thunderclap headache 10 years earlier, during coitus. There were no abnormalities on examination. His brain computed tomography scan was normal and cerebrospinal fluid analysis showed no xanthochromia, 15 WBC/mm³ and 10 RBC/mm³. Lumbar puncture was repeated two days later (WBC = 3/mm³ and RBC = 43/mm³). An initial digital cerebral angiography showed a diffuse segmental intracerebral vasospasm. A new angiography after 15 days was normal. He remains headache-free after twenty six months. In conclusion, patients who have thunderclap headache with normal brain CT and cerebrospinal fluid without xantochromia should be investigated for this syndrome.

El síndrome de vasoconstricción cerebral reversible se caracteriza por una cefalea lancinante asociada a una vasoconstricción multifocal de las arterias cerebrales, en pacientes sin hemorragia subaracnoidea causada por aneurismas. La vasoconstricción se revierte en un plazo de tres meses. Presentamos un paciente varón de 44 años que experimentó una cefalea lancinante durante el acto sexual. Un episodio similar repitió 36 horas después, pero mientras estaba en reposo. El paciente había sufrido una cefalea lancinante durante el coito, 10 años antes. El examen físico fue normal. La tomografía cerebral estaba normal y el líquido cefalorraquídeo era claro, con 15 leucocitos y 10 eritrocitos por mm³. Una angiografía cerebral digital mostró un vasoespasmo intracerebral difuso segmentario. Una nueva angiografía, efectuada 15 días después, fue normal. El paciente está libre de cefaleas después de 26 meses de seguimiento.

Hallazgos imaginológicos en el síndrome de phaces: reporte de caso / Imaging findings in phaces syndrome: case report

Los hemangiomas de tipo capilar son los tumores de la infancia más frecuentes, principalmente en niños menores de un año de edad y usualmente afectan la cabeza y el cuello. Por lo general, están solitarios; sin embargo, aproximadamente un 20% de los niños con grandes hemangiomas cervicofaciales tendrán una de las anomalías asociadas en el síndrome de PHACES, un raro síndrome neurocutáneo de predominio en el sexo femenino, con características mayores, como malformaciones cerebrales en la fosa posterior, hemangiomas de tipo capilar, anomalías arteriales, coartación de aorta, defectos cardiacos y anormalidades oculares. Cuando se asocia con hendidura esternal o rafe supraumbilical, es referido como síndrome de PHACES. Se presenta el caso de una niña de cuatro años de edad con hemangioma facial congénito asociado con anomalías vasculares cerebrales y de la fosa posterior.

Capillary hemangiomas of infancy are the most common childhood tumors, mainly in children under 1 year old, and they usually involve the head and neck. They are usually solitary, but about 20% of the children with large cervicofacial hemangiomas will have one of the anomalies associated with PHACES syndrome. PHACES is a rare neurocutaneous syndrome with female predominance and features such as: brain malformations in the posteriorfossa, hemangiomas, arterial anomalies, coarctation of the aorta, heart defects, and ocular abnormalities. When associated with sternal slit and/or supraumbilical Raphe, it is referredto as PHACES syndrome. The case of a 4-year-old child with congenital facial hemangioma associated to the posterior fossa and with cerebral vascular anomalies is presented.

Stability control and its effect assessment of rat midge cerebral artery occlusion model / 国际脑血管病杂志

Objective To search for the methods of inducing the high stability rat middle cerebral artery occlusion (MCAO) model and to noninvasively assess the method of model effect. Methods Six kinds of filaments with different diameters were used to induce rat MCAO models and their success rate, incidence of subarachnoid hemorrhage, and infarct volume were compared. The model scores were performed to assess the model effect after the operation and at 24 hours after reperfusion. Results Higher model success rate and lower incidence of subarachnoid hemorrhage were achieved when the 0. 28 mm in diameter and 0.32-0.34 mm in tip diameter filaments were used. 1he sensibility and specificity were higher when the model scores were performed at 24 hours after reperfusion. Conclusions Using the filaments of 0.28 mm in diameter and 0. 32-0. 34 mm in tip diameter for intraluminal thread could improved the stability of the models. The model scores at 24 hours after reperfusion could noninvasively assess the model effect.

The Difference of Platelet Aggregability in Patients with Cerebral Infarction accordigng to Type of Anti-platelet Agents

BACKGROUND: Platelets play a key role in many occlusive vascular disorders and anti-platelet agents are the most important therapeutic strategy in preventing the recurrence of cerebral infarction. In order to know the platelet aggregability according to the strategy of anti-platelet agents, we measured platelet aggregability in patients who were taking anti-platelet agents for cerebral infarction. METHODS: Platelet aggregability in response to adenosine diphosphate (ADP) or collagen was measured in whole blood samples from 175 patients (48 females and 137 males). It was analyzed according to the type of cerebral infarction, vascular risk factors, and each anti-platelet agent. RESULTS: Platelet aggregability induced by ADP or collagen was significantly increased in patients with large artery atherosclerotic infarction compared to those with small vessel disease. Among anti-platelet regimens, combined therapy with aspirin and clopidogrel decreased platelet aggregability most effectively. CONCLUSIONS: These findings suggest that anti-platelet treatment should be tailored to the vascular status of each patient, and that combination therapy with aspirin and clopidogrel can effectively modulate platelet aggregability in preventing the recurrence of cerebral infarction.

Relation Between the Distribution of Cerebral Atherosclerosis and Stroke Risk Factors in Patients with Extracranial Carotid Disease

BACKGROUND: In Korean patients, atherosclerotic lesions are more often found in the intracranial rather than in the extracra-nial cerebral arteries compared to Caucasian patients. However, extracranial carotid artery lesions are increasingly recognized in recent years. (recognized by who? Do you mean increasingly found in Korean patients ?) Although some studies have shown Asians to have more intracranial diseases, patients with intracranial stenosis often have extracranial disease. The aim of this investigation was to determine the frequency of combined intracranial atherosclerotic lesions in patients with extracranial carotid disease and to analyze the differences in stroke risk factors between patients with pure extracranial carotid artery disease and those who have combined extra- and intracranial artery disease. METHODS: We reviewed 100 consecutive patients with extracranial carotid artery stenosis (defined as > 30% narrowing of diameter) or occlusion proven by a conventional angiogra-phy. We investigated the distribution of atherosclerotic lesions on the angiography and compared risk factors for atherosclerosis between the pure extracranial carotid occlusive group and the combined extra- and intracranial artery occlusive group. RESULTS: Among 100 patients with extracranial carotid occlusive lesions, combined intracranial stenosis (>30% narrowing of diameter) or occlusion was seen in 67 patients. Multivariate analysis showed that diabetes mellitus was the only factor that was associated with the combined extra- and intracranial artery occlusive groups (p < 0.05). CONCLUSIONS: The combined extra- and intracranial atherosclerotic lesions was were frequently seen in Korean patients. Diabetes mellitus may play an important role in the devel-opment of intracranial atherosclerosis in patients who have combined extra- and intracranial occlusive disease.