Moyamoya disease is a chronic, occlusive cerebrovascular disease, characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain.
These diagnostic criteria of the moyamoya disease, stated by the Research Committee on Spontaneous Occlusion of the Circle of Willis (moyamoya disease) in Japan, are well established and generally accepted as the definition of this rare entity. On the contrary to the diagnosis of definitive moyamoya disease, there is some confusion in the terminology and understanding of quasi-moyamoya disease; moyamoya disease in association with various disease entities, such as atherosclerosis, autoimmune diseases, Down syndrome, etc. Although the clinical management is not affected by these semantic distinctions, terminological confusion may interfere with the international collaboration of the clinical investigation of these rare conditions 1).
The perforating arteries in the basal ganglia and thalamus markedly dilate and function as an important collateral circulation, called as “moyamoya” vessels. The posterior cerebral artery are also involved in a certain subgroup of patients. Therefore, cerebral hemodynamics is often impaired especially in the frontal lobe, leading to transient ischemic attack (TIa) and cerebral infarction. Furthermore, the dilated, fragile moyamoya vessels often rupture and cause intracranial hemorrhage 2) 3).
Unilateral and bilateral moyamoya disease (MMD).
Ischemic-type Moyamoya Disease
see Suzuki staging.
Ladner et al performed digital subtraction angiography and noninvasive structural and hemodynamic MRI, and they outline a new classification system for patients with moyamoya that they have named Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD).
Healthy control volunteers (n = 11; age 46 ± 12 years [mean ± SD]) and patients (n = 25; 42 ± 13.5 years) with angiographically confirmed moyamoya provided informed consent and underwent structural (T1-weighted, T2-weighted, FLAIR, MR angiography) and hemodynamic (T2*- and cerebral blood flow-weighted) 3-T MRI. Cerebrovascular reactivity (CVR) in the internal carotid artery territory was assessed using susceptibility-weighted MRI during a hypercapnic stimulus. Only hemispheres without prior revascularization were assessed. Each hemisphere was considered symptomatic if localizing signs were present on neurological examination and/or there was a history of transient ischemic attack with symptoms referable to that hemisphere. The PIRAMD factor weighting versus symptomatology was optimized using binary logistic regression and receiver operating characteristic curve analysis with bootstrapping. The PIRAMD finding was scored from 0 to 10. For each hemisphere, 1 point was assigned for prior infarct, 3 points for reduced CVR, 3 points for a modified Suzuki Score ≥ Grade II, and 3 points for flow impairment in ≥ 2 of 7 predefined vascular territories. Hemispheres were divided into 3 severity grades based on total PIRAMD score, as follows: Grade 1, 0-5 points; Grade 2, 6-9 points; and Grade 3, 10 points.
In 28 of 46 (60.9%) hemispheres the findings met clinical symptomatic criteria. With decreased CVR, the odds ratio of having a symptomatic hemisphere was 13 (95% CI 1.1-22.6, p = 0.002). The area under the curve for individual PIRAMD factors was 0.67-0.72, and for the PIRAMD grade it was 0.845. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively.
A scoring system for total impairment is proposed that uses noninvasive MRI parameters. This scoring system correlates with symptomatology and may provide a measure of hemodynamic severity in moyamoya, which could be used for guiding management decisions and evaluating intervention response 4).
A study indicated a higher overall autoimmune disease prevalence in unilateral than in bilateral MMD. Unilateral MMD may be more associated with autoimmune disease than bilateral MMD. Different pathogenetic mechanisms may underlie moyamoya vessel formation in unilateral and bilateral MMD 5).
The histopathological features of the middle cerebral artery (MCA) and superficial temporal artery (STA) from moyamoya disease (MMD) and their relationships with gender, age, angiography stage were explored. The causes and the clinical significance of vasculopathy of STA were also discussed. The clinical data and specimens of MCA and STA from 30 MMD patients were collected. Twelve samples of MCA and STA from non-MMD patients served as control group. Histopathological examination was then performed by measuring the thickness of intima and media, and statistical analysis was conducted. The MCA and STA specimens from MMD group had apparently thicker intima and thinner media than those from the control group. There was no significant pathological difference between the hemorrhage group and non-hemorrhage group, and between the males and females in MMD patients. Neither the age nor the digital subtraction angiography (DSA) stage was correlated with the thickness of intima in MCA and STA. MMD is a systemic vascular disease involving both intracranial and extracranial vessels. Preoperative external carotid arteriography, especially super-selective arteriography of the STA, benefits the selection of donor vessel 6).
In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD.
The aim of a retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations.
The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed.
The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome.
The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early-onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment 7).
Children and adults with moyamoya disease may have different clinical presentations. The symptoms and clinical course vary widely, with the disease ranging from being asymptomatic to manifesting as transient events to causing severe neurologic deficits. Adults experience hemorrhage more commonly; cerebral ischemic events are more common in children.
Children may have hemiparesis, monoparesis, sensory impairment, involuntary movements, headaches, dizziness, or seizures. Mental retardation or persistent neurologic deficits may be present.
Adults may have symptoms and signs similar to those in children, but intraventricular, subarachnoid, or intracerebral hemorrhage of sudden onset is more common in adults.
Fang et al., aimed to determine which aspects of executive function are impaired in patients with MMD, in addition to the specific dysexecutive functions present among its clinical subtypes and the mechanisms underlying dysexecutive function in these patients.
The authors administered 5 typical executive function tests (the Stroop test, the Hayling Sentence Completion Test [HSCT], the verbal fluency [VF] test, the N-back test, and the Sustained Attention to Response Task [SART]) to 49 patients with MMD and 47 IQ-, age-, education-, and social status-matched healthy controls. The dysexecutive questionnaire (DEX) was also used to assess participants' subjective feelings about their executive function.
A total of 39 of the patients were evaluated by CT perfusion (CTP) before the assessments were performed, and the correlations among the performances of the patients on the above tests with the parameters of cerebral blood volume, cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) in the frontal lobes of these patients were also analyzed.
Many aspects of executive function in the patients with MMD were significantly poorer than those in the healthy controls, and the patients performed particularly poorer on the VF test, HSCT, N-back test, and SART. The patients with hemorrhagic MMD exhibited worse executive inhibition, executive processing, and semantic inhibition compared with those with ischemic MMD, but the latter group presented a worse working memory and poorer sustained attention. There were no significant differences in the DEX scores between the patients with MMD and healthy controls. The other findings were as follows: CBF was significantly positively correlated with the number correct on part B of the HSCT (r = 0.481, p = 0.01) and accuracy on the 0-back task of the N-back (r = 0.346, p = 0.031); MTT was significantly positively correlated with accuracy on the 2-back task of the N-back (r = 0.349, p = 0.034) and factor 5 of the DEX (r = 0.359, p = 0.032); and TTP was significantly positively correlated with the number correct on part B of the HSCT (r = 0.402, p = 0.034) and the 1-back reaction time of the N-back (r = 0.356, p = 0.026).
The patients with MMD exhibited impairments in semantic inhibition, executive processing, working memory, and sustained attention, but they were not aware of these deficits. Moreover, differences in dysexecutive function existed between the different subtypes of MMD. Hypoperfusion of the frontal lobe may be related to working memory and semantic inhibition impairments in patients with MMD 8).
Movement disorders are a rare manifestation of Moyamoya angiopathy (MMA). Data on prevalence and clinical presentation are warranted. Possible involuntary movements include focal motor seizures, tremor, limb-shaking transient ischemic attacks, choreiform and spastic or dystonic movement disorders.
Kraemer et al developed a questionnaire to systematically assess movement disorders in MMA. Patients' history of involuntary movements and their clinical presentation were assessed systematically by interview. Additionally, demographic data were assessed as well as localization of movements, possible trigger factors and the presence of other symptoms.
The questionnaire was administered to 63 European patients with MMA. The response rate was high with 93.6% participating patients. Twenty-eight patients (47.4%) reported involuntary movement disorders including periodic tremor, irregular jerks, involuntary movements with loopy or pranced character, stiffness and muscle cramps. From those patients, 16 (57.1%) individuals had the symptoms prior to the diagnosis of MMA. The most common involuntary movements were irregular jerks witnessed by 17 (60.7%) patients, followed by stiffness and muscle cramps in 10 (35.7%). Eight (28.6%) Patients suffered from unintended loopy and pranced character, while 4 individuals (14.3%) remembered periodic tremor. Of the 28 patients who witnessed movement disorders, 23 had undergone revascularization surgery (82.1%). From the latter subgroup, movement disorders were reversed in 7 out of 12 patients (58.3%) with irregular jerks and 4 out of 7 patients (57.1%) with unintended loopy and pranced character.
The study elucidates the high incidence of movement disorders in an unselected consecutively recruited cohort of European MMA patients 9).
Quantification of the severity of vasculopathy and its impact on parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response in patients with moyamoya.
Computational fluid dynamics (CFD) analysis on eight patients (5 female, 3 male) with MMD treated by EDAS (encephalo-duro-arterio-synangiosis) between 2011 and 2012. All the eight patients presented with haemorrhage, with subsequent 4-12 month follow-up done using Magnetic Resonance Angiography (MRA) to capture auto-remodelling. Karunanithi et al. calculated percentage change in flow rate and pressure drop indicator (ΡDI) across the Left and Right ICA. Pressure drop indicator (PDI) is defined as the difference of pressure reduction within the carotid arteries, measured at post-op and follow up, using patient specific inflow rates. The measured percentage flow change and pressure reduction showed an increase at follow up for improved patients (characterised by angiography according to the method of Matsushima), who did not develop any complications after surgery. The inverse was observed in patients who were clinically classified as no change and retrogressed (according to the method of Matsushima) cases post-operation. This elucidates the findings of a new parameter that may well play a critical role as an assistive clinical decision making tool in MMD 10).
see Cerebral Infarction.