Mallory, Grant W. MD*; Bower, Regina S. MD*; Nwojo, Macaulay E. MD*; Taussky, Philipp MD‡; Wetjen, Nicholas M. MD*; Varzoni, Thais C. MD‡; Hanel, Ricardo A. MD‡; Meyer, Fredric B. MD*
Moyamoya disease is a rare cerebrovascular disease characterized by idiopathic stenosis or occlusion of the terminal internal carotid, anterior cerebral, or middle cerebral artery bilaterally with the presence of collateral abnormal vascular networks.1 Takeuchi and Shimizu2 are credited with first describing the disease, and Suzuki and Takaku3 further expanded on the angiographic progression of the disease. Cases with angiographic findings similar to moyamoya but with unilateral disease or associated conditions (Down syndrome, neurofibromatosis type 1, etc) have been called moyamoya syndrome. The vast majority of surgical series have been confined to moyamoya disease in Asian populations4-6 because they have a higher prevalence compared with whites and African Americans.7 There is also a moderate number of surgical series evaluating outcomes in pediatric populations.8-13 Few studies, however, have been conducted on a North American population14-17; therefore, less is known about the disease features and outcomes in this population. We present our experience in a North American cohort of patients with moyamoya disease comprising white and African American adults.
PATIENTS AND METHODS
Under Institutional Review Board approval, institutional databases were searched for patients who underwent revascularization procedures for moyamoya disease at the Mayo Clinic Rochester and Mayo Clinic Florida. A total of 75 non-Asian patients undergoing 110 procedures were identified between 1979 and 2011. Confirmation of the correct diagnosis was performed by critical review of the angiogram reports or the studies when available. The patients included in this study had angiograms depicting either unilateral or bilateral typical moyamoya changes, including paraclinoid carotid stenosis extending to the M1 segment, proliferation of lenticulostriate arteries, and other collateralization through the posterior circulation.
Baseline Demographics and Outcomes
Baseline clinical data included race, age at presentation, presenting symptoms, and angiographic findings (location and laterality of involved arteries). Comorbidities were also analyzed, including known associations with moyamoya, cerebrovascular risk factors, and autoimmune disease. The primary outcome assessed was a ≥ 30-day event rate, defined as an ischemic stroke or hemorrhage occurring at ≥ 30 days after surgery. Secondary outcomes included perioperative events (ischemic stroke or transient ischemic attacks, hemorrhage) and complications (wound infection, mortality). The majority of patients underwent subsequent clinical follow-up and imaging at 6 months to a year (magnetic resonance angiography or cerebral angiography at 1 year) after the last revascularization procedure to evaluate graft patency. Follow-up thereafter was at the discretion of the operating surgeon or cerebrovascular neurologists. Charts were reviewed until the last contact. Extended follow-up and efforts to obtain additional secondary outcomes were gathered with a standardized follow-up questionnaire based in part on modified Rankin criteria.18 Attempts were made to contact all patients, who were allowed to respond by either phone or mail. Patients were asked to subjectively rate their quality of life on a 7-point scale, with 7 being rated as very good and 1 as very bad. Patients were also asked about employment and disability status, their ability to ambulate and perform activities of daily living without assistance, whether they were able to drive, if they returned to normal activities after surgery, and whether their disease affected their relationship with family or friends. In addition, patients were asked if they had any further symptoms to extend follow-up in assessing ≥ 30-day event rates.
After induction of general anesthesia, the superficial temporal artery (STA) is mapped with Doppler ultrasound (anterior and posterior divisions). The larger of the 2 divisions based on a preoperative angiogram is then dissected free under the operative microscope. Once adequate length is obtained, the STA is irrigated with heparin and papaverine. The temporalis muscle is incised in a T and reflected inferiorly for a future encephalomyosynangiosis. A circular craniotomy is performed. Under the operative microscope, the dura is opened in cruciate, and the leaflets are cauterized inverted under the bone edges. Multiple incisions are made in the arachnoid. Once an adequate donor artery is chosen, the artery is occluded with 2 number 4 wire clips. The artery is incised. The STA is anastomosed to the middle cerebral artery (MCA) donor branch with multiple interrupted 9-0 monofilament sutures. Doppler is performed to confirm patency of the anastomosis. In 32 patients, anastomotic flow was also determined with a Charbel microflow probe (Transonic Systems, Inc). The temporalis muscle is sewn to the dura with running 4-0 Prolene sutures. The inferior portion of the bone flap is partially rongeured off to allow passage of the STA and muscle and then secured to the skull with the temporalis muscle underneath the bone flap. The wound is then closed in remaining anatomic layers. In 10 patients with unacceptably small donor arteries, an indirect arteriomyoduralsynangiosis was performed.
All statistical analyses were performed with JMP 9.0.1 software. Baseline characteristics were compared among whites and African Americans with the Fisher exact test. Kaplan-Meier curves were used to estimate 5- and 10-year event rates. Each procedure was analyzed independently. Event-free intervals were measured from the time of surgery to either the last contact or date of vascular event. Log-rank statistics were used to assess differences in event rates between procedure types (combined, direct, and indirect). Fisher exact methods were used to assess significant associations with recurrent stroke.
A total of 75 non-Asian patients undergoing 110 procedures were included. Baseline characteristics and the type of procedures performed are summarized in Tables 1 and 2. The majority of the procedures performed combined direct and indirect revascularization techniques (n = 88). The mean age of our patient cohort was 42 ± 15 years (range, 18-85 years). The majority of patients treated were female (n = 57). Mean follow-up time after surgery was 47 months (median, 22.5 months; maximum, 427 months). Seventy-one of the 75 patients were white, and 4 were African American. No baseline differences were noted between whites and African Americans. Most of the cohort had bilateral disease (n = 49) compared with unilateral disease (n = 26). Disease was isolated to the internal carotid artery in 13% (n = 10), was seen in the internal carotid artery with MCA involvement in 13% (n = 10), and involved > 3 arterial territories in 74% (n = 55). All patients were symptomatic, with the most common presenting symptoms being ischemic stroke (n = 46), followed by transient ischemic attacks (n = 26) and hemorrhage (n = 8). Other less common presenting symptoms included headache and cognitive decline or memory loss. A moderate portion of the cohort (44%) had cerebrovascular risk factors, including hyperlipidemia (n = 10), hypertension (n = 9), diabetes mellitus (n = 12), a history of smoking (n = 13), or prior radiation (n = 2). Only 3 patients had known associations with moyamoya syndrome, which included Down syndrome, neurofibromatosis type 1, and fibromuscular dysplasia. Two patients had a history of head trauma. Interestingly, 15% (n = 11) had a history of autoimmune disease or hypothyroidism. The prevalence of cerebrovascular risk factors in comparison to the US population is shown in Table 3.19-21
Perioperative ischemic events occurred in 5 patients (4.5%). Of these, 1 patient experienced a transient ischemic attack. Three experienced minor ischemic strokes, 1 of which occurred contralateral to the operated hemisphere in a patient with bilateral disease. Fortunately, the strokes were minor and did not adversely affect functional recovery at follow-up. Two patients experienced hyperperfusion syndrome after bypass without permanent deficits. There were no intraparenchymal hemorrhages. Two patients had subdural hematomas from the muscle grafts that required evacuation without deficits. There was 1 perioperative death secondary to a pulmonary embolus. Three patients developed ischemic wound edges that required debridement and closure.
Intraoperative Blood Flow Measurements and Graft Patency
Although intraoperative patency was confirmed with Doppler in all direct and combined cases when available, anastomotic cerebral blood flow via the Charbel probe was available in only 32 cases. Mean anastomotic flow in these select individuals was 26.4 ± 17.5 mL/min and was highly variable (range, 5-90 mL/min; median, 24 mL/min). Angiographic follow-up data were available in 91 of the 100 combined and direct procedures (example shown in Figure 1). Bypass patency was confirmed in 88 of the 91 cases (97%). The remaining 3 patients had delayed occlusions without symptoms and had developed collaterals in the interim.
Events occurring > 30 days from surgery occurred in a total of 4 patients (3.6%). Of these 4 patients, 2 patients had hemorrhages, 1 had a transient ischemic attack, and 1 had a contralateral stroke. The 5- and 10-year event rates via Kaplan-Meier curves were 5.8% and 9.9%, respectively (Figure 2). Log-rank statistics revealed no differences in event-free survival with respect to techniques (P = .55). A significant association was found with a history of thyroid disease and recurrent stroke (P = .05) with the Fisher exact methods. There were positive trends with preoperative hypertension (P = .07) and autoimmune disease (P = .06), although they did not reach statistical significance.
Quality of Life
Quality-of- life data were available in 19 patients via follow-up questionnaires (25% response rate). The median follow-up in this subset of patients was 94 months. The average subjective quality-of-life rating was 5.6 on a 7-point scale (7 being very good). The employment rate was 53%. Nearly half (47%) of patients reported being disabled, although 95% maintained the ability to drive. All were able to ambulate independently. The majority (74%) were independent in activities of daily living and were able to resume the same activity level before surgery (modified Rankin Scale score, 0-1).
The Natural History and Surgery
The natural history of typical moyamoya has previously been outlined in a number of series and generally is poor.22-25 Kuroda et al23 studied 86 hemispheres in 63 patients and found a progression rate of 17.4% per hemisphere and of 23.8% per patient. A large portion with unilateral disease (38.9% per Kelly et al22) will eventually develop bilateral disease. The stroke rate in asymptomatic patients is 3.2%/y.26 Once a patient has become symptomatic, the risk of recurrent stroke is much higher, with the reported range in the literature being 10.3% per year24 to 16% per year or 80.95% at 5 years.25 Indirect and direct bypass techniques have been shown to alter the natural history. Hallemeier et al16 found that the cumulative stroke risk at 5 years decrease to 17%. Similarly, Kraemer et al25 reported a reduction to 27% in Europeans, and more recently, Guzman et al15 noted a reduction to 5.6% at 5 years in a North American population. Our results are nearly identical; our 5- and 10-year cumulative stroke rates were 5.8% and 9.9%.
Although the overall low event rate (n = 4) in the present series is consistent with previous studies, there is a potential limitation in assuming independence in patients undergoing bilateral procedures. If a first-time revascularization lowers the contralateral stroke risk, evaluating each procedure independently could underestimate cumulative stroke rates. Nonetheless, our results and existing literature suggest that symptomatic patients benefit from revascularization. Whether asymptomatic patients also benefit from revascularization remains to be determined, although the relatively low perioperative risk (4.5%) compared with the natural history (3.2%/y stroke risk) suggests that they may also benefit as well.
Quality of Life
Although we had a limited number of quality-of-life surveys, this information indicates that in addition to lowering risk of recurrent stroke, revascularization positively affects quality of life. After surgery, more than half of the patients were able to return to work. The majority of patients were able to drive, and approximately 70% were able to resume normal activities and to maintain independence in activities of daily living. Few studies have directly examined quality of life after surgery, although they also have found improvement in quality of life. Guzman et al15 found significant improvement in quality of life as measured by the modified Rankin Scale score. An earlier series by Choi et al27 found significant improvement in activities of daily living in surgically treated patients (55% vs 26%).
Risk Factors for Recurrent Stroke
Interestingly, we found significant correlations with risk of recurrent stroke after revascularization with a history of thyroid disease (hypothyroidism and hyperthyroidism) and positive trends with autoimmune disease and hypertension. The significance of the correlations is unclear. Foremost, because they are based on a relatively small number of patients, they should be interpreted with caution because there is a possibility that the positive trends reflect sampling error. However, the following suggests that thyroid disease, autoimmune disease, and hypertension may play a role in the pathophysiology of the disease. First, one of the 4 strokes observed was contralateral, which implicates continued progression as the cause of the delayed stroke. In addition, there was a surprisingly high incidence of both a history of autoimmune disease or thyroid disease (15%) and hypertension (12%) among our cohort. Of the 6 patients with thyroid disorders, 5 had primary hypothyroidism: 1 had Hashimoto hypothyroidism and the other 4 had primary hypothyroidism without further delineated types. The other patient initially had Graves disease but was secondarily hypothyroid after treatment. Interestingly, 3 of the 6 patients had other autoimmune-mediated diseases (diabetes mellitus type 1 and primary biliary cirrhosis). Graves disease, a known autoimmune-mediated thyroid disease, has previously been described in association with moyamoya syndrome.28,29 Furthermore, the presence of thyroid autoantibodies has been associated with the development of moyamoya.30,31 Hypertension, on the other hand, may be a secondary phenomenon. Renovascular stenosis has been shown to occur in 5% of patients with moyamoya, suggesting that some patients may have renal artery involvement.32
Postoperative Hyperperfusion Syndrome
Another distinguishing feature of the select cohort from prior Asian and pediatric series appears to be a lower incidence of postoperative hyperfusion syndrome. In Asian populations, the incidence reported in the literature ranges from 6.7% to 50%, depending on the definition (radiographic vs symptomatic) and method of study,33-37 with recent studies suggesting the rate of symptomatic hyperfusion to be about 20% to 30%.36,38 Only 2 patients (1.8%) in the present series developed symptomatic hyperfusion after bypass. Similarly, Guzman et al15 noted transient neurological deficits in only 3.3% of their North American cohort (n = 450). Reasons for the lower incidence are not entirely clear. Previously cited risk factors for hyperperfusion in Asian cohorts include increased preoperative cerebral blood volume,37 intraoperative cerebral blood flow,35 perioperative blood pressure,33 and adult and hemorrhagic onset as presenting features.36 Notably, the present and previously published North American series15-17 show that hemorrhage is less common at initial presentation in this subset. If hemorrhagic presentation is a risk factor, it may partially explain the finding of a lower postoperative rate of hyperfusion. The other aforementioned risk factors have not been well studied in non-Asian moyamoya populations as they relate to the development of hyperperfusion. We suspect that differences in anastomotic flow, however, may also be contributory. Okada et al6 studied anastomotic flow in 15 moyamoya patients after STA-MCA bypass who presented with ischemia and found the mean anastomotic flow to be 34.1 mL/min compared with 26.4 mL/min in the present series. Interestingly, Lee et al39 found that the higher anastomotic flows after STA-MCA bypass in 292 patients correlated with postoperative stroke, hemorrhage, and transient neurological deficits. Because anastomotic flow was not available in a large part of our cohort, no firm conclusions can be made owing to the high potential for selection bias.
Proposed Classification System
There is confusion in the neurosurgery literature as to what is meant by moyamoya disease. When considering the specific genotype of an Asian population with bilateral angiographic findings, all surgeons would agree with use of the term moyamoya disease. With other genotypes like Down syndrome or neurofibromatosis, terms including moyamoya disease, moyamoya syndrome, secondary moyamoya, or moyamoya phenomenon are used interchangeably. This study indicates that autoimmune disease is yet another potential type of this disease because the angiograms are interchangeable with those with classic moyamoya disease. Hence, it would be reasonable to codify all genotype-associated moyamoya patients as moyamoya disease and to assign the term moyamoya syndrome to patients with unilateral or bilateral disease with an origin associated with autoimmune, vascular risk factors, or as-yet identified reasons. Another classification option to further avoid confusion and to help researchers identify etiologies and direct treatments would be to classify moyamoya on a genetic and etiological basis (Table 4). Genetic causes have been implicated primarily in Asian patients40-47 and, to lesser extent, in white populations and genetic syndromes (ie, Down syndrome and neurofibromatosis).48-52 These could be designated moyamoya type 1 (Asian genotype) and moyamoya type 2 (white genotype and other genetic syndromes). Furthermore, autoimmune disorders30,53-59 and atherosclerosis/vasculitis60-66 have been associated with the moyamoya phenotype and could be designated moyamoya type 3 and 4, respectively. Figure 3 shows select examples.
We report favorable results with direct and indirect revascularization for moyamoya in an understudied adult population. The 5- and 10-year cumulative risks of stroke were 5.8% and 9.9%. Perioperative stroke risk was 4.5%. Trends were found with recurrent stroke and a history of thyroid disease, hypertension, and autoimmune disease, which suggests that they may play a role in the pathophysiology and disease progression of moyamoya in this subset of patients.
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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I congratulate the authors on wringing any data or conclusions from this relatively small series of moyamoya patients obtained from the surgical records of the Mayo Clinic over a 32-year period. I found their article interesting and well written. Only 75 “moyamoya” patients were operated on at this tertiary referral center, which is known especially for departmental expertise in vascular neurosurgery—ample evidence of the rarity of this condition in actual practice.
The authors’ observations regarding the association of thyroid disease and additional autoimmune disorders such as primary biliary cirrhosis, along with the genetic conditions like Down syndrome and neurofibromatosis, with a moyamoya phenomenon have been confirmed by many previous authors, as the authors note in their Discussion. The authors’ proposed classification of moyamoya patients into 4 groups—Asian, genetic, autoimmune, and atherosclerotic—is intriguing.
I have several concerns with their conclusions. The study is woefully underpowered for the conclusions that are made, despite the statistical support they provide. Their follow-up data, with survival tables, are presented as significant, but in the body of the article, it is apparent that there are very few late clinical examinations for follow-up purposes, and only 19 of their 75 patients returned a questionnaire regarding quality of life. The authors describe their surgical technique in detail, but readers will want to see for themselves how effective these combined surgical procedures have been, especially in the 10 patients in whom no suitable donor vessel was found and indirect procedures were required. In fact, none of the postoperative studies that the authors provide show any of the arteriograms from the “combined surgical approach” cases. A few more of the preoperative arteriograms in their most controversial moyamoya group—the atherosclerotic, hypertensive patients—would also be instructive because many of these patients in my opinion have occlusive disease only, with none of the hallmarks of moyamoya disease such as the presence of basal moyamoya vessels and spontaneous transdural collateral.
Many of us do not believe that these patients have moyamoya and would anticipate that their response to a purely indirect procedure, for example, might be suboptimal. It would have been interesting to see how these patients responded to their procedures from an imaging standpoint.
R. Michael Scott
The authors reported the surgical outcomes and predictors of stroke in a North American white and African American adult moyamoya populations at the Mayo Clinic. According to their data, they proposed a new classification system of moyamoya patients into 4 groups: Asian genotype, white genotype and other genetic syndrome, autoimmune diseases, and atherosclerosis. This classification system could be useful in perioperative management of moyamoya disease. Stricter blood pressure control is essential for Asian moyamoya patients in light of the high prevalence of hyperperfusion syndrome after revascularization surgery compared with non-Asian moyamoya patients. Controlling autoimmune disease such as thyroid disease leads to the prevention of the exacerbation of moyamoya disease itself. Recently, moyamoya disease has been analyzed from another genetic viewpoint, and the gene attracting the most attention is RNF213.1 RNF213 is reported to be related to age at onset or the degree of severity of moyamoya disease.2 We hope that the authors will investigate the correlation between RNF 213 and the factors of classification proposed in the next stage.
Tomohito Hishikawa, Isao Date
1. Liu W, Morito D, Takashima S, et al.. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542. PubMed | CrossRef Cited Here... |
2. Miyatake S, Miyake N, Touho H, et al.. Homozygous c. 14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78(11):803–810. View Full Text | PubMed | CrossRef Cited Here... |
The authors retrospectively reviewed 75 non-Asian moyamoya patients undergoing 110 surgeries at the Mayo Clinic and examined outcomes after revascularization for white and African American adults. Perioperative ischemic events occurred in 5 patients (4.5%), consistent with previous reports. It should be noted, however, that the incidence of hyperperfusion syndrome was as low as 1.8% (2 of 110) in their series, contrary to the relatively high incidence of symptomatic cerebral hyperperfusion among Asian moyamoya patients, ranging from 16.7% to 38.2%. The authors raised the important suggestion that substantial risk of hyperperfusion syndrome after revascularization could be much higher in Asian patients compared with white moyamoya patients, although the underlying pathology is undetermined.
Further understanding of the difference in early perioperative response between Asian and non-Asian patients is essential because the management of ischemia and the management of hyperperfusion are contradictory to each other, and both perioperative infarction and hemorrhagic conversion of hyperperfusion could lead to significant morbidity. Because the susceptibility gene for moyamoya disease, RNF213, was recently identified among Asian patients,1 comparative genetic analysis between Asian and white patients would be of great interest. Alternatively, comparative evaluation of inflammatory biomarkers, including matrix metalloproteinases,2,3 that relate to blood-brain barrier maintenance or hemorrhagic conversion may address this important issue.
1. Kamada F, Aoki Y, Narisawa A, et al.. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Human Genet. 2011;56(1):34–40. Cited Here...
2. Kang HS, Kim JH, Phi JH, et al.. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010;81(6):673–678. View Full Text | PubMed | CrossRef Cited Here... |
3. Fujimura M, Watanabe M, Narisawa A, et al.. Increased expression of serum matrix metalloproteinase-9 in patients with moyamoya disease. Surg Neurol. 2009:72(5):476–480. PubMed | CrossRef Cited Here... |