Moyamoya disease (MMD) is a rare bilateral cerebrovascular occlusive disorder of unknown etiology; it causes hemodynamic dysfunction that leads to neurocognitive impairment18). Usually, MMD is diagnosed after a cerebral hemorrhage in adults and a transient ischemic attack in children3,4,5,12). Obviously, after cerebrovascular event, neurocognitive function is impaired; however, even before the irreversible event, the chronically insufficient cerebral blood flow status can impact the patient's neurocognitive function1). Compared to pediatric patients, the neurocognitive impairment of adult patients diagnosed with MMD is underestimated and not thoroughly evaluated; thus, it is infrequently reported and, to date, has not been well described20). Recent reports have documented cognitive impairment in some adults with MMD11). In addition, there is some preliminary evidence that cerebral revascularization may slow or arrest progressive cognitive decline, or even improve cognition, in this disease10). However, these studies do not clearly define the effects of stroke or its sequelae. There were reports about neurocognitive profile of pediatric MMD patients pre- and post-revascularization surgery; however, to the best of our knowledge there are no analytic reports of cognitive dysfunction in adult MMD patients pre- and post-revascularization surgery14). We attempted to determine the neurocognitive profile and cognitive impairment of adult MMD patients and whether superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery can improve cognitive function manifesting as hemodynamic impairment without stroke.

Data from five patients were analyzed in the present study. In all five cases, TFCA was performed prior to surgery to conform the presence of an occlusive lesion (Fig. 1A). The unilateral STA-MCA bypass surgery was performed successfully without complications (Fig. 1B, C). A preoperative MRI diffusion study found no evidence of infarction (Fig. 1D). Preoperative perfusion MRI showed MTT and TTP prolongation (Fig. 1E, F). Brain perfusion SPECT with and without acetazolamide confirmed decreased reserve capacity in the right frontal lesion (Fig. 1G, H). The postoperative TFCA showed adequate patency of the bypass; hemodynamic evaluation of the surgical sites via MRI perfusion and brain perfusion SPECT imaging with and without acetazolamide on postoperative day 7 showed improvement (Fig. 1I-L). The patients underwent a follow-up SNSB test within three 3 months of the STA-MCA bypass surgery. Data from pre- and post-operative cognitive function tests were compared and analyzed (Fig. 2, 3).

Pre- and post-operative MR perfusion and brain perfusion SPECT showed postoperative improvement of hemodynamic status. The perfusion MRI and SPECT images were compared (Fig. 1E-L). The postoperative MRI perfusion showed improvement in the MCA region where the STA is connected to the 4th segment of the MCA branch. In addition, the SPECT image showed improvement in reserve capacity. The results of the MRI perfusion and SPECT images correlated well and documented the successful surgery result with improved progression of hemodynamic status. Comparison of pre- and post-operative cognitive function revealed SNSB improvement. Fig. 2 shows the comparison of preoperative and postoperative z-score mean standardized results of neuropsychological measurements and the differences of the two results in eight domains. In general all patient results improved postoperatively except general mental status. However, these findings only attained statistical significance in the memory domain. Visuospatial function, inhibitory control, and memory are frequently impaired domains. Few patients had severe dysfunction (≥3 SDs below the normative mean) in specific domain. However, impairment of visuospatial function and inhibitory control domain were patient-specific rather than general; thus, the p-values of these domains were not statistically significant. For example, one patient scored -11.46 on the preoperative evaluation; it improved to -2.08 postoperatively, which represented an approximately 9 SD improvement in the visuospatial domain. The memory domain was the most improved domain following STA-MCA bypass, specifically in delayed recall. The visual memory domain improved in four of five patients. The memory domain was specifically analyzed in Fig. 3. Although both immediate and delayed recall improved, the improvement of delayed recall was statistically significant (p-values=0.038 for verbal memory and 0.042 for visual memory) together with the improvement of subjective symptoms.

MMD is a rare cerebrovascular disorder characterized by progressive stenosis and occlusion of the internal carotid and the anterior and middle cerebral arteries11). MMD is diagnosed via confirming the cerebrovascular occlusion of the distal internal carotid artery (ICA), proximal anterior cerebral artery (ACA) and/or the MCA via CTA, or TFCA13). MRI perfusion or brain perfusion SPECT with and without acetazolamide is used to evaluate the hemodynamic status of the brain due to chronic hypoperfusion from diminished vascularity15). Usually, MMD is diagnosed after a cerebral stroke in adults and a transient ischemic attack in children3,4,5,12). The need for revascularization surgery has been extensively researched5,16,20).

In children with MMD, diminished cerebral perfusion in MMD may lead to regional dysfunction in the absence of overt infarction8). Among pediatric patients, intellectual ability is an ongoing focus of research. Thus, there are many reports assessing intellectual ability. Furthermore, cognitive impairments are not infrequent in children with MMD, despite normal general intellectual function,7) William et al.21) reported that children with MMD demonstrated lower intelligence and poorer executive function than test standardization samples. It is a recent concept that in adult MMD patients, chronic hypoperfusion can lead to cognitive impairment. Jefferson et al.8) emphasized the importance of cognitive function evaluation for chronic cerebrovascular disorders including MMD. Karzmark et al.10) documented that MMD in adults can impair cognition, particularly in the domain of executive function. Calviere et al.1) reported a high rate of cognitive impairment in six of 10 patients that significantly affected executive function.

Frequently, the cognitive impairment in adult patients is underestimated and neglected. Mogensen et al.15) reported decreased executive function in an adult population with MMD; it was most strongly associated with secondary damage to the brain parenchyma, manifested by white matter disease or cortical stroke. Diagnosis of MMD in adult patients following stroke, either ischemic or hemorrhagic, obscures the influence of chronic hypoperfusion; consequently, cognitive dysfunctions are frequently not assessed or misinterpreted. Because the cognitive impairment slowly progresses over time17,18) and many patients assume that the symptoms are due to the aging process rather than chronic hypoperfusion. There are some reports, both in children14,20) and in adults1,20) that note that cerebral revascularization may slow or arrest progression and perhaps even improve cognition; however, these studies do not clearly define the effects of stroke.10) Lee et al.14) analyzed improvement in the level of intelligence after indirect bypass surgery in pediatric MMD patients; they found that the long-term outcome of cognitive function was poorer in the nonsurgical group. These reports were limited to pediatric patients. In the current study, the samples were adult MMD patients without a history of a cerebrovascular event, and all patients enrolled in this study were evaluated for an undiagnosed stroke event and present hemodynamic status. We analyzed the cognitive improvement comparing pre- and post-revascularization surgery in stroke-free adults.

The SNSB is one of the most commonly used neuropsychological tests in Korea for assessing cognitive function; the normal range is based on the analysis of 447 healthy subjects. The standard test indices are age, education, and sex (adjusted to interpretation)9). Comparing the pre- and post-operative cognitive function test, the results of postoperative cognitive function test showed substantial improvement in the memory domain together with the recovery of the patients' subjective symptoms. The results of the postoperative cognitive function test showed improvement, compared to preoperative status. The neurocognitive impairment differs between adult and pediatric populations. Intelligence is the most affected cognitive parameter in children, whereas executive function is the most impaired parameter in adults20). The pediatric samples with MMD had an almost normal, age-appropriate level of intelligence and neurocognitive function before surgery and their cognitive function appeared to be maintained postoperatively14). For adult MMD patients, the focus of the cognitive impairment should be on executive function and memory domains. The preoperative results of impaired cognition domains were similar to those of previous studies. Mental efficiency, executive function, and expressive language abilities were found to be the domains most affected in previous reports1,8,10,15,20). Memory and basic sensory capacities were reported to be relatively intact in other studies, which differed from the present study. Weinberg et al.20) concluded that of all cognitive parameters tested, memory showed the lowest rate of impairment; therefore, the medial temporal function is relatively spared in patients with MMD. In contrast, our study showed that memory and visuospatial functions were the most impaired, followed by executive function. In all five patients, statistically significant improvement was found in the memory domain, specifically delayed recall memory. Since MMD is a disease primarily affecting the distal ICA and proximal middle and anterior cerebral artery, usually the ACA and MCA regions and their watershed areas are affected2,6,19). The impairment of frontal perfusion in MMD can be explained by the distribution of arterial occlusive lesions, usually limited to the ICAs, and sparing the posterior circulation, and the development of a pial collateral supply from the posterior cerebral arteries to the middle and anterior cerebral arteries1). As a result, the executive, memory domains could be impacted by chronic hypoperfusion; thus, they would benefit the most from revascularization.

Our study has several limitations. First, there was a limitation in patient selection. Because all the patients were selected from symptomatic individuals who sought medical care, there was selection bias. Enrolled samples were biased toward patients with the greatest neurocognitive impairment, with variable clinical symptoms such as headache, dizziness, or even transient ischemic attacks. Second, because MMD is a rare disease it does not comprise an adequate sample size to detect potential differences in race, gender or institution. Third, our study is limited to patients who underwent revascularization surgery. Fourth, the difference of neurocognitive impairment between the non-surgical group and the surgical group were not compared. Therefore, we do not have complete understanding of the progression of cognitive impairment under conservative management. Fifth, SNSB can evaluate all cognitive domains; however, the battery does not provide a global cognitive function (GCF) score. The standard index of age range was 55 to 80 years with a mean age of 67.63 years (female : 67.51; male 67.79)9). The mean age of our patients was 43.2 years, which was younger than the standard index of the exam; therefore, there is uncertainty in regard to the results regarding the age factor. The results may appear milder than the actual degree of cognitive impairment. Also the duration to complete the exam is approximately 90-120 minutes. For some patients, it is a long enough time for inattention to occur, which would compromise the results. Further studies that comprise a larger patient population with pre- and post-operation neurocognitive evaluation are essential for the conduction of a multivariable analysis.

In our preliminary study, we found that a large proportion of patients with adult MMD demonstrated disruption of neurocognition. Cognitive impairment could ensue after a focal neurologic deficit; this could be followed by a hemorrhagic event or infarction. However, we also suggest the possibility of chronic hypoperfusion as the primary cause of the cognitive impairment in MMD. The result of the SNSB comparing preoperative and postoperative STA-MCA bypass surgery showed remarkable improvements in the memory domain. Although further study is needed, the importance of performing a neurocognitive evaluation should be emphasized. This would more comprehensively assess the full clinical impact of MMD; furthermore, cognitive dysfunction may be an indicator for earlier intervention with perfusion procedures that would benefit cognitive function.