Identifying important factors for successful surgery in patients with lateral temporal lobe epilepsy.

OBJECTIVE: Lateral temporal lobe epilepsy (LTLE) has been diagnosed in only a small number of patients; therefore, its surgical outcome is not as well-known as that of mesial temporal lobe epilepsy. We aimed to evaluate the long-term (5 years) and short-term (2 years) surgical outcomes and identify possible prognostic factors in patients with LTLE. METHODS: This retrospective cohort study was conducted between January 1995 and December 2018 among patients who underwent resective surgery in a university-affiliated hospital. Patients were classified as LTLE if ictal onset zone was in lateral temporal area. Surgical outcomes were evaluated at 2 and 5 years. We subdivided based on outcomes and compared clinical and neuroimaging data including cortical thickness between two groups. RESULTS: Sixty-four patients were included in the study. The mean follow-up duration after the surgery was 8.4 years. Five years after surgery, 45 of the 63 (71.4%) patients achieved seizure freedom. Clinically and statistically significant prognostic factors for postsurgical outcomes were the duration of epilepsy before surgery and focal cortical dysplasia on postoperative histopathology at the 5-year follow-up. Optimal cut-off point for epilepsy duration was eight years after the seizure onset (odds ratio 4.375, p-value = 0.0214). Furthermore, we propose a model for predicting seizure outcomes 5 years after surgery using the receiver operating characteristic curve and nomogram (area under the curve = 0.733; 95% confidence interval, 0.588-0.879). Cortical thinning was observed in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group (p-value < 0.01, uncorrected). CONCLUSIONS: The identified predictors of unfavorable surgical outcomes may help in selecting optimal candidates and identifying the optimal timing for surgery among patients with LTLE. Additionally, cortical thinning was more extensive in the poor surgical group.

Surgical outcome and prognostic factors in epilepsy patients with MR-negative focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasia (FCD) represents a heterogeneous group of disorders of the cortical formation and is one of the most common causes of epilepsy. Magnetic resonance imaging (MRI) is the modality of choice for detecting structural lesions, and the surgical prognosis in patients with MR lesions is favorable. However, the surgical prognosis of patients with MR-negative FCD is unknown. We aimed to evaluate the long-term surgical outcomes and prognostic factors in MR-negative FCD patients through comprehensive presurgical data. METHODS: We retrospectively reviewed data from 719 drug-resistant epilepsy patients who underwent resective surgery and selected cases in which surgical specimens were pathologically confirmed as FCD Type I or II. If the epileptogenic focus and surgical specimens were obtained from brain areas with a normal MRI appearance, they were classified as MR-negative FCD. Surgical outcomes were evaluated at 2 and 5 years, and clinical, neurophysiological, and neuroimaging data of MR-negative FCD were compared to those of MR-positive FCD. RESULTS: Finally, 47 MR-negative and 34 MR-positive FCD patients were enrolled in the study. The seizure-free rate after surgery (Engel classification I) at postoperative 2 year was 59.5% and 64.7% in the MR-negative and positive FCD groups, respectively (p = 0.81). This rate decreased to 57.5% and 44.4% in the MR-negative and positive FCD groups (p = 0.43) at postoperative 5 years. MR-negative FCD showed a higher proportion of FCD type I (87.2% vs. 50.0%, p = 0.001) than MR-positive FCD. Unilobar cerebral perfusion distribution (odds ratio, OR 5.41) and concordance of interictal epileptiform discharges (OR 5.10) were significantly associated with good surgical outcomes in MR-negative FCD. CONCLUSION: In this study, MR-negative and positive FCD patients had a comparable surgical prognosis, suggesting that comprehensive presurgical evaluations, including multimodal neuroimaging studies, are crucial for obtaining excellent surgical outcomes even in epilepsy patients with MR-negative FCD.

Gamma Knife Radiosurgery for Incidental, Symptomatic Unruptured, and Ruptured Brain Arteriovenous Malformations.

BACKGROUND: This study was performed to investigate clinical characteristics and outcome after gamma knife radiosurgery (GKS) in patients with incidental, symptomatic unruptured, or ruptured arteriovenous malformations (AVMs). METHODS: A total of 491 patients with brain AVMs treated with GKS from June 2002 to September 2017 were retrospectively reviewed. All patients were classified into the incidental (n = 105), symptomatic unruptured (n = 216), or ruptured AVM (n = 170) groups. RESULTS: The mean age at diagnosis of incidental, symptomatic unruptured, and ruptured AVMs was 40.3, 36.7, and 27.6 years, respectively. The mean nidus volume was 3.9, 5.7, and 2.4 cm3, respectively. Deep venous drainage was identified in 34, 54, and 76% patients, respectively. There were no significant differences in obliteration rates after GKS between the 3 groups (64.8, 61.1, and 65.9%, respectively) after a mean follow-up period of 60.5 months; however, patients with incidental AVM had a significantly lower post-GKS hemorrhage rate than patients with symptomatic unruptured or ruptured AVMs (annual hemorrhage rate of 1.07, 2.87, and 2.69%; p = 0.028 and p = 0.049, respectively). CONCLUSIONS: There is a significant difference in clinical and anatomical characteristics between incidental, symptomatic unruptured, and ruptured AVMs. The obliteration rate after GKS is not significantly different between the 3 groups. Meanwhile, an older age at diagnosis and lower hemorrhage rate after GKS in incidental AVMs suggest that they have a more indolent natural course with a lower life-long risk of hemorrhage.

Prospective Screening of Extracranial Systemic Arteriopathy in Young Adults with Moyamoya Disease.

Background RNF213 is a major susceptibility gene for moyamoya disease (MMD), characterized by chronic progressive steno-occlusion of the intracranial arteries. However, coincidental extracranial arteriopathy is sporadically described in a few cases and in children with MMD. Methods and Results This study prospectively enrolled 63 young adults (aged 20-49 years) without a known history of systemic vascular diseases who were confirmed to have definite (bilateral, n=54) or probable (unilateral, n=9) MMD, as per typical angiographic findings. Coronary and aorta computed tomography angiography was performed to characterize extracranial arteriopathy and investigate its correlation with clinical characteristics and MMD status, including the RNF213 p.Arg4810Lys variation (c.14429G>A, rs112735431). Altogether, 11 of 63 patients (17%) had significant (>50%) stenosis in the coronary (n=6), superior mesenteric (n=2), celiac (n=2), renal (n=1), and/or internal iliac artery (n=1). One patient showed both mesenteric and iliac artery stenosis. Patients with extracranial arteriopathy were more likely to have diabetes mellitus and posterior cerebral artery involvement. Moreover, a higher prevalence of extracranial arteriopathy was observed in the presence of the RNF213 p.Arg4810Lys variant (67% in homozygotes). After controlling for diabetes mellitus and posterior cerebral artery involvement, the p.Arg4810Lys variant was independently associated with extracranial arteriopathy (additive model; P=0.035; adjusted odds ratio, 4.57; 95% CI, 1.11-27.20). Conclusions Young adults with MMD may have concomitant extracranial arteriopathy in various locations. Patients with RNF213 variants, especially the p.Arg4810Lys homozygous variant, should be screened for systemic arteriopathy.

Moyamoya Disease and Spectrums of RNF213 Vasculopathy.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. A polymorphism (R4810K) in the Ring Finger Protein 213 (RNF213) gene, at chromosome 17q25.3, is the strongest genetic susceptibility factor for MMD in East Asian populations. MMD was regarded prevalent in childhood and in East Asian populations. However, the so-called MMD could represent only the tip of the iceberg. MMD is increasingly reported in adult patients and in Western populations. Moreover, the RNF213 variant was recently reported to be associated with non-MMD disorders, such as intracranial atherosclerosis and systemic vasculopathy (e.g., peripheral pulmonary artery stenosis and renal artery stenosis). In this review, we summarize the spectrums of RNF213 vasculopathy in terms of clinical and genetic phenotypes. Continuous efforts are required for pathophysiology-based diagnoses and treatment, which will benefit from collaboration between clinicians and researchers, and between stroke and vascular physicians.

The Role of Anterior Thalamic Deep Brain Stimulation as an Alternative Therapy in Patients with Previously Failed Vagus Nerve Stimulation for Refractory Epilepsy.

Deep brain stimulation (DBS) has provided new treatment options for refractory epilepsy; however, treatment outcomes of DBS in refractory epilepsy patients previously treated with vagus nerve stimulation (VNS) have not been clarified. Herein, treatment outcomes of DBS of the anterior nucleus of the thalamus (ANT-DBS) in patients who had previously experienced VNS failure are reported. Seven patients who had previously experienced VNS failure underwent ANT-DBS device implantation. VNS was turned off before DBS device implantation. Monthly seizure counts starting from baseline to 12-18 months after DBS were analyzed. Five (71.3%) of the 7 patients experienced a >50% reduction of seizure counts after DBS; 1 responder reached a seizure-free status after DBS therapy. Of the 2 nonresponders, 1 subject showed improvement in seizure strength and duration, which lessened the impact of the seizures on the patient's quality of life. This is the first study in which favorable outcomes of ANT-DBS surgery were observed in individual patients with refractory epilepsy who had not responded to prior VNS. Further studies with a larger number of subjects and longer follow-up period are needed to confirm the feasibility of ANT-DBS in patients who have previously experienced VNS failure.

Gamma Knife Radiosurgery for ARUBA-Eligible Patients with Unruptured Brain Arteriovenous Malformations.

BACKGROUND: A randomized trial of unruptured brain arteriovenous malformations (ARUBA) reported superior outcomes in conservative management compared to interventional treatment. There were numerous limitations to the study. This study aimed to investigate the efficacy of gamma knife radiosurgery (GKS) for patients with brain arteriovenous malformations (AVMs) by comparing its outcomes to those of the ARUBA study. METHODS: We retrospectively reviewed ARUBA-eligible patients treated with GKS from June 2002 to September 2017 and compared against those in the ARUBA study. AVM obliteration and hemorrhage rates, and clinical outcomes following GKS were also evaluated. RESULTS: The ARUBA-eligible cohort comprised 264 patients. The Spetzler-Martin grade was Grade I to II in 52.7% and III to IV in 47.3% of the patients. The mean AVM nidus volume, marginal dose, and follow-up period were 4.8 cm³, 20.8 Gy, and 55.5 months, respectively. AVM obliteration was achieved in 62.1%. The annual hemorrhage rate after GKS was 3.4%. A stroke or death occurred in 14.0%. The overall stroke or death rate of the ARUBA-eligible cohort was significantly lower than that of the interventional arm of the ARUBA study (P < 0.001) and did not significantly differ from that of the medical arm in the ARUBA study (P = 0.601). CONCLUSION: GKS was shown to achieve a favorable outcome with low procedure-related morbidity in majority of the ARUBA-eligible patients. The outcome after GKS in our patients was not inferior to that of medical care alone in the ARUBA study. It is suggested that GKS is rather superior to medical care considering the short follow-up duration of the ARUBA study.

Clinical Usefulness of Intraoperative Motor-Evoked Potential Monitoring during Temporal Lobe Epilepsy Surgery.

BACKGROUND AND PURPOSE: We aimed to determine the effectiveness of intraoperative neurophysiological monitoring focused on the transcranial motor-evoked potential (MEP) in patients with medically refractory temporal lobe epilepsy (TLE). METHODS: We compared postoperative neurological deficits in patients who underwent TLE surgery with or without transcranial MEPs combined with somatosensory evoked potential (SSEP) monitoring between January 1995 and June 2018. Transcranial motor stimulation was performed using subdermal electrodes, and MEP responses were recorded in the four extremity muscles. A decrease of more than 50% in the MEP or the SSEP amplitudes compared with baseline was used as a warning criterion. RESULTS: In the TLE surgery group without MEP monitoring, postoperative permanent motor deficits newly developed in 7 of 613 patients. In contrast, no permanent motor deficit occurred in 279 patients who received transcranial MEP and SSEP monitoring. Ten patients who exhibited decreases of more than 50% in the MEP amplitude recovered completely, although two cases showed transient motor deficits that recovered within 3 months postoperatively. CONCLUSIONS: Intraoperative transcranial MEP monitoring during TLE surgery allowed the prompt detection and appropriate correction of injuries to the motor nervous system or ischemic stroke. Intraoperative transcranial MEP monitoring is a reliable modality for minimizing motor deficits in TLE surgery.

Prognostic factors determining poor postsurgical outcomes of mesial temporal lobe epilepsy.

OBJECTIVES: To investigate the long-term postoperative outcomes and predictive factors associated with poor surgical outcomes in mesial temporal lobe epilepsy (MTLE). MATERIALS AND METHODS: We enrolled patients with MTLE who underwent resective surgery at single university-affiliated hospital. Surgical outcomes were determined using a modified Engel classification at the 2nd and 5th years after surgery and the last time of follow-up. RESULTS: The mean duration of follow-up after surgery was 7.6 ± 3.7 years (range, 5.0-21.0 years). 334 of 400 patients (83.5%) were seizure-free at the 5th postoperative year. Significant predictive factors of a poor outcome at the 5th year were a history of generalized tonic clonic (GTC) seizures (odds ratio, OR; 2.318), bi-temporal interictal epileptiform discharge (IED) (OR; 3.107), bilateral hippocampal sclerosis (HS) (OR; 5.471), unilateral HS and combined extra-hippocampal lesion (OR; 5.029), and bi-temporal hypometabolism (BTH) (OR; 4.438). Bi-temporal IED (hazard ratio, HR; 2.186), BTH (HR; 2.043), bilateral HS (HR; 2.541) and unilateral HS and combined extra-hippocampal lesion (HR; 2.75) were independently associated with seizure recurrence. We performed a subgroup analysis of 208 patients with unilateral HS, and their independent predictors of a poor outcome at the 5th year were BTH (OR; 5.838) and tailored hippocampal resection (OR; 11.053). CONCLUSION: This study demonstrates that 16.5% of MTLE patients had poor long-term outcomes after surgery. Bilateral involvement in electrophysiological and imaging studies predicts poor surgical outcomes in MTLE patients.

Cav-1 (Caveolin-1) and Arterial Remodeling in Adult Moyamoya Disease.

Background and Purpose- Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease characterized by progressive stenosis and negative remodeling of the distal internal carotid artery (ICA). We hypothesized that cav-1 (caveolin-1)-a protein that controls the regulation of endothelial vesicular trafficking and signal transduction-is associated with negative remodeling in MMD. Methods- We prospectively recruited 77 consecutive patients with MMD diagnosed via conventional angiography. Seventeen patients with intracranial atherosclerotic stroke and no RNF213 mutation served as controls. The outer distal ICA diameters were examined using high-resolution magnetic resonance imaging. We evaluated whether the degree of negative remodeling in the patients with MMD was associated with RNF213 polymorphism, cav-1 levels, or various clinical and vascular risk factors. We also investigated whether the derived factor was associated with negative remodeling at the cellular level using the tube formation and apoptosis assays. Results- The serum cav-1 level was lower in the patients with MMD than in the controls (0.47±0.29 versus 0.86±0.68 ng/mL; P=0.034). The mean ICA diameter was 2.48±0.98 mm for the 126 affected distal ICAs in patients with MMD and 3.84±0.42 mm for the asymptomatic ICAs in the controls ( P<0.001). After adjusting for confounders, cav-1 levels (coefficient, 1.018; P<0.001) were independently associated with the distal ICA diameter in patients with MMD. In vitro analysis showed that cav-1 downregulation suppressed angiogenesis in the endothelial cells and induced apoptosis in the smooth muscle cells. Conclusions- Our findings suggest that cav-1 may play a major role in negative arterial remodeling in MMD.

Risk of Recurrent Chronic Subdural Hematoma Associated with Early Warfarin Resumption: A Matched Cohort Study.

OBJECTIVE: Studies on resuming anticoagulation after burr-hole drainage for chronic subdural hematoma (CSDH) are limited. To evaluate the safety for early warfarin resumption after burr-hole drainage, we conducted a retrospective matched cohort study. METHODS: Between January 2008 and April 2015, 36 patients with warfarin-related unilateral CSDH and 151 patients with ordinary unilateral CSDH were enrolled in this study. Patients taking warfarin were managed homogeneously according to the study protocol, and the usual dosage of warfarin was resumed within 2 or 3 days of burr-hole drainage to reach a target international normalized ratio (INR) of 2.1. The primary outcome, defined as recurrent CSDH requiring repeated burr-hole drainage within 3 months of the initial surgery, was compared between the two groups. RESULTS: The primary outcome was observed in 4 (11%) of the 36 patients taking warfarin and in 18 (12%) of the 151 ordinary patients. After propensity score matching, the primary outcome was observed in 3 of 33 patients (9%) in the matched warfarin cohort and 11 of 74 patients (15%) in the matched ordinary cohort. When the results were analyzed using the generalized estimating equation, no significant difference was observed in the rate of recurrent CSDH between the 2 groups (P = 0.411). In addition, we found that recurrent CSDH was not related to postoperative international normalized ratio levels (P = 0.332). CONCLUSIONS: There was no definitive association between postoperative early warfarin resumption and the recurrence rate of CSDH. Patients with warfarin-related CSDH and a strong indication for anticoagulation can be managed by resuming warfarin within 3 days of burr-hole drainage.

Modified Arachnoid Plasty Reduces Chronic Subdural Hematoma after Unruptured Aneurysm Clipping : Technical Note.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a rare complication of unruptured intracranial aneurysm (UIA) clipping surgery. To prevent postoperative CSDH by reducing subdural fluid collection, we applied the modified arachnoid plasty (MAP) during the UIA clipping surgery to seal the dissected arachnoid plane. METHODS: This retrospective study included 286 patients enrolled from July 2012 to May 2015. We performed arachnoid plasty in all patients, with MAP used after June 17, 2014. Patients were divided into two groups (non-MAP vs. MAP), and by using uni- and multivariate analyses, baseline characteristics, and relationships with postoperative CSDH between the two groups were analyzed. The degree of preoperative brain atrophy was estimated using the bicaudate ratio (BCR) index. RESULTS: Ten patients (3.5%) among 286 patients had postoperative CSDH after clipping. Nine (3.1%) were in the non-MAP group, and one (0.9%) was in the MAP group. The higher BCR index showed statistical significance with occurrence of postoperative CSDH in both uni- (p=0.018) and multivariate (p=0.012, odds ratio [OR] 8.547, 95% confidence interval [CI] 1.616-45.455) analyses. MAP was associated with a lower risk of postoperative CSDH (p=0.022, OR 0.068, 95% CI 0.007-0.683). CONCLUSION: This study shows that the degree of preoperative brain atrophy is associated with an increased occurrence of CSDH after clipping and that MAP could help reduce the risk of postoperative CSDH after unruptured aneurysm clipping via a lateral supraorbital approach.

Frequency and significance of rare RNF213 variants in patients with adult moyamoya disease.

PURPOSE: Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by stenosis of the internal carotid arteries with compensatory development of collateral vessels. Although a founder variant of RNF213, p.Arg4810Lys (c.14429G>A, rs112735431), is a major genetic risk factor for MMD in East Asians, the frequency and disease susceptibility of other variants in this gene remain largely unknown. In the present study, we investigated the association of RNF213 variants with MMD in Korean patients and population controls. METHODS: For all RNF213 variants listed in the Human Gene Mutation Database (HGMD) as disease-causing or likely disease-causing mutations for MMD, genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genetic data from 264 adult patients with MMD were analyzed and compared with two control populations comprised of 622 and 1,100 Korean individuals, respectively. RESULTS: Among the 30 RNF213 variants that were listed in the HGMD, p.Arg4810Lys was identified in 67.4% (178/264) of patients with MMD and showed a significantly higher allele frequency than in the controls, giving an odds ratio of 63.29 (95% confidence interval, 33.11-120.98) for the 622 controls and 48.55 (95% confidence interval, 31.00-76.03) for the 1100 controls. One additional variant, p.Ala5021Val (c.15062C>T, rs138130613), was identified in 0.8% (2/264) of patients; however, the allele frequencies were not significantly different from those in the controls. CONCLUSIONS: These results suggest that, in our cohort of Korean patients, the p.Arg4810Lys is the only variant that is strongly associated with MMD among the 30 RNF213 variants listed in the HGMD.

Intractable Epilepsy with Solitary Cerebral Calcification.

Cerebral calcification is a common incidental finding upon brain imaging and its epileptogenicity is often underestimated. Here, we report a case of intractable epilepsy arising in conjunction with a solitary cerebral calcification. A 42-year-old male with intractable epilepsy was admitted to the epilepsy clinic for invasive epilepsy surgery. Brain magnetic resonance imaging revealed a slight high-intensity signal change in the right amygdala and a small, calcified lesion in the right lateral temporal region. The patient underwent invasive monitoring with subdural electrodes. He had five habitual seizures with automatisms and fast activity. These seizures initiated in the right lateral temporal area just above the solitary calcified lesion. Neuropathology of the calcified lesion showed no specific findings apart from a fibrocalcific nodule. Thus, although solitary cerebral calcifications may be an asymptomatic or coincidental finding in some patients, they may also have a highly epileptogenic focus.

Low flow velocity in the middle cerebral artery predicting infarction after bypass surgery in adult moyamoya disease.

OBJECTIVE Direct and indirect bypass surgeries are recognized as the most effective treatments for preventing further stroke in adults with moyamoya disease (MMD). However, the risk factors for postoperative infarction after bypass surgery for MMD are not well established. Therefore, the objective of this study was to investigate the risk factors for postoperative infarction. In particular, the authors sought to determine whether transcranial Doppler (TCD) ultrasonography measurements of mean flow velocity (MFV) in the middle cerebral artery (MCA) could predict postrevascularization infarction. METHODS The medical records of patients with MMD who underwent direct bypass surgery at the authors' institution between July 2012 and April 2015 were reviewed. The MFV in the MCA was measured with TCD ultrasonography and categorized as high (> 80 cm/sec), medium (40-80 cm/sec), and low (< 40 cm/sec). Postoperative MRI, including diffusion-weighted imaging, was performed for all patients within a week of their surgery. Angiographic findings were classified according to the Suzuki scale. Postrevascularization infarction was defined as any diffusion restriction on postoperative MRI scans. Postoperative neurological status was assessed through a clinical chart review, and the modified Rankin Scale was used to evaluate clinical outcomes. RESULTS Of 43 hemispheres in which bypass surgery for MMD was performed, 11 showed postrevascularization infarction. Ten of these hemispheres had low MFV and 1 had medium MFV in the ipsilateral MCA. In both univariate and multivariate analyses, a low MFV was associated with postrevascularization infarction (adjusted OR 109.2, 95% CI 1.9-6245.3). A low MFV was also statistically significantly associated with more advanced MMD stage (p = 0.02). CONCLUSIONS A low MFV in the ipsilateral MCA may predict postrevascularization infarction. Bypass surgery for MMD appears to be safe in early-stage MMD. Results of TCD ultrasonography provide clinical data on the hemodynamics in MMD patients before and after revascularization.

Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease.

BACKGROUND: Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear. METHODS: We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease. RESULTS: Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity. CONCLUSION: Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines.

A Polymorphism in RNF213 Is a Susceptibility Gene for Intracranial Atherosclerosis.

BACKGROUND: Both intracranial atherosclerotic stenosis (ICAS) and moyamoya disease (MMD) are prevalent in Asians. We hypothesized that the Ring Finger protein 213 gene polymorphism (RNF213), a susceptibility locus for MMD in East Asians, is also a susceptibility gene for ICAS in patients whose diagnosis had been confirmed by conventional angiography (absence of basal collaterals) and high-resolution MRI (HR-MRI, presence of plaque). METHODS: We analyzed 532 consecutive patients with ischemic events in the middle cerebral artery (MCA) distribution and relevant stenotic lesion on the distal internal carotid artery or proximal MCA, but no demonstrable carotid or cardiac embolism sources. Additional angiography was performed on 370 (69.5%) patients and HR-MRI on 283 (53.2%) patients. RESULTS: Based on angiographic and HR-MRI findings, 234 patients were diagnosed with ICAS and 288 with MMD. The RNF213 variant was observed in 50 (21.4%) ICAS patients and in 119 (69.1%) MMD patients. The variant was observed in 25.2% of patients with HR-MRI-confirmed ICAS. Similarly, 15.8% of ICAS patients in whom MMD was excluded by angiography had this variant. Among the ICAS patients, RNF213 variant carriers were younger and more likely to have a family history of MMD than non-carriers were. Multivariate testing showed that only the age of ICAS onset was independently associated with the RNF213 variant (odds ratio, 0.97; 95% CI, 0.944-0.99). CONCLUSIONS: RNF213 is a susceptibility gene not only for MMD but also for ICAS in East Asians. Further studies are needed on RNF213 variants in ICAS patients outside East Asian populations.

Recurrent Bleeding in Hemorrhagic Moyamoya Disease : Prognostic Implications of the Perfusion Status.

OBJECTIVE: Hemorrhagic moyamoya disease (hMMD) is associated with a poor clinical course. Furthermore, poorer clinical outcomes occur in cases of recurrent bleeding. However, the effect of hemodynamic insufficiency on rebleeding risk has not been investigated yet. This study evaluated the prognostic implications of the perfusion status during the clinical course of adult hMMD. METHODS: This retrospective study enrolled 52 adult hMMD patients between April 1995 and October 2010 from a single institute. Demographic data, clinical and radiologic characteristics, including hemodynamic status using single photon emission computed tomography (SPECT), and follow up data were obtained via a retrospective review of medical charts and imaging. Statistical analyses were performed to explore potential prognostic factors. RESULTS: Hemodynamic abnormality was identified in 44 (84.6%) patients. Subsequent revascularization surgery was performed in 22 (42.3%) patients. During a 58-month (median, range 3-160) follow-up assessment period, 17 showed subsequent stroke (hemorrhagic n=12, ischemic n=5, Actuarial stroke rate 5.8±1.4%/year). Recurrent hemorrhage was associated with decreased basal perfusion (HR 19.872; 95% CI=1.196-294.117) and omission of revascularization (10.218; 95%; CI=1.532-68.136). CONCLUSION: Decreased basal perfusion seems to be associated with recurrent bleeding. Revascularization might prevent recurrent stroke in hMMD by rectifying the perfusion abnormality. A larger-sized, controlled study is required to address this issue.

Surgical versus medical treatment for children with epileptic encephalopathy in infancy and early childhood: Results of an international multicenter cohort study in Far-East Asia (the FACE study).

OBJECTIVE: To compare the seizure and developmental outcomes in infants and young children with epileptic encephalopathy who have undergone surgical and medical treatments. METHODS: An international, multicenter, observational cohort study was undertaken. A total of 317 children aged <6 years, who had frequent disabling seizures despite intensive medical treatments, were registered. Among the enrolled children, 250 were treated medically (medical group), 31 underwent resective surgery (resective group), and 36 underwent palliative surgery [callosotomy (n=30) or vagal nerve stimulation (n=6); palliative group] on admission. Seizure and developmental outcomes were obtained for 230 children during the 3-year follow-up period. Cox proportional hazard model was used to adjust for clinical backgrounds among treatment groups when comparing the seizure-free survival rates. RESULTS: At the 3-year follow-up, seizure-free survival was 15.7%, 32.1%, and 52.4% in the medical, palliative, and resective groups, respectively. The adjusted hazard ratios for seizure recurrence in the resective and palliative groups versus the medical group were 0.43 (95% CI, 0.21-0.87, P=0.019) and 0.82 (95% CI, 0.46-1.46, P=0.50), respectively; the former was statistically significant. Regarding the developmental outcome, the mean DQs in the resective group increased significantly compared to those in the medical group during the follow-up (P<0.01). As for subgroup analysis, better seizure and development outcomes were demonstrated in the resective group compared to the medical group in children with nonsyndromic epilepsies (those to which no known epilepsy syndromes were applicable). SIGNIFICANCE: These results suggest that surgical treatments, particularly resective surgeries, are associated with better seizure and developmental outcomes compared with successive medical treatment. The present observations may facilitate the identification of infants and young children with epileptic encephalopathy who could benefit from surgery.

Feasibility and Efficacy of Olfactory Protection Using Gelfoam and Fibrin Glue during Anterior Communicating Artery Aneurysm Surgery.

OBJECTIVE: Patients treated with surgical clipping for anterior communicating artery (A-com) aneurysm often complain of anosmia, which can markedly impede their quality of life. We introduce a simple and useful technique to reduce postoperative olfactory dysfunction in A-com aneurysm surgery. METHODS: We retrospectively reviewed the medical records of patients who underwent surgical clipping for unruptured aneurysm from 2011-2013 by the same senior attending physician. Since March 2012, olfactory protection using gelfoam and fibrin glue was applied in A-com aneurysm surgery. Therefore we categorized patients in two groups from this time-protected group and unprotected group. RESULTS: Of the 63 enrolled patients, 16 patients showed postoperative olfactory dysfunction-including 8 anosmia patients (protected group : unprotected group=1 : 7) and 8 hyposmia patients (protected group : unprotected group=2 : 6). Thirty five patients who received olfactory protection during surgery showed a lower rate of anosmia (p=0.037, OR 10.516, 95% CI 1.159-95.449) and olfactory dysfunction (p=0.003, OR 8.693, 95% CI 2.138-35.356). Superior direction of the aneurysm was also associated with a risk of olfactory dysfunction (p=0.015, OR 5.535, 95% CI 1.390-22.039). CONCLUSION: Superior direction of aneurysm appears associated with postoperative olfactory dysfunction. Olfactory protection using gelfoam and fibrin glue could be a simple, safe, and useful method to preserve olfactory function during A-com aneurysm surgery.