Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.

Middle meningeal artery embolization for chronic subdural hematoma: a systematic review.

Background: Chronic subdural hematoma (cSDH) is one of the most common diseases in neurosurgery. Middle meningeal artery embolization (MMAE) is reportedly an option to prevent recurrence or avoid surgery in patients with cSDH. This study was performed to review the evidence on MMAE for cSDH and evaluate its safety, efficacy, indications, and feasibility. Methods: We systematically reviewed the literature according to the PRISMA guidelines using an electronic database. The search yielded 43 articles involving 2,783 patients who underwent MMAE. Results: The hematoma resolution, recurrence, and retreatment rates in the MMAE-alone treatment group (n = 815) were 86.7%, 6.3%, and 9.6%, respectively, whereas those in the prophylactic MMAE with combined surgery group (n = 370) were 95.6%, 4.4%, and 3.4%, respectively. The overall MMAE-related complication rate was 2.3%. Conclusion: This study shows that MMAE alone is, although not immediate, as effective as evacuation surgery alone in reducing hematoma. The study also shows that combined treatment has a lower recurrence rate than evacuation surgery alone. Because MMAE is a safe procedure, it should be considered for patients with cSDH, especially those with a high risk of recurrence.

Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease.

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype-phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

Application of protective superficial temporal artery to middle cerebral artery bypass through the lateral supraorbital approach: Technical note.

OBJECTIVE: The lateral supraorbital (LSO) approach is a minimally invasive craniotomy widely used in the surgical treatment of intracranial aneurysms (IAs). A protective bypass is considered a safety measure in high-risk and complex clipping procedures to maintain distal cerebral flow. However, the protective bypass has so far only been applied through a pterional or larger craniotomy. We aimed to describe the characteristics of the superficial temporal artery to middle cerebral artery (STA-MCA) bypass through the LSO craniotomy to treat complex IAs. METHODS: We retrospectively identified six patients with complex IAs who underwent clipping and a protective STA-MCA bypass through the LSO approach between January 2016 and December 2020. The STA donor artery was harvested through the same curvilinear skin incision with a small extension, and it was anastomosed to the opercular segment of the MCA. Subsequently, aneurysm clipping followed standardized steps. RESULTS: Anastomosis was successful in all patients. Despite requiring temporary occlusion of the parent artery, all aneurysms were successfully clipped without any neurological deterioration. CONCLUSIONS: A protective STA-MCA bypass is feasible through the LSO approach with certain technical modifications. This technique helps protect distal cerebral flow for safe clip placement in the treatment of complex IAs with the associated benefits of a less invasive craniotomy.

Predictive factors for improvement of symptomatic cerebral vasospasm following subarachnoid hemorrhage by selective intra-arterial administration of fasudil hydrochloride.

BACKGROUND: Symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH) is a significant cause of delayed cerebral ischemia that leads to poor outcomes. Selective intra-arterial administration of fasudil hydrochloride (IAF) has been adopted for its vasodilatory effect on spasm arteries to prevent delayed cerebral ischemia. However, its effect on clinical outcomes and predictive factors for good recovery are not fully understood. This study aimed to investigate the outcomes of selective IAF and identify predictive factors for good outcomes in patients with cerebral vasospasm after SAH. METHODS: A retrospective study of 36 patients with cerebral vasospasm following SAH who underwent selective IAF at our institution between January 2014 and May 2022 was conducted. We evaluated the improvements in neurological findings before and after selective IAF. Statistical analyses were performed to determine factors associated with good outcomes. RESULTS: Selective IAF improved the neurological findings in 26 patients (72.2%). Pre-therapeutic absence of cerebral infarction in more than 1/3 of the spasm artery perfusion area was significantly associated with an improvement in neurological findings (p < 0.0001). Furthermore, there was a tendency for a good outcome when the age was younger (p = 0.093), and the spasm was limited to peripheral vessels (p = 0.065). CONCLUSION: Our study indicates that selective IAF has a promising effect in improving symptomatic vasospasm, except when a large cerebral infarction exists in the spasm artery perfusion area. Early consideration of selective IAF could be recommended once patients experience symptomatic cerebral vasospasm after SAH.

Coagulation Technique for Remodeling Anastomosis Spaces in Bypass Surgery.

Cerebrovascular bypass techniques are the current cornerstone methods to achieve cerebral revascularization for moyamoya disease or syndrome and select cases of vascular pathologies, such as intracranial atherosclerotic occlusive disease and complex aneurysms. Factors influencing bypass efficiency include graft patency, short temporary occlusion time, and precise anastomosis. On the basis of our senior author's vast experience with 1300 bypasses, we recommend performing the anastomosis with the minimal number of stitches as achievable to avoid stenosis of the artery's internal lumen that may occur with unnecessary, additional stitches, preserving patency. After completing the anastomosis, when a leak occurs between the sutures, cottonoid tamponade, hemostatic materials, or adding 1 or 2 sutures to the space is often enough to close the gap. However, additional suture placement can be difficult, which might cause stenosis of the anastomosis and reduce blood flow. In this video, we introduce a bipolar coagulation technique for remodeling the anastomosis orifices, as an alternative manner, when minor leakages occur between the knots (Video 1). We demonstrate this technique in an adult moyamoya disease patient who underwent a superficial temporal artery-to-middle cerebral artery bypass, in this case coagulation of the donor artery wall at the anastomosis made possible to adapt the edges of the donor artery precisely to the recipient artery wall by shrinking its redundancy between the stitches. The most important task is to coagulate the donor side orifice precisely with low-power bipolar coagulation and never coagulate the recipient artery. This coagulation technique is a simple alternative to stop further leakage, and it prevents placing an additional suture and reduces temporary occlusion time.

Horizontal stent deployment via extracranial-intracranial bypass in coil embolization of basilar apex aneurysms: technical report.

BACKGROUND: The endovascular treatment of large, wide-necked basilar apex aneurysms (BAAs) remains challenging. Although horizontal stent deployment across both P1 segments of the posterior cerebral arteries (PCAs) would be an optimal strategy in coil embolization of wide-necked BAAs, this is only feasible in cases with anatomically favorable access. In rare circumstances, large-diameter conduits of extracranial-intracranial (EC-IC) bypass can also provide a good access route for endovascular treatment of complex intracranial aneurysms. METHODS: We describe the technique of accessing the PCA via EC-IC bypass grafts and deploying a stent horizontally across the neck of BAA and its coil embolization. We provide a detailed technical review and describe some pitfalls of the procedure. RESULTS: Two patients underwent EC-IC bypass surgery prior to the treatment of a large, wide-necked BAA. The radial artery and saphenous vein were used as grafts, respectively. To facilitate coil embolization for a large BAA, a PCA-to-PCA horizontal stent was deployed via the bypass graft. Trans-cell and jailing techniques were used, respectively. Both aneurysms were completely occluded, and the patients were discharged without any neurological deficit. CONCLUSION: Horizontal stent deployment via EC-IC bypass grafts can be performed safely, providing proper closure of the aneurysmal neck and apposition to both PCAs, facilitating complete coil embolization.

Five-Day Bed Rest Reduces Postoperative Intracerebral Hemorrhage After Direct Bypass for Moyamoya Disease.

OBJECTIVE: Postoperative intracerebral hemorrhage (ICH) after direct bypass surgery for Moyamoya disease could contribute to neurologic deterioration. The aim of this study was to evaluate the effectiveness of 5-day bed rest in reducing the occurrence of postoperative ICH. METHODS: This study included 122 consecutive hemispheres in 87 Japanese adult MMD patients, composed of 80 control hemispheres from historical data and 42 hemispheres after 5-day bed rest. They all underwent direct bypass surgery. The incidence of postoperative ICH and neurologic deterioration assessed via the modified Rankin Scale were investigated and statistically analyzed. RESULTS: Postoperative ICH was observed in 9 out of the 80 (11.3%) control patients, but not in the 42 patients with 5-day bed rest. The incidence of postoperative ICH and neurologic deterioration via the modified Rankin Scale were significantly different between the 2 groups (P = 0.0268 and 0.0078, respectively). Univariate logistic analysis revealed that 5-day bed rest significantly reduced the incidence of postoperative ICH (P = 0.0048). CONCLUSIONS: Five-day bed rest after direct bypass surgery dramatically can reduce the incidence of postoperative ICH and neurologic deterioration after direct bypass surgery.

Outcome of Endovascular Therapy Aiming for Single-session Obliteration of Intracranial Dural Arteriovenous Fistulas.

The goal of dural arteriovenous fistula (dAVF) treatment is obliteration of the arteriovenous shunt and/or retrograde leptomeningeal venous drainage (RLVD). Single-session obliteration could improve symptoms early and reduce risk of neurological sequelae. This study investigated the efficacy and adverse events of endovascular therapy (EVT) aiming for single-session obliteration in dAVF treatment. We retrospectively examined post-treatment arteriovenous shunt status, number of treatments per case, treatment-related complications, and long-term outcome in 92 dAVF patients who underwent initial EVT at our institution. Single-session obliteration was intended in all cases, but a second session was performed in cases of partial shunt occlusion or remaining RLVD. Complete occlusion was achieved in 85 cases (92.4%) after the single session; RLVD was obliterated in 66 of the 67 Borden type II and III cases combined (98.5%). A second session was necessary in seven cases (7.6%). Complete shunt obliteration was eventually achieved in all cases. The average number of treatments was 1.08 per case. dAVF-related stroke and mortality did not occur after the treatment. On the other hand, radiation-induced skin erythema and alopecia, although all symptoms were transient, occurred in 26 cases (28.3%). Over an average 60.2-month follow-up period, recurrence was observed in seven cases (7.6%). Single-session obliteration was successful in 92% of cases. Especially, single-session obliteration of RLVD may contribute to early prevent of future stroke events. However, reducing total radiation dose during each session is an issue of further study.

High-flow bypass using saphenous vein grafts with trapping of ruptured blood blister-like aneurysms of the internal carotid artery: patient series.

BACKGROUND: Trapping an aneurysm after the establishment of an extracranial to intracranial high-flow bypass is considered the optimal surgical strategy for ruptured blood blister-like aneurysms (BBAs) of the internal carotid artery (ICA). For high-flow bypass surgeries, a radial artery graft is generally preferred over a saphenous vein graft (SVG). However, SVGs can be advantageous in acute-phase surgeries because of their greater length, easy manipulability, ability to act as high-flow conduits, and reduced risk of vasospasms. In this study, the authors presented five cases of ruptured BBAs treated with high-flow bypass using an SVG followed by BBA trapping, and they reported on surgical outcomes and operative nuances that may help avoid potential pitfalls. OBSERVATIONS: After the surgeries, there were no ischemic or hemorrhagic complications, including symptomatic vasospasms. In three of the five cases, postoperative modified Rankin scale scores were between 0 and 2 at the 3-month follow-up. In one case, the SVG spontaneously occluded after surgery while the protective superficial temporal artery (STA) to middle cerebral artery (MCA) bypass became dominant, and the patient experienced no ischemic symptoms. LESSONS: High-flow bypass using an SVG with a protective STA-MCA bypass followed by BBA trapping is a safe and effective treatment strategy.

Pre-Therapeutic Factors Predicting for the Necessity of Rescue Treatments in Mechanical Thrombectomy.

Objective: Mechanical thrombectomy for acute large vessel occlusion (LVO) is currently widely performed. However, rescue treatment (RT), such as percutaneous transluminal angioplasty (PTA) and stenting, is occasionally required, particularly in the case of atherothrombotic brain infarction (ATBI) or dissection. As RT requires higher levels of therapeutic skills and additional devices, early prediction of its performance and preparation are important. We retrospectively investigated the pre-therapeutic factors for predicting the necessity of RT. Methods: We reviewed 149 consecutive patients who underwent mechanical thrombectomy for acute LVO between April 2014 and December 2019. Eight patients were excluded because of missing clinical data. RT was performed when severe stenosis was observed in occluded vessels or proximal to them during mechanical thrombectomy. We investigated pre-therapeutic neurological, laboratory, and radiological findings in the 141 remaining patients, and compared them between RT and non-RT groups. Results: RT was performed on 23 of the 141 patients. We found four pre-therapeutic factors with significantly different rates between RT/non-RT as follows: (1) Atrial fibrillation 8.7%/71.1% (p <0.001), (2) diabetes mellitus 39.1%/19.5% (p = 0.04), (3) susceptibility vessel sign (SVS) by T2-weighted imaging 17.4%/66.1% (p <0.001), and (4) tapered occlusion by magnetic resonance angiography (MRA) 47.8%/11.9% (p <0.001). The plasma level of brain natriuretic peptide (BNP) was also significantly different between the two groups. When the BNP level was less than 70 pg/mL, the sensitivity for being in the RT group was 86.9% and the specificity was 83.5%. Conclusion: Pre-therapeutic findings, such as diabetes mellitus, tapered occlusion, absence of atrial fibrillation, negative SVS, and BNP level less than 70 pg/mL, are predictors of RT in mechanical thrombectomy.

[Advantages and Pitfalls of the Lateral Supraorbital Approach as Less Invasive Surgery for Unruptured Anterior Circulation Aneurysms].

The lateral supraorbital approach(LSOA)is widely accepted as a less invasive surgical technique compared with the conventional pterional approach(PA). However, only a few studies have reported less invasiveness associated with LSOA. To evaluate this issue, we retrospectively investigated the surgical outcomes in 133 patients who underwent LSOA and 28 patients who underwent PA for unruptured anterior circulation aneurysms. We analyzed operation time, postoperative symptoms and complications, and the length of postoperative hospitalization(in days)for each method. All aneurysms were successfully clipped regardless of the approach. The operation time was significantly shorter, the postoperative headache rate was lower, resumption of oral intake was more rapid, and length of hospitalization was shorter in the LSOA group. Statistical significance was not observed in the postoperative complication rates. Compared with conventional PA, LSOA was associated with less invasiveness and better patient satisfaction. LSOA is a safe and effective alternative to conventional PA, following optimal patient selection.

Spontaneous Persistent Primitive Trigeminal Artery-Cavernous Sinus Fistula Successfully Treated by Multipronged Coil Embolization: Case Report and Literature Review.

BACKGROUND: A spontaneous persistent primitive trigeminal artery-cavernous sinus fistula (PCF) is extremely rare. Until recently, endovascular treatment for PCF involving transarterial and/or transvenous coil embolization of the cavernous sinus (with/without the persistent trigeminal artery) was commonly performed. However, it may result in remaining shunt flow or exacerbation of cranial nerve palsy. CASE DESCRIPTION: A 51-year-old woman presented with headache and left abducens palsy. Digital subtraction angiography demonstrated a direct fistula between the cavernous segment of the persistent primitive trigeminal artery (PPTA) and posterosuperior compartment of the left cavernous sinus (CS). Three microcatheters were guided into the fistula as follows: 1) through the PPTA to the CS from the left internal carotid artery, 2) through the PPTA to the CS from the basilar artery, and 3) through the CS to the PPTA from the internal jugular vein. Using the double-catheter technique in a multidirectional fashion, shunt occlusion was achieved with a small number of coils. No signs of recurrence were observed during the follow-up period. CONCLUSIONS: The multipronged approach is safe and effective for embolization of a small tortuous artery and shunt segment to avoid incomplete shunt occlusion.

Correction to: Efficacy of superficial temporal artery-middle cerebral artery double bypass in patients with hemorrhagic moyamoya disease: surgical effects for operated hemispheric sides.

Table 2 of the original version of this article contained an added data. Correct Table 2 is presented here.

Efficacy of superficial temporal artery-middle cerebral artery double bypass in patients with hemorrhagic moyamoya disease: surgical effects for operated hemispheric sides.

The effects of superficial temporal artery to middle cerebral artery (STA-MCA) double bypass on recurrent hemorrhage in the operated hemisphere in hemorrhagic moyamoya disease (HMD) have not been clearly demonstrated. This study evaluated the effectiveness of STA-MCA double bypass in the prevention of further hemorrhagic or ischemic events in the operated hemispheric sides in comparison to the conservatively treated non-operated sides. We retrospectively analyzed 52 hemispheres of 36 patients with adult-onset HMD treated with STA-MCA double bypass. Twenty and 16 patients underwent unilateral (unilateral group) and bilateral (bilateral group) surgery, respectively. In addition, the perioperative and long-term outcomes of the 52 operated sides and 20 non-operated sides in the unilateral group were compared. All bypass surgeries were successful, but 21% of the operated sides showed hyperperfusion as estimated by our methods. Perioperative mortality and morbidity rate were 0% and 5.6%, respectively. Concerning long-term follow-up, the annual rebleeding rate (ARR) in the unilateral and bilateral group was 2.7% and 2.6%/person-year, respectively (p = 0.256). The ARR in the operated and non-operated sides was 1.1% and 1.8%/side-year, respectively (p = 0.163). Two of 20 non-operated sides suffered from ischemic infarction during the follow-up period, while none of the 52 operated sides experienced ischemic events (p < 0.05). Although the long-term rebleeding rate in the operated hemisphere tended to be lower after STA-MCA double bypass compared with that in the non-operated hemisphere, the difference was not statistically significant. In conclusion, while STA-MCA double bypass could not clearly prevent rebleeding, it can prevent further ischemic attacks in patients with HMD.

Neurosurgical Management and Outcomes of Cerebrovascular Disease in Pediatric Patients with Heart Disease.

Antithrombotic treatment has substantial risks, even in pediatric patients. We retrospectively evaluated the management and outcomes of consecutive pediatric patients who underwent neurosurgical treatment for cerebrovascular disease with cardiovascular disease between 1998 and 2017. Patients were divided into patients with comorbid cardiovascular disease (group I); and patients with cardiovascular disease as a primary disease of intracranial complication, without (group IIa) or with (group IIb) extracorporeal circulations. Postoperative resumption of antithrombotic agents was generally initiated within 48 h. Our study included 26 patients; five were categorized as group I, 15 as group IIa, and six as group IIb. All intracranial diseases in groups IIa and IIb were exclusively hemorrhagic. Preoperative anticoagulation therapy was used in one patient (20%) in group I, 13 patients (86.7%) in group IIa, and six patients (100%) in group IIb. Postoperative intracranial hemorrhagic events were observed in one patient (20%) in group I, three patients (20%) in group IIa, and four patients (66.7%) in group IIb. Re-operations were conducted in two (13.3%) and three patients (50%) in groups IIa and IIb, respectively. Death occurred in five (33.3%) and four patients (66.7%) in groups IIa and IIb, respectively. The remaining two patients in group IIb returned to candidate status for implantation. Emergent surgery for patients with intracranial hemorrhage associated with cardiovascular disease has a high risk of postoperative hemorrhagic events and high rate of re-operations with poor vital outcomes, especially in patients with extracorporeal circulations. We should consider maximum neurosurgical treatment achievable with optimal management of antithrombotic treatment.

Transient Focal Magnetic Resonance Imaging Abnormalities After Status Epilepticus Showed 11C-Methionine Uptake with Positron Emission Tomography in a Patient with Cerebral Cavernous Malformation.

BACKGROUND: Transient focal magnetic resonance imaging (MRI) abnormalities after status epilepticus (SE) are rarely seen in patients with benign brain tumors, and the underlying mechanism is still unknown. We report a rare case of cerebral cavernous malformation with transient focal MRI abnormalities around the tumor and accumulation of 11C-methionine on positron emission tomography (PET) after SE. These findings mimicked those of a glioma because the MRI and methionine PET findings were similar. We also speculate about the cause of this phenomenon in relation to pathologic findings of this case. CASE DESCRIPTION: A 51-year-old man suffered from SE. MRI demonstrated a focal T2/fluid-attenuated inversion recovery hyperintense area. 11C-methionine PET showed high accumulation of methionine in the same lesion. The initial diagnosis was low-grade glioma. However, these MRI abnormalities were transient and completely resolved. The patient underwent surgical removal of the tumor, and the histologic diagnosis was typical cavernous malformation. Pathologic findings of the gyrus around the tumor revealed mild gliosis with proliferating astrocytes but no evidence of glioma. CONCLUSIONS: This case suggests that transient focal MRI abnormalities after SE may indicate reversible cortical brain edema. Accumulation of 11C-methionine on PET could occur in the corresponding lesion even if no malignant tumor is present. Because distinguishing transient MRI abnormalities after SE from a glioma is difficult, repeated imaging studies should be performed in patients with brain tumor-related seizures.

[The development of care farming for elderly people with cognitive impairment to enhance social inclusion: A feasibility study of rice-farming care for elderly people with cognitive impairment].

AIM: The aim of this study was to assess the feasibility of rice-farming care among elderly people with cognitive impairment as a tool for social inclusion. METHODS: Eight elderly individuals with cognitive impairment (7 men, 1 woman, mean age 68.3 years old) participated in the program over 25 weeks. The cognitive function, well-being, and depression were assessed before and after the program period. The degree of participants' independence during the program was also assessed. Semi-structured interviews with the participants and caregivers were held after the program period. RESULTS: The average participation rate was 93.0%. There were no unexpected events, and the subjects carried out farmwork almost independently. Regarding their well-being, two participants who scored below the cut-off criterion of mental health before the study scored above the cut-off after the study. Regarding depression, two participants who scored positive with a two-question case-finding instrument no longer scored positive after the study. Interviews with the participants showed that they enjoyed the program, especially because they had peers, a role, and gained positive emotions. Interviews with the caregivers showed that they had recognized for the first time what people can do with their skills. CONCLUSION: The results of the present study indicate that rice-farming was a feasible method of care with a positive impact on the well-being and depression of elderly people with cognitive impairment and enhanced their social participation, drawing out their individual strengths.