Jun Haruma

Mannitol enhances therapeutic effects of intra-arterial transplantation of mesenchymal stem cells into the brain after traumatic brain injury

Traumatic brain injury (TBI) sustained in a traffic accident or a fall is a major cause of death that affects a broad range of ages. The aim of this study was to investigate the therapeutic effects of intra-arterial transplantation of mesenchymal stem cells (MSCs) combined with hypertonic glycerol (25%) or mannitol (25%) in a TBI model of rats. TBI models were produced with a fluid percussion device. At 24h after TBI, MSCs (1×10(6)cells/100μl) with glycerol or mannitol were administered via the right internal carotid artery. Rats were evaluated behaviorally and immunohistochemically, and hyperpermeability of the blood-brain barrier (BBB) induced by hypertonic solutions was explored. Compared to PBS or glycerol, the administration of mannitol resulted in increased BBB disruption. The mannitol-treated rats showed significant improvement in motor function. Intra-arterial transplantation of MSCs caused no thromboembolic ischemia. Immunohistochemically, more MSCs were observed in the injured brain tissues of mannitol-treated rats than in glycerol or PBS-treated rats at 24h after transplantation. Intra-arterial transplantation of MSCs combined with mannitol is an effective treatment in a TBI model of rats. This technique might be used for patients with diseases of the central nervous system including TBI.

Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats

Although delayed cerebral vasospasm (DCV) following subarachnoid hemorrhage (SAH) is closely related to the progression of brain damage, little is known about the molecular mechanism underlying its development. High mobility group box-1 (HMGB1) plays an important role as an initial inflammatory mediator in SAH. In this study, an SAH rat model was employed to evaluate the effects of anti-HMGB1 monoclonal antibody (mAb) on DCV after SAH. A vasoconstriction of the basilar artery (BA) associated with a reduction of nuclear HMGB1 and its translocation in vascular smooth muscle cells were observed in SAH rats, and anti-HMGB1 mAb administration significantly suppressed these effects. Up-regulations of inflammation-related molecules and vasoconstriction-mediating receptors in the BA of SAH rats were inhibited by anti-HMGB1 mAb treatment. Anti-HMGB1 mAb attenuated the enhanced vasocontractile response to thrombin of the isolated BA from SAH rats and prevented activation of cerebrocortical microglia. Moreover, locomotor activity and weight loss recovery were also enhanced by anti-HMGB1 mAb administration. The vasocontractile response of the BA under SAH may be induced by events that are downstream of responses to HMGB1-induced inflammation and inhibited by anti-HMGB1 mAb. Anti-HMGB1 mAb treatment may provide a novel therapeutic strategy for DCV and early brain injury after SAH.

Epidemiology of Dural Arteriovenous Fistula in Japan: Analysis of Japanese Registry of Neuroendovascular Therapy (JR-NET2)

We developed the Japanese Registry of Neuroendovascular Therapy 2 (JR-NET2) database and used the information for a retrospective, nation-wide multicenter, observational study to clarify the clinical characteristics, current status of procedures, and outcome of patients treated by neuroendovascular therapy in Japan. In this report, we analyzed the clinical characteristics of dural arteriovenous fistulas (dAVFs) in the JR-NET2 database. All patients with dAVFs treated with endovascular therapy in 150 Japanese hospitals were included. Patient characteristics, clinical presentations, and imaging characteristics were analyzed. A total of 1,075 patients with dAVFs underwent 1,520 endovascular procedures. Of 1,075 patients, 45% were men and 55% were women. The mean age was 65 ± 13 years. The most frequent location of dAVFs was the cavernous sinus (43.6%), followed by the transverse-sigmoid sinus (TSS) (33.4%). Twelve percent of the patients had intracranial hemorrhage, 9% had venous infarction, and 3% had convulsion. The statistically significant independent risk factors of intracranial hemorrhage were TSS, superior sagittal sinus (SSS), tentorium, anterior cranial fossa, cranio-cervical junction, cortical venous reflux (CVR), and varix. Risk factors of venous infarction were age older than 60 years, male sex, TSS, SSS, and CVR. Risk factors of convulsion were male sex, SSS, and CVR. This is the largest nationwide report, to date, of the clinical characteristics of dAVFs treated by neuroendovascular therapy. CVR was a major risk factor of aggressive symptoms.

Cerebral vasospasm in patients over 80 years treated by coil embolization for ruptured cerebral aneurysms.

Object. The effect on clinical outcomes of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in patients over 80 years who underwent coil embolization was evaluated. Methods. Forty-four cases were reviewed and divided into two groups according to patient age: Group A, 79 years or younger, and Group B, 80 or older. Patient characteristics, prevalence of symptomatic vasospasm, modified Rankin Scale (mRS) scores at discharge and frequency of symptomatic vasospasm in patients with mRS scores of 3–6 were analyzed. Results. Thirty-two (73%) of the 44 cases were categorized as Group A and 12 (27%) as Group B. Group B had a significantly higher prevalence of symptomatic vasospasm compared to Group A (P = 0.0040). mRS scores at discharge were significantly higher in Group B than in Group A (P = 0.0494). Among cases with mRS scores of 3–6, there was a significantly higher frequency of symptomatic vasospasm in Group B than in Group A (P = 0.0223). Conclusions. In our cohort of aneurysmal SAH patients treated by coil embolization, patients over 80 years of age were more likely to suffer symptomatic vasospasm, which significantly correlated with worse clinical outcomes, than those 79 years and under.

NADH fluorescence imaging and the histological impact of cortical spreading depolarization during the acute phase of subarachnoid hemorrhage in rats

OBJECTIVE Although cortical spreading depolarization (CSD) has been observed during the early phase of subarachnoid hemorrhage (SAH) in clinical settings, the pathogenicity of CSD is unclear. The aim of this study is to elucidate the effects of loss of membrane potential on neuronal damage during the acute phase of SAH. METHODS Twenty-four rats were subjected to SAH by the perforation method. The propagation of depolarization in the brain cortex was examined by using electrodes to monitor 2 direct-current (DC) potentials and obtaining NADH (reduced nicotinamide adenine dinucleotide) fluorescence images while exposing the parietal-temporal cortex to ultraviolet light. Cerebral blood flow (CBF) was monitored in the vicinity of the lateral electrode. Twenty-four hours after onset of SAH, histological damage was evaluated at the DC potential recording sites. RESULTS Changes in DC potentials (n = 48 in total) were sorted into 3 types according to the appearance of ischemic depolarization in the entire hemisphere following induction of SAH. In Type 1 changes (n = 21), ischemic depolarization was not observed during a 1-hour observation period. In Type 2 changes (n = 13), the DC potential demonstrated ischemic depolarization on initiation of SAH and recovered 80% from the maximal DC deflection during a 1-hour observation period (33.3 ± 15.8 minutes). In Type 3 changes (n = 14), the DC potential displayed ischemic depolarization and did not recover during a 1-hour observation period. Histological evaluations at DC potential recording sites showed intact tissue at all sites in the Type 1 group, whereas in the Type 2 and Type 3 groups neuronal damage of varying severity was observed depending on the duration of ischemic depolarization. The duration of depolarization that causes injury to 50% of neurons (P50) was estimated to be 22.4 minutes (95% confidence intervals 17.0-30.3 minutes). CSD was observed in 3 rats at 6 sites in the Type 1 group 5.1 ± 2.2 minutes after initiation of SAH. On NADH fluorescence images CSD was initially observed in the anterior cortex; it propagated through the entire hemisphere in the direction of the occipital cortex at a rate of 3 mm/minute, with repolarization in 2.3 ± 1.2 minutes. DC potential recording sites that had undergone CSD were found to have intact tissue 24 hours later. Compared with depolarization that caused 50% neuronal damage, the duration of CSD was too short to cause histological damage. CONCLUSIONS CSD was successfully visualized using NADH fluorescence. It propagated from the anterior to the posterior cortex along with an increase in CBF. The duration of depolarization in CSD (2.3 ± 1.2 minutes) was far shorter than that causing 50% neuronal damage (22.4 minutes) and was not associated with histological damage in the current experimental setting.

A Case of Traumatic Vertebral Arteriovenous Fistula Treated by Internal Trapping of the Vertebral Artery

BACKGROUND Traumatic vertebral arteriovenous fistula (TVAVF) is an uncommon disease that occurs after traumatic injury. Here we report a case of TVAVF presenting with cervical bruit successfully treated by internal trapping using coils. CASE PRESENTATION A 66-year-old man was transferred to our hospital after falling into a ditch. Initial CT revealed a C2 fracture into the right transverse foramen, and the patient had been treated with conservative management. A vascular abnormality was suspected because the patient exhibited cervical bruit on admission. CT angiography revealed right TVAVF at the V2 segment of the right vertebral artery (VA) near the C2 fracture. Digital subtraction angiography also revealed right TVAVF between the V2 segment of the right VA and the vertebral venous plexus, draining into the right internal jugular vein and the deep cervical vein as well as the intracranial venous system. The fistula was also opacified by retrograde flow from the contralateral VA through the union, while the flow in the basilar artery was antegrade. The patient was diagnosed with TVAVF with large transection of the right VA, and underwent endovascular treatment with internal trapping of the right VA using coils starting distal to the transection and proceeding in a proximal direction. After treatment, the right VAVF and right VA were completely occluded. The patient achieved clinical symptom resolution with no neurological deficits. CONCLUSION Endovascular treatment with internal trapping of the VA using coils is safe and effective against TVAVF.

[Stent-Assisted Coil Embolization of a Dissecting Aneurysm of the Posterior Cerebral Artery: A Case Report].

Dissecting aneurysms of the posterior cerebral artery (PCA) are rare, especially those at the P1 segment. Here, we describe the case of a 57-year-old woman with a subarachnoid hemorrhage (SAH). Computed tomography angiography (CTA) and digital subtraction angiography (DSA) revealed a small (3 mm) dissecting aneurysm with the typical pearl-and-string sign at the right P1 segment. Fourteen days after onset, the patient developed aphasia. DSA revealed vasospasm of the right middle cerebral artery, and we performed endovascular treatment by the intra-arterial injection of 1-(5-isoquinolinesulfonyl) homopiperazine. After this treatment, the patients symptoms recovered immediately. Vertebral angiography revealed enlargement of the dissecting aneurysm (up to 7 mm diameter). We started a loading dose of 300 mg aspirin and 400 mg clopidogrel after observing growth of the aneurysm. Fifteen days after onset, we performed a stent-assisted coil embolization, and obtained nearly complete obliteration of the aneurysm with preserved patency of the parent artery. Six-month follow-up DSA demonstrated complete occlusion of the aneurysm with good patency of the stented PCA; the patient was at modified Rankin Scale 1. In the treatment of ruptured dissecting aneurysms, parent vessel occlusion (PVO) with aneurysm is common. However, PVO may cause both cerebral infarction of the distal area and perforator occlusion of the occluded vessel. Stent-assisted coil embolization can preserve parent vessel flow and obliterate the aneurysm. Stents offer a therapeutic alternative for PCA dissecting aneurysms, especially when PVO cannot be tolerated.