Combined Strategy of Burr Hole Surgery and Elective Craniotomy under Intracranial Pressure Monitoring for Severe Acute Subdural Hematoma.

Burr hole surgery in the emergency room can be lifesaving for patients with acute subdural hematoma (ASDH). In the first part of this study, a strategy of combined burr hole surgery, a period of intracranial pressure (ICP) monitoring, and then craniotomy was examined for safe and effective treatment of ASDH. Since 2012, 16 patients with severe ASDH with indications for burr hole surgery were admitted to Kenwakai Otemachi Hospital. From 2012 to 2016, craniotomy was performed immediately after burr hole surgery (emergency [EM] group, n = 10). From 2017, an ICP sensor was placed before burr hole surgery. After a period for correction of traumatic coagulopathy, craniotomy was performed when ICP increased (elective [EL] group, n = 6). Patient background, bleeding tendency, intraoperative blood transfusion, and outcomes were compared between the groups. In the second part of the study, ICP was measured before and after burr hole surgery in seven patients (including two of the six in the EL group) to assess the effect of this surgery. Activated partial thromboplastin time (APTT) and prothrombin time-international normalized ratio (PT-INR) were significantly prolonged after craniotomy in the EM group, but not in the EL group, and the EM group tended to require a higher intraoperative transfusion volume. The rate of good outcomes was significantly higher in the EL group, and ICP was significantly decreased after burr hole surgery. These results suggest the value of burr hole surgery followed by ICP monitoring in patients with severe ASDH. Craniotomy can be performed safely using this method, and this may contribute to improved outcomes.

Hounsfield Unit Value of Interpeduncular Cistern Hematomas Can Predict Symptomatic Vasospasm.

Background and Purpose- Symptomatic vasospasm is an important factor that affects the outcomes of aneurysmal subarachnoid hemorrhage. Subarachnoid blood volume can predict symptomatic vasospasm, and we postulated that the blood clot density would also be an important factor involved in such events. The present study aimed to determine the relationship between the incidence of symptomatic vasospasm and the Hounsfield unit (HU) value of the interpeduncular cistern that reflects the density of hematomas. Methods- Data from 323 patients admitted and treated at a single center between 2008 and 2017 within 24 hours of subarachnoid hemorrhage onset were retrospectively analyzed. Initial HU values of the interpeduncular cistern were measured using CT, then correlations with the incidence of symptomatic vasospasm and HU values as well as other variables were assessed. Results- Symptomatic vasospasm developed in 54 (16.7%) of the 323 patients. The incidence of symptomatic vasospasm was low (1.8%, 2/166) for HU <50, but this incidence increased greatly when the HU value exceeded 50 (23.7%, 22/93 for HU >50 to ≤60, and 45.3%, 29/64 for HU >60). The odds ratio for symptomatic vasospasm was 2.0 (95% CI, 1.6-2.4) per 5 HU increase. Symptomatic vasospasm correlated significantly with intraventricular hemorrhage (P=0.05) and with intracerebral hematoma (P=0.046) but even more significantly with the HU value of the interpeduncular cistern (P<0.0001). Conclusions- The HU value of the interpeduncular cistern on initial CT is an accurate and reliable predictor of symptomatic vasospasm.

Cilostazol decreases duration of spreading depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Traditionally, angiographic vasospasm (aVS) has been thought to cause delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, successful treatment of aVS alone does not result in improved neurological outcome. Therefore, there may be other potential causes of poor neurological outcome, including spreading depolarization (SD). A recent study showed beneficial effects of cilostazol on DCI and neurological outcome. The present prospective clinical trial and experimental study focused on effects of cilostazol on SDs. METHODS: Fifty aSAH patients were treated with clip ligation and randomly assigned to a cilostazol (n = 23) or control group (n = 27). Effects of cilostazol on DCI, aVS, and SDs, measured with subdural electrodes, were examined. The effect of cilostazol on SD-induced perfusion deficits (spreading ischemia) was assessed in an aSAH-mimicking model. RESULTS: There was a trend for less DCI in the cilostazol group, but it did not reach our threshold for statistical significance (13.0% vs 40.0%, odds ratio = 0.266, 95% confidence interval [CI] = 0.059-1.192, p = 0.084). However, the total SD-induced depression duration per recording day (22.2 vs 30.2 minutes, ß = -251.905, 95% CI = -488.458 to -15.356, p = 0.043) and the occurrence of isoelectric SDs (0 vs 4 patients, ß = -0.916, 95% CI = -1.746 to -0.085, p = 0.037) were significantly lower in the cilostazol group. In rats, cilostazol significantly shortened SD-induced spreading ischemia compared to vehicle (Student t test, difference = 30.2, 95% CI = 5.3-55.1, p = 0.020). INTERPRETATION: Repair of the neurovascular response to SDs by cilostazol, as demonstrated in the aSAH-mimicking model, may be a promising therapy to control DCI. Ann Neurol 2018;84:873-885.

Idiopathic basal ganglia calcification associated with cerebral micro-infarcts: a case report.

BACKGROUND: Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disorder characterized by symmetric intracranial calcium deposition. We report a patient with IBGC associated with cerebral infarction due to impairment of cerebrovascular reactivity based on single-photon emission computed tomography (SPECT) with acetazolamide challenge. CASE PRESENTATION: A 66-year-old male presented with right conjugate deviation, right hemiparesis and total aphasia due to a convulsive seizure. Brain computed tomography showed symmetric calcifications in the bilateral basal ganglia, thalamus, cerebellar dentate nuclei, which were consistent with IBGC. Diffusion-weighted brain magnetic resonance imaging showed multiple small infarctions in the bilateral cerebral subcortical area. In the search for the cause of cerebral infarction, SPECT with acetazolamide challenge revealed heterogeneous impairment of cerebrovascular reactivity in the whole brain, despite the absence of evidence for steno-occlusive changes in proximal arteries. CONCLUSION: Cerebrovascular insufficiency due to the lack of elasticity caused by microvascular calcification might have been one of the pathophysiological features of IBGC in this case. Thus, vascular calcification may cause cerebrovascular disturbance and could lead to ischemic stroke in patients with IBGC.

[Effect of Platelet Concentrate Transfusion on Prognosis of Patients with Intracerebral Hemorrhage Treated with Anti-Platelet Agents].

BACKGROUND: A recent randomized control study(the PATCH trial)found no beneficial effect of platelet concentrate(PC)transfusion on the prognosis of patients with intracerebral hemorrhage(ICH)treated with anti-platelet agents(APAs). However, the trial excluded surgical cases. In this study, we examined the effect of PC on ICH, including patients who received surgical treatment. METHOD: A retrospective cohort analysis was performed in 23(11 males, 12 females)of 35 patients diagnosed with ICH and treated with APAs between January 2010 and December 2015 at the Department of Neurosurgery, Yamaguchi University Hospital. Twelve patients were excluded due to the use of anticoagulants or replenishment of coagulation factors. RESULTS: PC transfusion was administered in 12 cases(PC group)but not administered in 11(non-PC group). Conservative therapy at admission was used in 7 and 9 cases in the PC and non-PC groups, respectively, and none of these cases showed hematoma enlargement during conservative therapy. Surgical treatment was performed in 6 and 2 patients in the PC and non-PC groups, respectively, and hematoma enlargement occurred postoperatively in one patient in each group. Outcomes at 3 months after onset showed no significant difference between the groups(mRS 0-3:6 vs. 5 cases, p=0.34). Patients who received PC had no serious adverse events during hospitalization. CONCLUSION: In this study, surgery after PC transfusion was performed without any problems. There was no difference in prognosis between patients who did and did not receive PC. These results suggest that surgery can be performed safely after PC transfusion.

Safety and Time Course of Drip-and-Ship in Treatment of Acute Ischemic Stroke.

BACKGROUND: The drip-and-ship approach allows intravenous tissue plasminogen activator therapy and adjuvant endovascular treatment in acute ischemic stroke, even in rural areas. Here, we examined the safety and time course of the drip-and-ship approach. METHODS: Fifty consecutive cases treated with the drip-and-ship approach (drip-and-ship group) in June 2009 to March 2016 were retrospectively examined. Changes in mean blood pressure, systemic complications, and neurological complications were compared according to method of transportation. Time courses were compared between drip-and-ship and direct admission groups during the same period. RESULTS: In the drip-and-ship group, 33 and 17 patients were transferred to hospital by ambulance and helicopter, respectively. One patient suffered hemorrhagic infarction during transportation by ambulance. Mean blood pressure change was lower in patients transferred by helicopter than ambulance (<5 mmHg versus 12.2 mmHg, respectively). The mean onset-to-door times in the drip-and-ship and direct admission groups were 71 and 64 minutes, respectively, and mean door-to-needle times were 70 and 47 minutes, respectively (P =.002). Although mean transportation time from the primary stroke hospital to our hospital was 32 minutes, the entry-to-exit time from the primary stroke hospital was 113 minutes. Thereafter, there was an average delay of 100 minutes until reperfusion compared with the direct admission group. CONCLUSIONS: Drip-and-ship was relatively safe in this small series. Transportation by helicopter was less stressful for acute ischemic stroke patients. It is important to reduce door-to-needle time and needle-to-departure time in the primary stroke hospital to minimize the time until treatment in cases of acute ischemic stroke.

D-Dimer Elevation as a Blood Biomarker for Detection of Structural Disorder in Mild Traumatic Brain Injury.

CT scans are useful in patients with traumatic brain injury (TBI), but the potential risks associated with ionizing radiation are unknown. Further, CT scans are not commonly available in developing countries. In this study, coagulopathy and abnormal fibrinolysis were investigated as blood biomarkers for detection of structural disorder in mild traumatic brain injury (TBI). A total of 88 patients with mild and isolated TBI (Glasgow Coma Scale [GCS] score 14-15) were admitted to Kenwakai Ootemachi Hospital between October 2014 and March 2016. After exclusion of those treated with oral antiplatelet agents and anticoagulants, 73 patients were included in this study. Patients were classified into those with (lesion [+]) and without (lesion [-]) intracranial structural disorder, based on CT scans at admission and follow-up CT or MRI. Age, GCS score, and blood test findings (platelet count, international normalized ratio of prothrombin time [PT-INR], activated partial thromboplastin time [APTT], fibrinogen, fibrin/fibrinogen degradation products [FDP], and D-dimer) on admission were compared between the two groups. The lesion(+) and lesion(-) groups comprised 54 (74%) and 19 patients (26%), respectively. In multivariate logistic regression analysis, D-dimer (3.6 vs. 0.8 µg/mL) was the only significant independent risk factor for structural disorder (p < 0.001). Platelet counts (23.9 vs. 23.5 × 104 /µL), PT-INR (1.05 vs. 1.07), APTT (29.3 vs. 31.7 sec), FDP (12 vs. 2.4 µg/mL), and fibrinogen levels (260.6 vs. 231.3 mg/dL) were not associated with structural disorder. These results show that D-dimer is associated with intracranial structural disorder in mild TBI.

Real-time ultrasound-guided endoscopic surgery for putaminal hemorrhage.

OBJECT: Endoscopic surgery plays a significant role in the treatment of intracerebral hemorrhage. However, the residual hematoma cannot be measured intraoperatively from the endoscopic view, and it is difficult to determine the precise location of the endoscope within the hematoma cavity. The authors attempted to develop real-time ultrasound-guided endoscopic surgery using a bur-hole-type probe. METHODS: From November 2012 to March 2014, patients with hypertensive putaminal hemorrhage who underwent endoscopic hematoma removal were enrolled in this study. Real-time ultrasound guidance was performed with a bur-hole-type probe that was advanced via a second bur hole, which was placed in the temporal region. Ultrasound was used to guide insertion of the endoscope sheath as well as to provide information regarding the location of the hematoma during surgical evacuation. Finally, the cavity was irrigated with artificial cerebrospinal fluid and was observed as a low-echoic space, which facilitated detection of residual hematoma. RESULTS: Ten patients with putaminal hemorrhage>30 cm3 were included in this study. Their mean age (±SD) was 60.9±8.6 years, and the mean preoperative hematoma volume was 65.2±37.1 cm3. The mean percentage of hematoma that was evacuated was 96%±3%. None of the patients exhibited rebleeding after surgery. CONCLUSIONS: This navigation method was effective in demonstrating both the real-time location of the endoscope and real-time viewing of the residual hematoma. Use of ultrasound guidance minimized the occurrence of brain injury due to hematoma evacuation.

A novel trigger for cholesterol-dependent smooth muscle contraction mediated by the sphingosylphosphorylcholine-Rho-kinase pathway in the rat basilar artery: a mechanistic role for lipid rafts.

Hyperlipidemia is a risk factor for abnormal cerebrovascular events. Rafts are cholesterol-enriched membrane microdomains that influence signal transduction. We previously showed that Rho-kinase-mediated Ca(2+) sensitization of vascular smooth muscle (VSM) induced by sphingosylphosphorylcholine (SPC) has a pivotal role in cerebral vasospasm. The goals of the study were to show SPC-Rho-kinase-mediated VSM contraction in vivo and to link this effect to cholesterol and rafts. The SPC-induced VSM contraction measured using a cranial window model was reversed by Y-27632, a Rho-kinase inhibitor, in rats fed a control diet. The extent of SPC-induced contraction correlated with serum total cholesterol. Total cholesterol levels in the internal carotid artery (ICA) were significantly higher in rats fed a cholesterol diet compared with a control diet or a ß-cyclodextrin diet, which depletes VSM cholesterol. Western blotting and real-time PCR revealed increases in flotillin-1, a raft marker, and flotillin-1 mRNA in the ICA in rats fed a cholesterol diet, but not in rats fed the ß-cyclodextrin diet. Depletion of cholesterol decreased rafts in VSM cells, and prevention of an increase in cholesterol by ß-cyclodextrin inhibited SPC-induced contraction in a cranial window model. These results indicate that cholesterol potentiates SPC-Rho-kinase-mediated contractions of importance in cerebral vasospasm and are compatible with a role for rafts in this process.

Cortical region-specific engraftment of embryonic stem cell-derived neural progenitor cells restores axonal sprouting to a subcortical target and achieves motor functional recovery in a mouse model of neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic encephalopathy (HIE) at birth could cause cerebral palsy (CP), mental retardation, and epilepsy, which last throughout the individual's lifetime. However, few restorative treatments for ischemic tissue are currently available. Cell replacement therapy offers the potential to rescue brain damage caused by HI and to restore motor function. In the present study, we evaluated the ability of embryonic stem cell-derived neural progenitor cells (ES-NPCs) to become cortical deep layer neurons, to restore the neural network, and to repair brain damage in an HIE mouse model. ES cells stably expressing the reporter gene GFP are induced to a neural precursor state by stromal cell co-culture. Forty-hours after the induction of HIE, animals were grafted with ES-NPCs targeting the deep layer of the motor cortex in the ischemic brain. Motor function was evaluated 3 weeks after transplantation. Immunohistochemistry and neuroanatomical tracing with GFP were used to analyze neuronal differentiation and axonal sprouting. ES-NPCs could differentiate to cortical neurons with pyramidal morphology and expressed the deep layer-specific marker, Ctip2. The graft showed good survival and an appropriate innervation pattern via axonal sprouting from engrafted cells in the ischemic brain. The motor functions of the transplanted HIE mice also improved significantly compared to the sham-transplanted group. These findings suggest that cortical region specific engraftment of preconditioned cortical precursor cells could support motor functional recovery in the HIE model. It is not clear whether this is a direct effect of the engrafted cells or due to neurotrophic factors produced by these cells. These results suggest that cortical region-specific NPC engraftment is a promising therapeutic approach for brain repair.

The effect of hypothermia therapy on cortical laminar disruption following ischemic injury in neonatal mice.

Hypothermia has been proposed as a treatment for reducing neuronal damage in the brain induced by hypoxic ischemia. In the developing brain, hypoxic ischemia-induced injury may give rise to cerebral palsy (CP). However, it is unknown whether hypothermia might affect the development of CP. The purpose of this study was to investigate whether hypothermia would have a protective effect on the brains of immature, 3-day old (P3) mice after a challenge of cerebral ischemia. Cerebral ischemia was induced in P3 mice with a right common carotid artery ligation followed by hypoxia (6% O2, 37°C) for 30 min. Immediately after hypoxic ischemia, mice were exposed to hypothermia (32°C) or normothermia (37°C) for 24 h. At 4 weeks of age, mouse motor development was tested in a behavioral test. Mice were sacrificed at P4, P7, and 5 weeks to examine brain morphology. The laminar structure of the cortex was examined with immunohistochemistry (Cux1/Ctip2); the number of neurons was counted; and the expression of myelin basic protein (MBP) was determined. The hypothermia treatment was associated with improved neurological outcomes in the behavioral test. In the normothermia group, histological analyses indicated reduced numbers of neurons, reduced cortical laminar thickness in the deep, ischemic cortical layers, and significant reduction in MBP expression in the ischemic cortex compared to the contralateral cortex. In the hypothermia group, no reductions were noted in deep cortical layer thickness and in MBP expression in the ischemic cortex compared to the contralateral cortex. At 24 h after the hypothermia treatment prevented the neuronal cell death that had predominantly occurred in the ischemic cortical deep layers with normothermia treatment. Our findings may provide a preclinical basis for testing hypothermal therapies in patients with CP induced by hypoxic ischemia in the preterm period.

Initial 'TTP Map-Defect' of Computed Tomography Perfusion as a Predictor of Hemorrhagic Transformation of Acute Ischemic Stroke.

BACKGROUND: Hemorrhagic transformation (HT) following acute ischemic stroke is a major problem, especially for the indication of reperfusion therapy including intravenous administration of recombinant tissue plasminogen activator (IV rt-PA). The specific predictive factors of HT have not yet been established. The present study evaluated the findings of computed tomography perfusion (CTP) images as predictors of subsequent HT to identify patients with low HT risk for reperfusion therapy such as IV rt-PA. METHODS: We retrospectively reviewed 68 consecutive stroke patients (41 males; mean age 72.9 years) with steno-occlusive lesions in the major trunk, including 10 patients who underwent IV rt-PA. Each HT was detected on a follow-up T2*-weighted magnetic resonance image until 2 weeks after stroke onset and categorized into four groups [hemorrhagic infarction (HI) type 1 and 2, and parenchymal hematoma (PH) type 1 and 2] according to the European Cooperative Acute Stroke Study (ECASS) classification. We assessed clinical features and radiological findings between the HT and non-HT groups or the PH2 and non-PH2 groups. The efficacy of initial time to peak (TTP) mapping of CTP for predicting HT or PH2 was evaluated. RESULTS: Thirty-four patients (50%) developed subsequent HT: 18 (52.9%) had HI and 16 (47.1%) had PH, including 9 PH2 patients (13.2%). IV rt-PA was not significantly associated with HT or PH2 occurrence. Forty of the 68 patients (59%) revealed defect areas on the initial TTP mapping (TTP map-defect), and 34 of these 40 patients (85%) developed secondary HT and 9 patients (22.5%) developed PH2. Initial 'TTP map-defect' was significantly associated with the occurrence of HT (p < 0.0001) and PH2 (p = 0.0070). Thirty of the 34 patients (88.2%) in the HT group experienced delayed recanalization of the occluded vessels, in contrast to only 8 of the 34 patients (23.6%) in the non-HT group. All patients of the PH2 group showed recanalization (p = 0.0042). In 40 'TTP map-defect'-positive patients, delayed recanalization was associated with the occurrence of HT (p < 0.0001) and PH2 (p = 0.0491). All 28 patients without 'TTP map-defect' did not develop HT, including 8 patients (28.6%) with delayed recanalization. CONCLUSIONS: Initial 'TTP map-defect' of CTP could accurately predict HT risk including PH2 risk and identify low-risk patients even in the delayed period.

Comparison of lumbar drainage and external ventricular drainage for clearance of subarachnoid clots after Guglielmi detachable coil embolization for aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Subarachnoid clots play an important role in development of delayed vasospasm after subarachnoid hemorrhage (SAH). The purpose of this study was to compare clearance of subarachnoid clots using external ventricular drainage (EVD) or lumbar drainage (LD) after Guglielmi detachable coil (GDC) embolization for aneurysmal SAH. METHODS: The subjects were 51 treated with GDC coil embolization for aneurysmal Fisher group 3 SAH within 72 h of ictus. Software-based volumetric quantification of the subarachnoid clots was performed on CT scans and the hemoglobin (Hb) level was measured in CSF drained from each catheter. RESULTS: Clearance of subarachnoid clots was more rapid in patients treated with LD (n=34) compared to those treated with EVD (n=17). The Hb level in CSF was significantly higher in the LD group on Days 4-5 after onset of SAH (P<0.05), but was higher in the EVD group on Days 8-9. The incidence of symptomatic vasospasm did not differ between the two groups. The rate of occurrence of a new low density area on CT scans was higher in patients treated with EVD, but not significantly higher than the rate in the LD group. CONCLUSION: GDC embolization followed by lumbar drainage accelerates the reduction of subarachnoid clots, but EVD may contribute to stasis of hemorrhage within subarachnoid spaces.

Fulminant tuberculous meningitis--autopsy case report.

A 56-year-old Japanese male presented with tuberculous meningitis (TBM) manifesting as irrational behavior. He underwent lumbar puncture, which showed inflammatory cerebrospinal fluid (CSF) findings. Administration of anti-tuberculosis (TB) agents was started on the day after admission (Day 1) because delayed treatment of TBM might be fatal. On Day 4, magnetic resonance (MR) imaging and MR angiography showed fresh infarctions, hydrocephalus, and stenoses of arteries. CSF drainage and biopsy of brain tissue were performed, but the pathological findings were non-specific. Frequent CSF examinations, cultures, and polymerase chain reaction were performed, but no positive finding of TB was obtained. He died on Day 14. Brain autopsy showed Langerhans giant cells and Ziehl-Neelsen-positive TB bodies. Unfortunately, our patient suffered very poor outcome irrespective of early anti-TB treatment starting Day 1, suggesting the probability of delayed admission or drug-resistant TB. TB infection including TBM has become rare in developed countries, and diagnosis remains difficult. Corticosteroid therapy may be effective for TBM, but may be restricted and ameliorate mortality but not morbidity. Further study is required to establish second line treatment if TBM is resistant to anti-TB agents and corticosteroid administration.

Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease.

For the safe clinical application of embryonic stem cells (ESCs) for neurological diseases, it is critical to evaluate the tumorigenicity and function of human ESC (hESC)-derived neural cells in primates. We have herein, for the first time, compared the growth and function of hESC-derived cells with different stages of neural differentiation implanted in the brains of primate models of Parkinson's disease. We herein show that residual undifferentiated cells expressing ESC markers present in the cell preparation can induce tumor formation in the monkey brain. In contrast, a cell preparation matured by 42-day culture with brain-derived neurotrophic factor/glial cell line-derived neurotrophic factor (BDNF/GDNF) treatment did not form tumors and survived as primarily dopaminergic (DA) neurons. In addition, the monkeys with such grafts showed behavioral improvement for at least 12 months. These results support the idea that hESCs, if appropriately matured, can serve as a source for DA neurons without forming any tumors in a primate brain.

Long-term outcome of cervical and thoracolumbar dural arteriovenous fistulas with emphasis on sensory disturbance and neuropathic pain.

BACKGROUND: Clinical features and prognosis of sensory disturbance in spinal dural arteriovenous fistula (SDAVF) have not been well documented. Here we report long-term outcomes and detailed sensory evaluations of surgically treated SDAVF, including 14 patients with the craniocervical fistulas. METHODS: Thirty-four consecutive patients with SDAVF treated at our institute during a period of 14 years were reviewed (mean age, 64.6 years; 67.6% men). Fistulas were located at the craniocervical junction in 14 patients (CC group) and in the thoracolumbar spine in 20 patients (TL group). In the CC group, six patients presented with subarachnoid hemorrhage. Fistulas were found incidentally in seven patients. One patient in the CC group and all patients in the TL group presented with progressive myelopathy. Most patients underwent microsurgery either alone (30 patients) or combined with embolization (3 patients). One patient was treated by embolization only. The follow-up ranged from 12 to 145 months (mean, 57 months). RESULTS: All but one patient in the CC group had excellent surgical outcome. Most patients in the TL group stabilized or improved neurologically. Shorter duration before treatment indicated better gait recovery. Important, a few patients in the TL group suffered worsening or development of new pain, as well as lesser degree of improvement in gait and micturition. Spinal cord atrophy was correlated with clinical deterioration. CONCLUSIONS: In craniocervical SDAVF, surgical treatment provides favorable long-term outcomes without risk of recurrence. In the thoracolumbar SDAVF, irreversible structural changes, such as spinal cord atrophy, may lead to poor recovery. Early diagnosis and treatment are thus warranted.

Neuroendoscopic evacuation of intraventricular hematoma associated with thalamic hemorrhage to shorten the duration of external ventricular drainage.

BACKGROUND: We report neuroendoscopic evacuation of an intraventricular hematoma (IVH) in 13 patients with thalamic hemorrhage. We discuss strategies to improve the outcome and to shorten the management period by using external ventricular drainage (EVD). METHODS: Patients were classified into fair (modified Rankin scale [mRS] grade 4 or less) and poor (mRS grade 5) outcome groups, and depending on the duration of EVD, into short (7 days or shorter) and long EVD (8 days or longer) groups. RESULTS: The postoperative residual IVH, graded using the Graeb score, was better for the fair outcome group than for the poor outcome group (3.9 [1.2] vs. 5.7 [1.0], P < 0.05). The postoperative Graeb score was significantly better for the short EVD group than for the long EVD group (3.6 [0.8] vs. 6.0 [0.6], P < 0.01). The duration of EVD was not correlated with the IVH at the fourth ventricle, but it was correlated with the IVH at the foramen of Monro (P < 0.05) and the third ventricle (P < 0.01). Reduction in the volume of thalamic hemorrhage had no effect on the neurological outcome or duration of EVD. CONCLUSION: Neuroendoscopic evacuation of the IVH at the foramen of Monro and the third ventricle shortened the duration of EVD for hydrocephalus caused by thalamic hemorrhage with IVH involvement. Removal of the thalamic hemorrhage and IVH at the fourth ventricle was not necessary.

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell-derived neural precursor cells.

Cell replacement therapy holds great promise as a means of treating neurological disorders, including Parkinson's disease. However, one of the major obstacles to the success of this treatment is the low survival rate of grafted cells, which probably results from mechanical damage, acute inflammation, and immunological rejection. To overcome this problem, we investigated the effect of different types of extracellular matrix (ECM) on the survival and differentiation of embryonic stem (ES) cell-derived neural precursor cells (NPCs). We tested materials from natural sources, including collagen, ornithine/laminin, and growth factor-reduced Matrigel (gfrMG), as well as the synthetic biomaterial PuraMatrix, which consists of self-assembling polypeptides. GfrMG efficiently supported cell survival, migration, and neurite outgrowth in vitro and promoted proliferation of grafted cells in vivo, resulting in larger graft volume and an increase in the number of TH-positive dopaminergic neurons in the graft. GfrMG did not induce dopaminergic differentiation directly; rather, it reduced the invasion of pan-leukocytic CD45-positive cells into the graft. Insofar as the inflammatory or immune response in the host brain inhibits neuronal differentiation of grafted NPCs, gfrMG may increase the number of TH-positive cells by suppressing this effect. Thus, gfrMG appears to provide a suitable scaffold that supports survival and differentiation of NPCs. However, because it is derived from mouse sarcomas, a human-derived matrix or synthetic biomaterial must be developed for clinical applications.

Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells.

Embryonic stem (ES) cells are a promising donor source for transplantation therapy, but several problems must be solved before they can be clinically useful. One of these is the host immune reaction to allogeneic grafts. In this article, we examine the effect of the host immune reaction on survival and differentiation of grafted ES cell-derived neural precursor cells (NPCs). We induced NPCs from mouse ES cells by stromal cell-derived inducing activity and then transplanted them into mouse brains with or without administering the immunosuppressant cyclosporine A (CsA). Two and 8 weeks following transplantation, the accumulation of host-derived microglia/macrophages and lymphocytes was observed around the graft. This effect was reduced by CsA treatment, although no significant difference in graft volume was observed. These data suggest that an immune response occurs in allografts of ES cell-derived NPCs. Intriguingly, however, the ratio of neurons to astrocytes in the graft was higher in immunosuppressed mice. Because inflammatory or immune cells produce various cytokines, we examined the effect of IL-1beta, IL-6, IFN-gamma, and TNF-alpha on the differentiation of NPCs in vitro. Only IL-6 promoted glial cell fate, and this effect could be reversed by the addition of an IL-6 neutralizing antibody. These results suggest that allogeneic ES cell-derived NPCs can cause an immune response by the host brain, but it is not strong enough to reject the graft. More important, activated microglia and lymphocytes can suppress neuronal differentiation of grafted NPCs in vivo by producing cytokines such as IL-6.

Generation of graftable dopaminergic neuron progenitors from mouse ES cells by a combination of coculture and neurosphere methods.

Parkinson's disease is characterized by a loss of midbrain dopamine (DA) neurons and is generally viewed as a potential target for stem cell therapy. Although several studies have reported the generation of postmitotic DA neurons from embryonic stem (ES) cells, it is unknown whether the proliferative progenitors of DA neurons can be isolated in vitro. To investigate this possibility, we have developed a combined approach in which ES cells are cocultured with PA6 stromal cells to expose them to stromal cell-derived inducing activity (SDIA) and are then cultured as neurospheres. Mouse ES cell colonies were detached from PA6 feeder cells after 8 days of SDIA treatment and then expanded as spheres for another 4 days in serum-free medium supplemented with fibroblast growth factor-2. The spheres exhibited neural stem cell characteristics and contained few DA neurons at this stage of culture. After being induced to differentiate on polyornithine/laminin-coated dishes for 7 days, these spheres generated DA neurons in vitro at a relatively low frequency. Intriguingly, addition of PA6 cell conditioned medium to the sphere culture medium significantly increased the percentage of DA neurons to 25-30% of the total number of neurons. Transplantation of conditioned medium-treated day 4 spheres, which contained DA neuron progenitors, into the mouse striatum resulted in the generation of a significant number of graft-derived DA neurons. These findings suggest that progenitors of DA neurons are generated and can proliferate in ES cell-derived neurospheres induced by serial SDIA and PA6 conditioned medium treatment.