Autologous bone marrow stromal cell transplantation for central nervous system disorders - recent progress and perspective for clinical application.

There is increasing evidence that the transplanted BMSC significantly promote functional recovery after CNS damage in the animal models of various kinds of CNS disorders, including cerebral infarct, traumatic brain injury and spinal cord injury. However, there are several shortages of information when considering clinical application of BMSC transplantation for patients with CNS disorders. In this review, therefore, we discuss what we should clarify to establish cell transplantation therapy as the scientifically proven entity in clinical situation and describe our recent works for this purpose. The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding circumstances and to protect the neurons by producing some neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. The BMSC can be expanded in vitro using the animal serum-free medium. Pharmacological modulation may accelerate the in vitro proliferation of the BMSC. Using in vivo optical imaging technique, the transplanted BMSC can non-invasively be tracked in the living animals for at least 8 weeks after transplantation. It is urgent issues to develop clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in clinical situation in the future.

Interstitial spinal-cord oedema in syringomyelia associated with Chiari type 1 malformations.

OBJECT: The pathophysiology of syringomyelia in Chiari type 1 malformations has not been clarified. Oedema-like spinal-cord swelling was recently reported in several pathological conditions, including Chiari type 1 malformations as a pre-syrinx state. However, the role of the pre-syrinx state in the development of syringomyelia is unknown. The purpose of this study is to investigate the parenchymal changes of the spinal cord in syringomyelia associated with Chiari type 1 malformations. METHODS: Pre- and postoperative MRI findings in 14 patients who underwent foramen magnum decompression in our institute were reviewed. The analysis was focused on differences in visualisation of the syrinx between T1- and T2-weighted images and abnormal parenchymal signal changes. There were 6 men and 8 women, aged from 6 to 79 years. No patients showed hydrocephalus. RESULTS: Twelve patients had large and expansive syrinx, whereas 2 patients showed small syrinx confined to the centre of the spinal cord. T2-weighted images displayed significantly larger intramedullary abnormal signal areas. Nine patients showed parenchymal hyperintensity areas around the enlarged central canal or base of the posterior white columns adjacent to the syringomyelic cavity. Such parenchymal hyperintensity areas markedly diminished with reduction of the syrinx after surgery and were considered to be interstitial oedema. CONCLUSIONS: From this study, the interstitial oedema of the spinal cord commonly accompanies syringomyelia with Chiari type 1 malformations. Accumulation of the extracellular fluid due to disturbed absorption mechanisms may play an important role in the pathophysiology of syringomyelia associated with Chiari type 1 malformations.

Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia.

Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PlGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PlGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PlGF gene (PlGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PlGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PlGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PlGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PlGF in both hMSC groups, but a greater increase in the PlGF-hMSC group. These data support the hypothesis that PlGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PlGF to the brain can be achieved by intravenous delivery of hMSCs.

Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

Intravenous infusion of bone marrow cells has demonstrated therapeutic efficacy in animal models of cerebral ischemia and spinal cord injury. We intravenously delivered human mesenchymal stem cells (SH2+, SH3+, CD34-, and CD45-) immortalized with a human-telomerase gene (hTERT-MSCs) and transfected with eGFP or LacZ into rats 12 h after induction of transient middle cerebral artery occlusion (MCAO), to study their potential therapeutic benefit. hTERT-MSCs were delivered at 12 h after lesion induction. Lesion size was assessed using MR imaging and spectroscopy, and histological methods. Functional outcome was assessed using the Morris water maze and a treadmill test. Intravenous delivery of hTERT-MSCs reduced lesion volume and the magnitude of the reduction and functional improvement was positively correlated with the number of cells injected. The reduction of lesion size could be assessed in vivo with MRI and MRS and was correlated with subsequent histological examination of the brain. This work demonstrates that highly purified hTERT-MSCs reduce cerebral infarction volume and improve functional outcome.

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

[Two cases of "steal VBI" with stenosis of the internal carotid artery].

Although previous reports have suggested "steal VBI" due to occlusive carotid artery diseases, there have been no reports that clearly define "steal VBI" from the viewpoint of cerebral hemodynamics. The authors presented two cases with "steal VBI" due to severe stenosis of the internal carotid artery. Both patients had well-developed collateral circulation through the ipsilateral posterior communicating artery. Although no occlusive lesion was found in the vertebrobasilar system, blood flow studies revealed impaired hemodynamics in the contralateral occipital lobe, which fact correlated with their neurological deficit, visual field disturbance. Carotid stenting markedly corrected the stenotic lesions, leading to neurological improvement. Follow-up blood studies showed normalization of hemodynamics in the contralateral occipital lobe. The findings strongly suggest that carotid surgery or stenting can improve cerebral hemodynamics in the carotid systems, resolving "steal VBI" due to developed collaterals from the posterior to the anterior circulation.

Effects of surgical revascularization on peripheral artery aneurysms in moyamoya disease: report of three cases.

OBJECTIVE AND IMPORTANCE: The beneficial effects of surgical revascularization on rebleeding in moyamoya disease remain unclear. This report is intended to clarify the effects of surgical revascularization on peripheral artery aneurysms, which represent one of the causes of intracranial bleeding in moyamoya disease. CLINICAL PRESENTATION: Findings for three female patients who experienced intracranial bleeding are presented. Cerebral angiography revealed that intracranial bleeding resulted from the rupture of peripheral artery aneurysms arising from dilated collateral vessels such as the lenticulostriate artery. INTERVENTION: The patients successfully underwent superficial temporal artery-middle cerebral artery anastomosis combined with encephaloduromyoarteriosynangiosis. Angiography demonstrated obliteration of the peripheral artery aneurysms, together with the disappearance or decrease in caliber of the parent collateral arteries, after surgery. None of the patients experienced rebleeding during the follow-up period (up to 52 mo). CONCLUSION: The results strongly suggest that surgical revascularization potentially improves cerebral circulation and decreases hemodynamic stress on collateral vessels, obliterating peripheral artery aneurysms.

[Diagnosis of cerebral aneurysm using 3-dimensional digital subtraction angiography].

Recent rapid advancement in the technology of magnetic resonance angiography and 3-dimensional computed tomography angiography has opened the door to a less-invasive diagnostic routine for the treatment of cerebral aneurysms. However, from the viewpoint of decision making concerning which treatment to use; conservative therapy; surgical intervention; or endovascular treatment, much more precise information is necessary. Recent progress of rotation digital subtraction angiography has introduced 3-dimensional digital subtraction angiography. In the past year, 28 cases involving 39 aneurysms have been studied using 3-dimensional angiography. This study was carried out, using a rotating C-arm, which rotates 220 degrees in 5.8 seconds. All raw data gathered was transferred to the workstation for image reconstruction. The purpose of this study was to evaluate the clinical potential of 3-dimensional digital subtraction angiography for the diagnosis of the cerebral aneurysms.

Cerebral revascularization for moyamoya disease in children.

Ninety-four patients with moyamoya disease (56 in the pediatric age group and 38 adults) were treated by revascularization surgery in the past 21 years (1979--2000). Combined surgery of the superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis and indirect revascularization of encaphalo-duro-arterio-myo-synangiosis (EDAMS) was performed. Ischemic attacks disappeared in most patients within 1 year (mean) after surgery in pediatric cases. No morbidity or mortality was experienced in the pediatric group. Some children with cerebral infarction before the surgery, however, had mild mental retardation even after the surgery. Early diagnosis and proper prophylactic surgical treatment is indispensable for pediatric patients with moyamoya. MR angiography is an important diagnostic modality for the screening and longitudinal follow-up of moyamoya disease.

Intraoperative measurement of arterial blood flow using a transit time flowmeter: monitoring of hemodynamic changes during cerebrovascular surgery.

BACKGROUND: The purpose of this study was to examine the utility and reliability of arterial flow measurements made with a transit time ultrasonic flowmeter for monitoring blood flow changes during intracranial and carotid surgery. METHOD: A total of 25 patients underwent intra-operative arterial blood flow measurements. The pulsatile flow curve and mean flow values were obtained using 1- to 6-mm transit time probes with a dual channel flowmeter. Four cases underwent aneurysm clipping, 11 cases superficial temporal artery (STA)--middle cerebral artery (MCA) bypass, 2 cases external carotid artery (ECA)--radial artery--MCA bypass for aneurysm trapping, and 8 cases carotid endarterectomy. In aneurysm clipping, blood flow in the branches distal to the aneurysm was measured before and after clipping. Blood flow in the STA was measured before and after STA-MCA anastomosis, and blood flow in the internal carotid artery (ICA) cervical portion was measured during carotid endarterectomy. Blood flow in the MCA and STA was monitored during radial artery grafting. FINDINGS: Blood flow in the STA was elevated after STA-MCA anastomosis. However, post-operative hyperperfusion syndrome was found in some cases whose flow elevation was over 50 ml/min. Also in one case of carotid stenosis, of which blood flow of ICA was elevated to 400 ml/min after carotid endarterectomy, hyperperfusion syndrome was found after surgery. In the cases of MCA aneurysm clipping, decreasing of M2 flow was detected when clipping caused bifurcation stenosis. INTERPRETATION: We found transit time flow measurement useful for management of cerebrovascular surgery: the technique was simple to use and provided stable, reliable results. The method was able to reveal distal branch flow diminution in aneurysm clipping, or residual flow during temporary clipping in aneurysm surgery, and has the potential to predict post-operative complications such as hyperperfusion by signalling over-elevation of donor artery flow in bypass surgery or ICA flow in carotid surgery.

Treatment outcome of single or hypofractionated single-isocentric stereotactic irradiation (STI) using a linear accelerator for intracranial arteriovenous malformation.

BACKGROUND AND PURPOSE: We investigated the use of hypofractionated stereotactic radiotherapy (HFSR) to reduce adverse radiation effects in comparison to single-fraction stereotactic radiosurgery (SRS) for intracranial arteriovenous malformations (AVMs). MATERIALS AND METHODS: This study includes 53 intracranial AVMs treated between 1991-1998. HFSR was selected for 26 AVMs with a maximum diameter > or 2.5 cm or at eloquent area. Twenty-seven patients were treated with SRS (18 AVMs < 2.5 cm at non-eloquent area, nine patients who were unfit for prolonged ring-wearing). The most frequent minimum dose (Dmin) was 20 Gy for SRS and 28 Gy for HFSR in four fractions. The mean follow-up duration was 34.6 months for SRS and 35.4 months for HFSR. RESULTS: As a whole, the 3 and 5-year actuarial obliteration rates were 64 and 92%. Age <20 years old (P=0.02) and a maximum diameter <2 cm were favorable factors (P=0.05). A difference in the distribution of patients was observed in size (> or =2.5 cm or not) (P<0.001) and location (eloquent or not) (P<0.001) between SRS and HFSR due to the treatment selection. However, no significant differences were observed in the actuarial rates of obliteration and transient increased signals with T2-weighted MR images between SRS and HFSR. Radiation necrosis occurred in two patients treated with SRS and in none with HFSR. Intracranial hemorrhage after treatment happened in two treated with SRS and three with HFSR. CONCLUSIONS: HFSR appears to be at least as effective as SRS in achieving complete obliteration of intracranial AVM, although its definitive role remains to be investigated.

[Preliminary results of PET activation study in cerebral arteriovenous malformation (AVM), using C15O2 and 18F-FDG].

The authors applied PET activation study to two patients with arteriovenous malformation (AVM) to localize primary motor cortex before surgery or embolization. The change in regional cerebral blood flow (rCBF) was measured during foot movements in Case 1 who had a 2-cm AVM located in the post-central gyrus. Superimposed PET/MRI images revealed that the rCBF increase was located in the pre-central gyrus. Its validity was confirmed by intraoperative cortical mapping using electrical median nerve stimulation. The patient safely underwent total removal of AVM. The change in regional cerebral metabolic rate for glucose (rCMRglc) was measured during hand movements in Case 2 who had a huge AVM over the central sulcus. Superimposed PET/MRI images revealed that hand movements significantly increased rCMRglc in the frontal cortex, which was separated from the original primary motor area. The patient safely underwent partial embolization, although he suffered transient weakness of the face after embolization. The preliminary results strongly suggest that PET activation study is useful to localize precisely cortical functions of the patients with AVM, thus reducing morbidity after treatment. The results also suggest that cortical functions may undergo translocation when huge AVM involves the eloquent area.

[Angioplasty with stenting for intracranial vertebral and basilar artery stenosis: three technical case reports and literature review].

Patients with intracranial vertebral artery (VA) or basilar artery (BA) stenosis have been mainly treated with medication. However, it has been reported that about 10% of patients experience restroke in the VBA territory, with a high rate of morbidity and mortality. Percutaneous transluminal angioplasty (PTA) is regarded as one of the treatments although it carries the risk of restenosis, recoil or dissection. Stent placement is, therefore, considered to be a further option for the treatment of intracranial artery stenosis since it can prevent the restenosis. We report three medical refractory cases of intracranial VA (2 cases) or BA stenosis (1 case) treated with stenting, none of which had complications and their symptoms disappeared or diminished. Angioplasty with the use of a stent device is regarded as a useful treatment for intracranial artery stenosis, but its risk and long-term result need to be investigated further.

[Intentional neck-plastic incomplete clipping followed by coil embolization for broad-necked distal BA aneurysms].

OBJECTIVE: We report three patients with broad-necked distal basilar artery (BA) aneurysms treated with intentional incomplete clipping followed by endovascular occlusion using Guglielmi detachable coils. METHODS: The location of the aneurysms was BA bifurcation in one patient and BA-superior cerebellar artery (SCA) in two. One patient presented with acute subarachnoid hemorrhage and two patients had incidental aneurysms. In two patients, endovascular treatment was thought to be difficult considering the morphology of the aneurysms and surgical treatment was performed as the first choice of treatment. One patient with a BA-SCA aneurysm underwent endovascular treatment using a remodelling technique first. However, it was impossible to place the coil preserving SCA, so surgical treatment was performed. In all patients, the attempt to pursue complete clipping was considered to be accompanied with high risks of morbidity, so neck-plastic incomplete clipping was performed intentionally. One to six days after the surgery, coil embolization was performed. RESULTS: In all patients, complete occlusion of the aneurysms was achieved and all patients had excellent clinical outcomes. CONCLUSION: Intentional neck-plastic incomplete clipping followed by endovascular coiling may be a useful treatment option for patients with broad-necked distal BA aneurysms.

Operative record using intraoperative digital data in neurosurgery.

BACKGROUND: The purpose of this study was to develop a new method for more efficient and accurate operative records using intra-operative digital data in neurosurgery, including macroscopic procedures and microscopic procedures under an operating microscope. METHODS: Macroscopic procedures were recorded using a digital camera and microscopic procedures were also recorded using a microdigital camera attached to an operating microscope. Operative records were then recorded digitally and filed in a computer using image retouch software and database base software. FINDINGS: The time necessary for editing of the digital data and completing the record was less than 30 minutes. Once these operative records are digitally filed, they are easily transferred and used as database. Using digital operative records along with digital photography, neurosurgeons can document their procedures more accurately and efficiently than by the conventional method (handwriting). INTERPRETATION: A complete digital operative record is not only accurate but also time saving. Construction of a database, data transfer and desktop publishing can be achieved using the intra-operative data, including intra-operative photographs.

[Clinical application of portable near infrared oximetry (HEO-200) to neurosurgical monitoring].

Near infrared spectroscopy (NIRS) have been accepted as a useful modality for non-invasive monitoring of brain oxygenation state. Using a newly developed NIRS apparatus, HEO-200, the authors continuously monitored the changes in the oxygenation state of brain hemoglobin during carotid endarterectomy (CEA) or carotid balloon occlusion tests (BOT) in 21 patients. Somatosensory evoked potentials (SEP), regional cerebral blood flow (rCBF) or transcranial Doppler sonography (TCD) were also employed to compare with the NIRS-responses. In 7 of 21 patients, the carotid artery occlusion caused a continuous deoxygenation of brain hemoglobin as well as a decrease in total hemoglobin. These findings correlated well with temporary neurological deficits and a marked reduction of rCBF in the ipsilateral hemisphere in patients who underwent carotid BOT under local anesthesia. The patients also showed a marked decrease in the N20 amplitude of SEP during CEA under general anesthesia. Restoration of blood flow immediately resolved these findings. The other 14 patients demonstrated no or only transient changes on NIRS as well as on SEP and rCBF study. HEO-200 could non-invasively monitor the relative changes of cerebral oxygenation state with good time resolution, and detect critical ischemia during CEA and carotid BOT.

Frontal lobe infarction due to hemodynamic change after surgical revascularization in moyamoya disease--two case reports.

A 60-year-old female and a 40-year-old male underwent surgical revascularization for moyamoya disease and suffered small infarction in the ipsilateral frontal lobe 3 or 4 days postoperatively. Neuroimaging suggested that the bypass flow had caused rapid progression of occlusive changes in the carotid forks, a diminishing of moyamoya vessels, and flow reduction in the anterior cerebral artery ipsilateral to surgery, leading to critical ischemia in the frontal lobe. Surgical revascularization improves the outcome of patients with moyamoya disease, but postoperative management such as hydration is important to avoid ischemic complications due to frontal lobe infarction.

Neovascularization (angiogenesis) after revascularization in moyamoya disease. Which technique is most useful for moyamoya disease?

The effects of direct and indirect revascularization for moyamoya disease were analyzed for each donor artery to determine which surgical procedure is most useful for the induction of neovascularization. In the past 12 years, 85 patients with moyamoya disease were surgically treated by combined surgery consisting of indirect revascularization via encephalo-duro-arterio-myo-synangiosis (EDAMS) and direct revascularization via the superficial temporal artery and the middle cerebral artery (STA-MCA) bypass. Among those patients, the post-operative changes in digital subtraction angiography were examined in 56 sides, including 34 sides in paediatric cases and 22 sides in adult cases. The neovascularization after indirect revascularization using the 1) superficial temporal artery (skin), 2) middle meningeal artery (dura mater), 3) deep temporal artery (temporal muscle) was analyzed. As results, in paediatric cases, the deep temporal artery and middle meningeal artery induced good neovascularization. However, the induction of neovascularization from the superficial temporal artery was not always good in most pediatric and adult cases. On the other hand, the direct bypass was useful in 90% of adult cases. In indirect revascularization surgery for moyamoya disease, the temporal muscle (the deep temporal artery) and the dura mater (the middle meningeal artery) are useful donors to the ischemic brain. The simple encephalo-arterio-synangiosis is not always effective. The direct bypass is a useful technique for adult moyamoya disease.

Digital recording in microsurgery. Technical note.

The authors examine the quality of intraoperative photography in which digital recording technology, including a microdigital camera and digital video paired with an operating microscope, is used during neurosurgery. A microdigital camera developed for this purpose (1.4 million pixels) was attached to an operating microscope and used during surgery. The same surgical views with precisely the same optical conditions were taken through the microscope by using both a conventional 35-mm camera and the microdigital camera, and the quality of the final output was compared. In addition, the quality of the digital camera photographs was compared with the still photograph clipped from the digital video recording. The quality of the photographs taken with a microdigital camera was superior to the quality of those obtained with the conventional 35-mm camera. The success rate of recording (what you see is what you get) was almost 100%. The quality of the still photographs clipped from the digital video was nearly equal to those taken with the digital camera. The microdigital camera system is superior to the conventional 35-mm camera in neurosurgery in terms of its success rate and the quality of the photography. It is also a space-saving system for storing the huge amount of data generated in the recording of surgical procedures, and the cost/performance ratio is superior to that of the conventional method. Digital technology including digital cameras and videos is very useful for clear recording of microsurgical procedures.