Intravenous infusion of mesenchymal stem cells improves impaired cognitive function in a cerebral small vessel disease model.

Cerebral small vessel disease (CSVD) is not only a cause of vascular dementia (VD) but also a contributing factor to Alzheimer's disease (AD). The essential pathological feature of CSVD is the disruption of blood-brain barrier (BBB). Dysfunction of BBB due to degeneration of both endothelial cells and pericytes in capillaries leads to neuronal damage and progressive brain atrophy. Moreover, deterioration of amyloid-ß (Aß) clearance due to the failure of the transvascular BBB transport system results in accumulation of Aß in the brain. Intravenous infusion of mesenchymal stem cells (MSCs) elicits functional recovery in experimental models including stroke and spinal cord injury. One effect of MSCs is to restore disrupted BBB through remodeling of microvasculature. Using spontaneously hypertensive rats (stroke-prone) with impaired cognitive function as a CSVD model, we have shown that infused MSCs has a therapeutic effect for cognitive function. Restoration of BBB function via remodeling of microvasculature and inhibition of Aß accumulation could inhibit progressive brain atrophy and lead to restore cognitive dysfunction. Gene expression analysis indicated that infused MSCs activates both transforming growth factor-ß and angiopoietin 1 signaling pathways and promotes the remodeling of microvasculature. Thus, infused MSCs may represent a novel therapy for both VD and AD.

Biological relevance of tissue factor and IL-6 in arteriovenous malformations.

Arteriovenous malformations (AVMs) are congenital abnormal vessels that shunt blood directly from the arterial to the venous system without a capillary bed. The underlying pathology of AVMs is not fully understood. The objective of the study was to determine the association between the expression patterns of tissue factor (TF) and interleukin-6 (IL-6) in AVMs with clinical and pathological findings. Eighteen cases of sporadic AVM with operative specimens were included in this study. The expression of messenger RNA (mRNA) of TF and IL-6 was assayed, and association with clinical factors was investigated. The distribution of TF and IL-6 was examined with immunofluorescence. The mRNA expression of TF was significantly higher in AVM specimens than in control tissues (P = 0.002) and significantly higher in the symptomatic group than in the asymptomatic group (P = 0.037). The mRNA expression of IL-6 was likewise significantly higher in AVM specimens than in control tissues (P = 0.038). Examination of immunostained sections indicated that TF+ cells were also positive for IL-6 and were distributed around normal endothelial cells and pericytes. Moreover, TF+/IL-6+ cells also expressed CD31, vascular endothelial growth factor receptor 2 (VEGFR2), and platelet-derived growth factor receptor beta (PDGFR-beta). These results suggest that TF is elevated in AVMs and that it mediates symptomatic events. IL-6 is associated with the angiogenic activity of TF, and both are present in the same abnormal endothelial cells and pericytes. These factors may have interactive effects and may serve in a prognostic role for AVMs.

Internal trapping following proximal clipping for a ruptured partially thrombosed giant aneurysm of the vertebral artery--case report.

A 52-year-old woman presented with a partially thrombosed giant aneurysm of the vertebral artery (VA) manifesting as a 3-month history of left hemiparesis. She developed subarachnoid hemorrhage during hospitalization and underwent emergency surgery for surgical proximal clipping and ventricular drainage with decompressive suboccipital craniectomy. She underwent additional surgery for endovascular coil embolization of the aneurysm and the affected distal VA on the 7th postoperative day. Although she suffered transient lower cranial nerve pareses and respiratory failure, her neurological condition improved gradually and she returned home with only slight ataxia and hoarseness 3 months after surgery. Magnetic resonance imaging obtained 28 months postoperatively revealed a remarkable decrease in the size of the aneurysm as well as reduction of the mass effect on the brainstem. Combined proximal clipping and internal trapping can solve the problems associated with treatment of giant aneurysms of VA by either direct surgery or endovascular surgery, and should be considered as a therapeutic option for giant aneurysms of the VA.

Significant improvement of visual functions after removal of an intracranial giant optic nerve glioma revealing exophytic growth: case report.

OBJECTIVE AND IMPORTANCE: Intracranial giant optic nerve gliomas, usually presumed as optic chiasmatic gliomas, are much less common. The architectural tumor form of optic nerve glioma without neurofibromatosis type 1 is usually the expansile-intraneural pattern. The exophytic optic nerve gliomas without neurofibromatosis type 1 are relatively uncommon. Surgical decompression for intracranial optic gliomas frequently leads to clinical improvement, but obvious improvement of vision is rare. We report a case that demonstrated significant recovery of visual function after removal of the intracranial giant optic nerve glioma, revealing exophytic growth. CLINICAL PRESENTATION: A 13-year-old boy presented with visual impairment in both eyes. Magnetic resonance images (MRI) disclosed a 6 cm diameter mass in the suprasellar area. On heavily T2-reversed MRIs, it was obvious that the intracranial portion of right optic nerve was enlarged, and optic tracts were shifted to the left by the tumor. The relationship of the tumor to the chiasma could not be affirmed on MRIs. INTERVENTION: A right frontotemporal craniotomy for decompression of the optic apparatus was performed. After the majority of the tumor was resected, it became clear that the tumor originated in the right optic nerve. The tumor exophytically grew and dislocated the optic chiasma and optic tracts. Significant improvement of visual functions began from the first week after surgery and continued gradually thereafter. The histological diagnosis was pilocytic astrocytoma. A follow-up MRI taken 4 years after surgery showed no regrowth of the residual tumor. CONCLUSION: Giant exophytic gliomas without neurofibromatosis type 1 may arise from the intracranial portion of an isolated optic nerve. Direct visualization of optic component by heavily T2-reversed MRI could more precisely delineate the relationship of the intracranial optic nerve glioma to the optic apparatus. Surgery may be indicated in giant exophytic intracranial optic nerve gliomas and preoperative postulated optic chiasmatic gliomas. Microsurgical resection can induce postoperative visual improvement without regrowth of the residual tumor.

Surgical management of the recurrence and regrowth of craniopharyngiomas.

OBJECT: The authors performed a retrospective analysis of a consecutive series of craniopharyngiomas and their recurrences, which were managed with surgery alone. METHODS: In the past 20 years, 37 consecutive patients with craniopharyngiomas underwent surgery without adjuvant radiotherapy. During that period there was a consistent strategy that surgical management was the first choice of treatment whenever possible. Of these 37 patients, 11 experienced tumor recurrence (29.7%) during the mean follow-up period of 11.1 years. Of these 11 patients, seven experienced recurrence after neuroimaging-confirmed total removal, and four patients experienced recurrence after partial or incomplete removal. In these 11 patients, surgical removal was performed 17 times. Using a proper surgical approach (mainly a basal interhemispheric approach) and meticulous microsurgical techniques, total removal of the recurrent tumor was achieved in nine surgeries (52.9). The mortality and morbidity rates associated with these 17 surgeries were 0% and 9.1%, respectively. In most cases, visual function was preserved or improved and intellectual performance was also preserved. CONCLUSIONS: Recurrence of craniopharyngioma can be safely managed by using meticulous contemporary microsurgical techniques without additional radiotherapy. The role of surgery and adjuvant radiotherapy for craniopharyngiomas may vary in the future, depending on innovations in treatment and technology. Nevertheless, surgery can be still a major therapeutic option in the management of recurrent craniopharyngiomas.

Autologous transplantation of expanded neural precursor cells into the demyelinated monkey spinal cord.

The objective of this study was to establish if neural precursor cells could safely be developed from biopsy of the subventricular zone (SVZ) in the non-human primate (marmoset), and to determine their myelinating potential after autologous transplantation into a demyelinated lesion. Small amounts of tissue were safely collected from the subventricular-subependymal zone of the adult primate brain under ultrasonography without any neurological deficit. Neural precursor cells were isolated and expanded in the presence of mitogen in vitro. The dorsal columns of the adult marmoset spinal cord were demyelinated by X-irradiation and intraspinal injections of ethidium bromide in the center of the radiation field. Cell suspensions of the neural precursors were microinjected through a micropipette into the demyelinated lesion site in the spinal cord. Lesions were histologically examined 3 weeks after transplantation. Light and electron microscopic examination of plastic embedded sections revealed a significant number of myelinating profiles in the transplantation zone; no myelination was observed in control lesions. The myelinated axons had predominantly peripheral patterns of myelination. These results demonstrate that autologous transplantation of neural precursor cells in the adult nonhuman primate can remyelinate demyelinated central nervous system (CNS) axons, thus suggesting the potential utility of such an approach in demyelinating lesions in humans.

A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats.

The primary objective of this study was to test the hypothesis that intravenous administration of autologous bone marrow cells could improve functional recovery after middle cerebral artery occlusion (MCAO) for 45 min in the rat and to determine specific time windows for efficacy. Mononuclear cells from autologous bone marrow were transfected with the LacZ reporter gene, and injected intravenously into rats at 3-72 h after induction of MCAO. Histological analysis of the ischemic lesion at 14 days after transplantation revealed reduced ischemic lesion volume. Lesion volume was 250+/-45 mm(3) (n=6) after MCAO without cell transplantation. Lesions were minimally detected by absence of 2,3,5-triphenyltetrazolium chloride (TTC) staining when bone marrow cells were infused 3 h after lesion induction. Lesions were clearly detected beginning with the 6-h postlesion group and became progressively larger at 12, 24 and 72 h (80+/-25, 140+/-18, and 180+/-22 mm(3), respectively; n=6 for each group). Transplanted LacZ(+) bone marrow cells accumulated extensively in and around the ischemic lesions, and immunohistochemistry suggests some neuronal and glial lineage differentiation. Behavioral testing (Morris water maze and Treadmill stress test) indicated greater functional recovery in the treated group. These findings suggest that early intervention with intravenous administration of autologous mononuclear cells from bone marrow can reduce lesion size in the MCAO model in the rat, and improve functional outcome.

Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord.

The remyelinating potential of autologous bone marrow cells was studied after direct injection and following intravenous injection into rats with a demyelinated lesion in the spinal cord. Both focal and intravenous injections of acutely isolated mononuclear bone marrow cell fractions resulted in varying degrees of remyelination. Suspensions of bone marrow cells collected from the same rat were delivered at varied concentrations (10(2) to 10(5) for direct injection and 10(4) to 10(7) for i.v. injections). The lesions were examined histologically 3 weeks after transplantation. Light microscopic examination revealed remyelination in the dorsal funiculus with both injection protocols, but the extent of remyelination was proportional to the number of injected cells. To attain the same relative density of remyelination achieved by direct injection, intravenous administration of cells required delivery of substantially more cells (two orders of magnitude). However, the availability of autologous bone marrow cells in large number and the potential for systemically delivering cells to target lesion areas without neurosurgical intervention suggest the potential utility of intravenous cell delivery as a prospective therapeutic approach in demyelinating disease.

[111In-DTPA cisterno SPECT for the diagnosis of CSF rhinorrhea: case report].

The authors report on a patient with postoperative CSF (cerebrospinal fluid) leakage subsequent to transsphenoidal surgery where cisterno SPECT (single photon emission computed tomography) demonstrated the precise location of a CSF fistula. Seven months after surgery, the patient suffered from CSF rhinorrhea and headache. MRI (Magnetic Resonance Imaging) revealed significant contrast on T1-weighted images resulting from measurements in the right sphenoid sinus, which were hyperintense relative to CSF. On the basis of signal intensity differences, MRI could not distinguish between CSF leakage and postoperative scarring. Therefore, we performed cisterno SPECT at the same time as RI cisternography with intrathecal lumbar injection of 111In-DTPA which revealed dramatic accumulation of the tracer in the right sphenoid sinus. The patient underwent re-operation via a transsphenoidal approach, and the CSF leakage was repaired using fat-in-fibrin glue and the sella floor was reconstructed by hydroxyapatite platinge. These results suggest that cisterno SPECT may be useful in identifying the precise location of CSF fistulae, while other techniques fail to show evidence of CSF leakage.

Hypothermia with heparin-coated circuits and low dose systemic heparinization in neurosurgery.

The purpose of this study was to evaluate the safety of profound hypothermic circulatory arrest with heparin-coated circuits and low dose systemic heparinization in the treatment of cerebral aneurysms. Surgery for giant intracranial aneurysms not operable using standard neurosurgical techniques was performed in 8 patients. All patients were placed on cardiopulmonary bypass using the closed-chest technique, except for the first patient who underwent open-chest bypass. Heparin was administered systemically (3,000 IU) and into the circuit (1,500 IU). Total circulatory arrest was begun at 20 degrees C. The D-dimer, alpha2 plasmin inhibitor-plasmin complex, thrombin-antithrombin III, and beta-thromboglobulin concentrations were measured to evaluate the changes in the coagulation and fibrinolytic systems during bypass. There were no neurologic or cardiac complications. None of the indicators of platelet activation, coagulation, or fibrinolysis were elevated. Hypothermic circulatory arrest combined with heparin-coated circuits and low dose systemic heparinization is safe for use in neurosurgery.