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Intracerebral hemorrhage (ICH) remains a common and debilitating form of stroke. This neurological emergency must be diagnosed and treated rapidly yet effectively. In this article, we review the medical, surgical, repair, and regenerative treatment options for managing ICH. Topics of focus include the management of blood pressure, intracranial pressure, coagulopathy, and intraventricular hemorrhage, as well as the role of surgery, regeneration, rehabilitation, and secondary prevention. Results of various phase II and III trials are incorporated. In summary, ICH patients should undergo rapid evaluation with neuroimaging, and early interventions should include systolic blood pressure control in the range of 140 mmHg, correction of coagulopathy if indicated, and assessment for surgical intervention. ICH patients should be managed in dedicated neurosurgical intensive care or stroke units where continuous monitoring of neurological status and evaluation for neurological deterioration is rapidly possible. Extravasation of hematoma may be helpful in patients with intraventricular extension of ICH. The goal of care is to reduce mortality and enable multimodal rehabilitative therapy.

Electrical stimulation of the cerebellar fastigial nucleus (FN) elicits a prolonged ( approximately 10 days) and substantial (50-80%) protection against ischemic and excitotoxic injuries. The mechanism(s) of protection are unknown. We investigated whether FN stimulation directly protects brain cells against apoptotic cell death in an in vitro rat brain slice culture model. Rats were electrically stimulated in FN or, as control, the cerebellar dentate nucleus (DN). Coronal slices through the forebrain were explanted, exposed to staurosporine, harvested, and analyzed for caspase-3 activity by a fluorescence assay. FN, but not DN, stimulation significantly reduced staurosporine-induced caspase-3 activity by 39 +/- 7% at 3 h, 31 +/- 3% at 6 h and 26 +/- 4% at 10 h of incubation. Immunocytochemistry revealed FN-specific reductions in activated caspase-3 mainly in glial-like cells throughout the forebrain. FN stimulation also results in a 56.5% reduction in cytochrome c release upon staurosporine incubation. We conclude that neuroprotection elicited from FN stimulation can directly modify the sensitivity of brain cells to apoptotic stimuli and thereby suppress staurosporine induced apoptosis in adult rat brain slices. This model indicates that neuroprotection can be studied in vitro and provides new insight into the potential role of glial cells in ischemic protection of neurons induced by FN stimulation.

SAH, blood accumulation in subarachnoid space (SS), is caused by rupture of intracranial aneurisms or by TBI. CSF circulating throughout SS and brain parenchyma forms glymphatic pathways for waste removal. We explored alterations to CSF circulation following SAH in C57BL mice at various time after perforation SAH. Fluorescent microspheres (μS, 0.02, 1.0 mm) were injected into the cisterna magna (CM). One hour later, their spread across the brain was monitored using in vivo multiphoton or ex vivo fluorescence microscopy. In naive mice, from CM μS spread to the brain stem, paraarterially along Willis circle, and further along middle cerebral artery and the ventral surface vessels toward the olfactory bulb. Caudally μS spread down the spinal cord. One hour after SAH, μS were confined to the CM and brain stem region limited by the rostral pons border indicating significant CSF flow impairment. The number of μS distributed to the spinal cord was also greatly reduced. Four days post SAH CSF flow remained arrest...

We sought to identify the medullary relay area mediating the elevations of regional cerebral blood flow (rCBF) and synchronization of the electroencephalogram (EEG) in the rat cerebral cortex elicited by hypoxic excitation of reticulospinal sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM). In anaesthetized spinalized rats electrical stimulation of RVLM elevated rCBF (laser-Doppler flowmetry) by 31 ± 6 %, reduced cerebrovascular resistance (CVR) by 26 ± 8 %, and synchronized the EEG, increasing the power of the 5–6 Hz band by 98 ± 25 %. Stimulation of a contiguous caudal region, the medullary cerebral vasodilator area (MCVA), had comparable effects which, like responses of RVLM, were replicated by microinjection of L-glutamate (5 nmol, 20 nl). Microinjection of NaCN (300 pmol in 20 nl) elevated rCBF (17 ± 5 %) and synchronized the EEG from RVLM, but not MCVA, while nicotine (1.2 nmol in 40 nl) increased rCBF by 13 ± 5 % and synchronized the EEG from MCVA. In intact rats nicotine lowered arterial pressure only from MCVA (101 ± 3 to 52 ± 9 mmHg). Bilateral electrolytic lesions of MCVA significantly reduced, by over 59 %, elevations in rCBF and, by 78 %, changes in EEG evoked from RVLM. Bilateral electrolytic lesions of RVLM did not affect responses from MCVA. Anterograde tracing with BDA demonstrated that RVLM and MCVA are interconnected. The MCVA is a nicotine-sensitive region of the medulla that relays signals elicited by excitation of oxygen-sensitive reticulospinal neurons in RVLM to reflexively elevate rCBF and slow the EEG as part of the oxygen-conserving (diving) reflex initiated in these neurons by hypoxia or ischaemia. Hypoxia or ischaemia of the medulla oblongata increases sympathetic nerve activity, elevates arterial pressure (AP), and induces expiratory apnoea and bradycardia (Dampney et al. 1979; Sun et al. 1992; Reis et al. 1994; Golanov & Reis, 1996a) in rat. It also increases regional cerebral blood flow (rCBF), but not regional cerebral glucose utilization (rCGU), and synchronizes the EEG (Golanov & Reis, 1994, 1996a). This integrated response simulates, in most respects, the diving reflex (Blix & Folkow, 1983), the prototypical oxygen-conserving reflex of mammals. The autonomic responses have been attributed to direct hypoxic excitation of tonically active sympathoexcitatory reticulospinal vasomotor neurons of the rostral ventrolateral reticular nucleus of the medulla (RVLM) (Sun & Reis, 1994a). In vivo these neurons are selectively, rapidly and reversibly excited by blockade of the respiratory chain by microinjection or microiontophoresis of NaCN (histotoxic hypoxia) (Sun & Reis, 1993). Moreover, restricted lesions of RVLM block the systemic and cerebrovascular responses to ischaemia and/or hypoxaemia (Dampney & Moon, 1980; Underwood et al. 1994; Golanov & Reis, 1996a). Indeed, to protect the brain from lack of oxygen may be an important function of the RVLM (Reis et al. 1994). Reticulospinal neurons of the RVLM function as premotor neurons, acting to initiate the integrated responses to hypoxia by activation of effector (motor) neurons distributed elsewhere in the CNS. Thus, the sympathetic responses can be attributed to activation of the RVL-spinal sympathoexcitatory pathway (Sun & Reis, 1996a), apnoea from activation through short intramedullary projections of the adjacent ventral respiratory cell group (Kita et al. 1994; Sun & Reis, 1996b), and bradycardia – from excitation of medullary cardiovagal neurons (Ross et al. 1984; Benarroch et al. 1986). However, the pathway(s) through which rCBF and the EEG are modified is unknown. Since the RVLM does not innervate the cerebral cortex (Ruggiero et al. 1989), the projection must be indirect. In this study we investigate whether a small area of the ventrolateral medulla serves to relay the signals generated by hypoxic excitation of the RVLM to elevate rCBF and synchronize the EEG in the cerebral cortex of rats. We report that an heretofore unrecognized paraambigual region of the bulbar reticular formation, which we term the medullary cerebral vasodilator area (MCVA), subserves this role.

Intracranial ependymoma is the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on the molecular biology of ependymomas has been reported in a few studies. Seventy-six patients with intracranial ependymomas were examined retrospectively for p53 DO-7 immunoexpression in tumor specimens. The results indicate significant association of aberrant p53 expression with high-grade ependymomas and demonstrate a close correlation with recurrence-free survival. All 22 of the p53-positive high-grade ependy-momas had recurred within the first 24 months after operation with a median recurrence-free survival time of 12 months. There were nine recurrences among 18 of high-grade p53-negative tumors with median recurrence-free survival time of 27 months. A multivariate analysis using a Cox proportional hazard model including both clinical and pathological factors exhibited an independent prognostic value for the p53 positivity only (P = 0.0015). A multivariate regression tree analysis (CART) graded tumors as follows: (i) low-grade (36 cases, recurrence rate = 19%); (ii) high-grade p53-negative (18 cases, recurrence rate = 50%); and (iii) high-grade p53-positive (22 cases, recurrence rate = 100%). A novel classification of ependymomas is proposed that should prove useful in designing an optimal treatment strategy.

A variety of chemotherapy protocols have been in-troduced for the treatment of glioblastoma, although overall these have not contributed to patient outcome. Data on the prognostic value of immunoexpression of chemoresistance-related proteins in malignant gliomas are very limited. One hundred and sixty-eight patients with cerebral glioblastomas who received combined treatment were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to glutathione S-transferase pi (GST pi), P-glycoprotein (P-GP) and metallothioneins (MT). The results demonstrated that survival time was found to be significantly shorter for glioblastomas containing = or > 20% of GST pi-immunostained cells and for tumors with P-GP positivity in neoplastic cells. In contrast, the survival time was found to be significantly longer in patients with neoplasms containing = or > 50% of MT-positive cells. Multivariate Cox regression analysis with application of clinical and immunohistochemical factors revealed independent prog-nostic significance for all of the above-mentioned varia-tions of protein expression. The findings suggest that variables of expression of the chemoresistance-related antigens are predictors for outcome in glioblastoma and that immunohistochemical analysis may provide useful information for the determination of optimal anti-cancer strategies in each case.

The brain can protect itself from ischemia and/or hypoxia by two distinct mechanisms which probably involve two separate systems of neurons in the CNS. One, which mediates a reflexive neurogenic neuroprotection, emanates from oxygen-sensitive sympathoexcitatory reticulospinal neurons of the RVLM. These cells, excited within seconds by reduction in blood flow or oxygen, initiate the systemic vascular components of the oxygen conserving (diving) reflex. They profoundly increase rCBF without changing rCGU and, hence, rapidly and efficiently provide the brain with oxygen. Upon cessation of the stimulus the systemic and cerebrovascular adjustments return to normal. The system mediating reflex protection projects via as-yet-undefined projections from RVLM to upper brainstem and/or thalamus to engage a small population of neurons in the cortex which appear to be dedicated to transducing a neuronal signal into vasodilation. It also appears to relay the central neurogenic vasodilation elicited from other brain regions, including excitation of axons innervating the FN. This mode of protection would be initiated under conditions of global ischemia and/or hypoxemia because the signal is detected by medullary neurons. The second neuroprotective system is represented in intrinsic neurons of the cerebellar FN and mediates a conditioned central neurogenic neuroprotection. The response can be initiated by excitation of intrinsic neurons of the FN and does not appear dependent upon RVLM. The pathways and transmitters that mediate the effect are unknown. The neuroprotection afforded by this network is long-lasting, persisting for almost two weeks, and is associated with reduced excitability of cortical neurons and reduced immunoreactivity of cerebral microvessels. This mode of neuroprotection, moreover, is not restricted to focal ischemia, as we have demonstrated that it also protects the brain against global ischemia and excitotoxic cell death. That the brain may have neuronal systems dedicated to protecting itself from injury, at first appearing to be a novel concept, is, upon reflection, not surprising since the brain is not injured in naturalistic behaviors characterized by very low levels of rCBF, diving and hibernation. An understanding of the pathways, transmitters, and molecules engaged in such protection may provide new insights into novel therapies for a range of disorders characterized by neuronal death.

Electrical stimulation of the cerebellar fastigial nucleus (FN) elevates regional cerebral blood flow (rCBF) independently of cerebral metabolism (rCGU) throughout brain. One hour of FN stimulation also reduces, by up to 50%, the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery in rat. Protected areas correspond to the ischemic penumbra. Neuroprotection, while reversible, persists for weeks after 1h of stimulation. It cannot be attributed to increasing rCBF and/or reducing rCGU to improve matching of flow and metabolism. Conditional stimulation of FN initiates long-lived inhibition of expression of peri-infarction depolarizing waves, possibly by altering potassium-channel function and suppresses induction of inducible nitric oxide synthase (iNOS) and ICAM in cerebral microvessels. The brain contains intrinsic networks which may protect the brain from ischemic injury, possibly by producing widespread and longterm suppression of electrical excitability and/or and expression of proinflammatory molecules.

1. We sought to determine whether hypoxic stimulation of neurons of the rostral ventrolateral reticular nucleus (RVL) would elevate regional cerebral blood flow (rCBF) in anaesthetized paralysed rats. 2. Microinjection of sodium cyanide (NaCN; 150-450 pmol) into the RVL rapidly (within 1-2 s), transiently, dose-dependently and site-specifically elevated rCBF1 measured by laser Doppler flowmetry, by 61.3 +/- 22.1% (P < 0.01), increased arterial pressure (AP; +30 +/- 8 mmHg; P < 0.01)1 and triggered a synchronized 6 Hz rhythm of EEG activity. 3. Following cervical spinal cord transection, NaCN and also dinitrophenol (DNP) significantly (P < 0.05) elevated rCBF and synchronized the EEG but did not elevate AP; the response to NaCN was attenuated by hyperoxia and deepening of anaesthesia. 4. Electrical stimulation of NaCN-sensitive sites in the RVL in spinalized rats increased rCBF measured autoradiographically with 14C iodoantipyrine (Kety method) in the mid-line thalamus (by 182.3 +/- 17.2%; P < 0.05) and cerebral cortex (by 172.6 +/- 15.6%; P < 0.05) regions, respectively, directly or indirectly innervated by RVL neurons, and in the remainder of the brain. In contrast regional cerebral glucose utilization (rCGU), measured autoradiographically with 14C-2-deoxyglucose (Sokoloff method), was increased in proportion to rCBF in the mid-line thalamus (165.6 +/- 17.8%, P < 0.05) but was unchanged in the cortex. 5. Bilateral electrolytic lesions of NaCN sensitive sites of RVL, while not altering resting rCBF or the elevation elicited by hypercarbia (arterial CO2 pressure, Pa,CO2, approximately 69 mmHg), reduced the vasodilatation elicited by normocapnic hypoxaemia (arterial O2 pressure, Pa,O2, approximately 27 mmHg) by 67% (P < 0.01) and flattened the slope of the Pa,O2-rCBF response curve. 6. We conclude that the elevation of rCBF produced in the cerebral cortex by hypoxaemia is in large measure neurogenic, mediated trans-synaptically over intrinsic neuronal pathways, and initiated by excitation of oxygen sensitive neurons in the RVL.