Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized Clinical Trial.

BACKGROUND AND PURPOSE: Stent-assisted coiling may improve angiographic results of endovascular treatment of unruptured intracranial aneurysms compared with coiling alone, but this has never been shown in a randomized trial. MATERIALS AND METHODS: The Stenting in the Treatment of Aneurysm Trial was an investigator-led, parallel, randomized (1:1) trial conducted in 4 university hospitals. Patients with intracranial aneurysms at risk of recurrence, defined as large aneurysms (≥10 mm), postcoiling recurrent aneurysms, or small aneurysms with a wide neck (≥4 mm), were randomly allocated to stent-assisted coiling or coiling alone. The composite primary efficacy outcome was "treatment failure," defined as initial failure to treat the aneurysm; aneurysm rupture or retreatment during follow-up; death or dependency (mRS > 2); or an angiographic residual aneurysm adjudicated by an independent core laboratory at 12 months. The primary hypothesis (revised for slow accrual) was that stent-assisted coiling would decrease treatment failures from 33% to 15%, requiring 200 patients. Primary analyses were intent to treat. RESULTS: Of 205 patients recruited between 2011 and 2021, ninety-four were allocated to stent-assisted coiling and 111 to coiling alone. The primary outcome, ascertainable in 203 patients, was reached in 28/93 patients allocated to stent-assisted coiling (30.1%; 95% CI, 21.2%-40.6%) compared with 30/110 (27.3%; 95% CI, 19.4%-36.7%) allocated to coiling alone (relative risk = 1.10; 95% CI, 0.7-1.7; P = .66). Poor clinical outcomes (mRS >2) occurred in 8/94 patients allocated to stent-assisted coiling (8.5%; 95% CI, 4.0%-16.6%) compared with 6/111 (5.4%; 95% CI, 2.2%-11.9%) allocated to coiling alone (relative risk = 1.6; 95% CI, 0.6%-4.4%; P = .38). CONCLUSIONS: The STAT trial did not show stent-assisted coiling to be superior to coiling alone for wide-neck, large, or recurrent unruptured aneurysms.

A Pragmatic Randomized Trial Comparing Surgical Clipping and Endovascular Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Surgical clipping and endovascular treatment are commonly used in patients with unruptured intracranial aneurysms. We compared the safety and efficacy of the 2 treatments in a randomized trial. MATERIALS AND METHODS: Clipping or endovascular treatments were randomly allocated to patients with one or more 3- to 25-mm unruptured intracranial aneurysms judged treatable both ways by participating physicians. The study hypothesized that clipping would decrease the incidence of treatment failure from 13% to 4%, a composite primary outcome defined as failure of aneurysm occlusion, intracranial hemorrhage during follow-up, or residual aneurysms at 1 year, as adjudicated by a core lab. Safety outcomes included new neurologic deficits following treatment, hospitalization of >5 days, and overall morbidity and mortality (mRS > 2) at 1 year. There was no blinding. RESULTS: Two hundred ninety-one patients were enrolled from 2010 to 2020 in 7 centers. The 1-year primary outcome, ascertainable in 290/291 (99%) patients, was reached in 13/142 (9%; 95% CI, 5%-15%) patients allocated to surgery and in 28/148 (19%; 95% CI, 13%-26%) patients allocated to endovascular treatments (relative risk: 2.07; 95% CI, 1.12-3.83; P = .021). Morbidity and mortality (mRS >2) at 1 year occurred in 3/143 and 3/148 (2%; 95% CI, 1%-6%) patients allocated to surgery and endovascular treatments, respectively. Neurologic deficits (32/143, 22%; 95% CI, 16%-30% versus 19/148, 12%; 95% CI, 8%-19%; relative risk: 1.74; 95% CI, 1.04-2.92; P = .04) and hospitalizations beyond 5 days (69/143, 48%; 95% CI, 40%-56% versus 12/148, 8%; 95% CI, 5%-14%; relative risk: 0.18; 95% CI, 0.11-0.31; P < .001) were more frequent after surgery. CONCLUSIONS: Surgical clipping is more effective than endovascular treatment of unruptured intracranial aneurysms in terms of the frequency of the primary outcome of treatment failure. Results were mainly driven by angiographic results at 1 year.

Flow Diversion in the Treatment of Intracranial Aneurysms: A Pragmatic Randomized Care Trial.

BACKGROUND AND PURPOSE: Flow diversion is a recent endovascular treatment for intracranial aneurysms. We compared the safety and efficacy of flow diversion with the alternative standard management options. MATERIALS AND METHODS: A parallel group, prerandomized, controlled, open-label pragmatic trial was conducted in 3 Canadian centers. The trial included all patients considered for flow diversion. A Web-based platform 1:1 randomly allocated patients to flow diversion or 1 of 4 alternative standard management options (coiling with/without stent placement, parent vessel occlusion, surgical clipping, or observation) as prespecified by clinical judgment. Patients ineligible for alternative standard management options were treated with flow diversion in a registry. The primary safety outcome was death or dependency (mRS > 2) at 3 months. The composite primary efficacy outcome included the core lab-determined angiographic presence of a residual aneurysm, aneurysm rupture, progressive mass effect during follow-up, or death or dependency (mRS > 2) at 3-12 months. RESULTS: Between May 2011 and November 2020, three hundred twenty-three patients were recruited: Two hundred seventy-eight patients (86%) had treatment randomly allocated (139 to flow diversion and 139 to alternative standard management options), and 45 (14%) received flow diversion in the registry. Patients in the randomized trial frequently had unruptured (83%), large (52% ≥10 mm) carotid (64%) aneurysms. Death or dependency at 3 months occurred in 16/138 patients who underwent flow diversion and 12/137 patients receiving alternative standard management options (relative risk, 1.33; 95% CI, 0.65-2.69; P = .439). A poor primary efficacy outcome was found in 30.9% (43/139) with flow diversion and 45.6% (62/136) of patients receiving alternative standard management options, with an absolute risk difference of 14.7% (95% CI, 3.3%-26.0%; relative risk, 0.68; 95% CI, 0.50-0.92; P = .014). CONCLUSIONS: For patients with mostly unruptured, large, anterior circulation (carotid) aneurysms, flow diversion was more effective than the alternative standard management option in terms of angiographic outcome.

Metameric spinal AVM: Long-term symptomatic relief achieved by embolization of the extradural component.

BACKGROUND: Metameric spinal cord arteriovenous malformations (AVMs) are rare lesions characterized by an intradural and extradural component. They are difficult to treat surgically by the endovascular route. We report a case in which symptomatic relief was achieved by embolization of the extradural component only. CASE PRESENTATION: A 35-year-old woman presented with acute worsening of back pain, weakness in the left leg and urinary retention. Spinal angiography showed a metameric spinal cord AVM with partial common venous drainage of the extradural and intradural components. CONCLUSIONS: Targeted embolization of the extradural component led to dramatic improvement of the patient's symptoms, probably by achieving venous decongestion. She remains neurologically stable at two years' follow-up.

Stent-assisted coiling of posterior inferior cerebellar artery aneurysm complicated by arterial avulsion.

BACKGROUND: Rapid development of new devices and techniques in endovascular neurosurgery allows treatment of complex intracranial vascular lesions. These treatments, however, are not without risk. We report a case of unusual vascular laceration during stent-assisted coiling of a posterior inferior cerebellar artery (PICA) aneurysm. CASE PRESENTATION: A 75-year-old female with a recurrent, previously coiled PICA aneurysm developed avulsion of the parent vessel followed by fatal bleeding while an attempt was made to place a microcatheter across the aneurysmal neck for stent-assisted coiling. CONCLUSIONS: Pathological examination was performed to understand the mechanism of the rupture. The most likely mechanism was straightening of the significant vascular tortuosity, excessive tension on the vessel origin and avulsion upon advancement of the microcatheter over the microguidewire.

Spontaneous resolution of posttraumatic middle meningeal artery pseudoaneurysm.

We present a case of traumatic pseudoaneurysm of the middle meningeal artery (demonstrated on CT angiogram) associated with epidural hematoma that spontaneously resolved without treatment. Follow-up CT angiogram and conventional angiogram done 2 weeks later demonstrated complete resolution of the pseudoaneurysm. The literature suggests that these lesions require urgent treatment because they have a high mortality rate. We highlight the lack of proper data regarding the natural history of this disease and therefore lack of treatment guidelines.

Delayed treatment with AMPA, but not NMDA, antagonists reduces neocortical infarction.

We tested the abilities of two potent non-N-methyl-D-aspartate (non-NMDA) glutamate antagonists [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX)] and [1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazep ine hydrochloride (GYKI 52466)] to reduce neocortical infarction following 2 h of transient middle cerebral artery occlusion in a hypertensive stroke model in the rat and compared these effects against, and in combination with, a potent NMDA antagonist [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-amine maleate (MK-801)]. In Expt. 1, an already established cytoprotective dose of Na(+)-NBQX (30 mg/kg i.p. x 3) was compared with saline (1 ml), the NMDA antagonist MK-801 (1 mg/kg i.p. x 3), and a combination of the same doses of both NBQX and MK-801. Initial doses were delayed to 90 min following occlusion with subsequent injections at the time of reperfusion and 30 min following reperfusion. Saline-treated rats sustained 181 +/- 32 mm3 (n = 15) of neocortical infarction (mean +/- SD). This was significantly reduced by NBQX to 137 +/- 25 mm3 (n = 15, p < 0.05) of damage. Neither MK-801 (170 +/- 33 mm3; n = 11) nor the combination of MK-801 and NBQX (169 +/- 20 mm3; n = 6) proved to be cytoprotective when given with a 90-min delay. In Expt. 2, NBQX (30 mg/kg) was dissolved (6 mg/ml) in 5% dextrose and compared with both saline and dextrose (1.2 ml) i.v. infusions given over a 4-h period starting 1 h after occlusion. Saline-treated rats had a mean infarct of 183 +/- 27 mm3 (n = 6), dextrose-treated had 200 +/- 30 mm3 (n = 9), while for NBQX-treated rats it was reduced to 129 +/- 60 mm3 (n = 10, p < 0.05). Intravenous NBQX precipitated into the renal tubules, causing nephrotoxicity. In Expt. 3, rats were given either saline (1 ml i.p.) or GYKI 52466 (10 mg/kg i.p.) at 30 and 90 min following occlusion and at 30, 90, and 150 min following reperfusion. Saline-treated rats sustained 187 +/- 27 mm3 of neocortical infarction (n = 7), while those treated with GYKI 52466 were protected, with 139 +/- 38 mm3 of infarction (n = 7, p < 0.05). A clinically useful role for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate antagonists in embolic stroke is envisaged if nontoxic drugs can be developed, since cerebroprotection was achieved with delayed treatment with both of these lead compounds.

A selective N-type Ca(2+)-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia.

SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an omega-conopeptide, was tested for cytoprotection following normothermic ischemia using both a four-vessel occlusion model of severe forebrain ischemia and a model of transient middle cerebral artery occlusion focal ischemia. Adult male Wistar rats were subjected to 10 min of forebrain ischemia followed by 7 days of reperfusion. A single dose of SNX-111 (5 mg/kg) was injected intravenously following delays of either 6 or 24 h after reperfusion. For 11 rats treated with saline, there was 78 +/- 13% CA1 neuronal injury (mean +/- SD); for 11 given SNX-111 delayed by 6 h, injury was reduced to 35 +/- 30% (p < 0.01); and remarkably, treatment delayed by 24 h (n = 10), still resulted in protection, with only 50 +/- 29% injury (p < 0.05). Adult male spontaneously hypertensive rats had transient occlusion of the right middle cerebral artery of 1.5- or 2-h duration followed by 22.5 or 22 h of reperfusion, respectively. Rats were randomly assigned to receive either saline or SNX-111 (5 mg/kg i.v.), with treatment starting immediately after reperfusion (1.5-h ischemic group) or at 1 h following the onset of ischemia (2-h ischemic group). In the 1.5-h ischemic group, saline-treated animals sustained 138 +/- 32 mm3 of neocortical infarction (n = 9), and SNX-111 treatment resulted in an infarct reduction to 76 +/- 25 mm3 (n = 9; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic factors derived from recursive partition analysis (RPA) of Radiation Therapy Oncology Group (RTOG) brain metastases trials applied to surgically resected and irradiated brain metastatic cases.

PURPOSE: (a) To identify the prognostic factors that determine survival after surgical resection and irradiation of tumors metastatic to brain. (b) To determine if the prognostic factors used in the recursive partition analysis (RPA) of brain metastases cases from Radiation Therapy Oncology Group (RTOG) studies into three distinct survival classes is applicable to surgically resected and irradiated patients. METHOD: The medical records of 125 patients who had surgical resection and radiotherapy for brain metastases from 1985 to 1997 were reviewed. The patients' disease and treatment related factors were analyzed to identify factors that independently determine survival after diagnosis of brain metastasis. The patients were also grouped into three classes using the RPA-derived prognostic parameters which are: age, performance status, state of the primary disease, and presence or absence of extracranial metastases. Class 1: patients < or = 65 years of age, Karnofsky performance status (KPS) of > or =70, with controlled primary disease and no extracranial metastases; Class 3: patients with KPS < 70. Patients who do not qualify for Class 1 or 3 are grouped as Class 2. The survival of these patients was determined from the time of diagnosis of brain metastases to the time of death. RESULTS: The median survival of the entire group was 9.5 months. The three classes of patients as grouped had median survivals of 14.8, 9.9, and 6.0 months respectively (p=0.0002). Age of < 65 years, KPS of > or = 70, controlled primary disease, absence of extracranial metastases, complete surgical resection of the brain lesion(s) were found to be independent prognostic factors for survival; the total dose of radiation was not. CONCLUSION: Based on the results of this study, the patients and disease characteristics have significant impact on the survival of patients with brain metastases treated with a combination of surgical resection and radiotherapy. These parameters could be used in selecting patients who would benefit most from such treatment.

Correlation between electrophysiological effects of mexiletine and ischemic protection in central nervous system white matter.

Protection of CNS white matter tracts in brain and spinal cord is essential for maximizing clinical recovery from disorders such as stroke or spinal cord injury. Central myelinated axons are damaged by anoxia/ischemia in a Ca(2+)-dependent manner. Leakage of Na+ into the axoplasm through Na+ channels causes Ca2+ overload mainly by reverse Na(+)-Ca2+ exchange. Na+ channel blockers have thus been shown to be protective in an in vitro anoxic rat optic nerve model. Mexiletine (10 microM-1 mM), an antiarrhythmic and use-dependent Na+ channel blocker, was also significantly protective, as measured by recovery of the compound action potential after a 60 min anoxic exposure in vitro. More importantly, mexiletine (80 mg/kg, i.p.) also significantly protected optic nerves from injury in a model of in situ ischemia. This in situ model is more clinically relevant as it addresses drug pharmacokinetics, toxicity and CNS penetration. Optic nerve recovery cycles (defined as shifts in latency of compound action potentials with paired stimulation) were used to measure the concentration of mexiletine in optic nerves after systemic administration, estimated at approximately 42 microM 1 h after a single dose of 80 mg/kg, i.p. These results indicate that mexiletine is able to penetrate into the CNS at concentrations sufficient to confer significant protection. Na+ channel blockers such as mexiletine may prove to be effective clinical therapeutic agents for protecting CNS white matter tracts against anoxic/ischemic injury.

The effects of caffeine on ischemic neuronal injury as determined by magnetic resonance imaging and histopathology.

The effects of caffeine on ischemic neuronal injury were determined in rats subjected to forebrain ischemia induced by bilateral carotid occlusion and controlled hypotension (50 mmHg for 10 min). High resolution (100 microns) multi-slice, multi-echo magnetic resonance images were obtained daily for three consecutive days post-operatively in sham-operated rats and in rats that received either saline vehicle (controls), a single i.v. injection of 10 mg/kg caffeine 30 min prior to an ischemic insult (acute caffeine group), or up to 90 mg/kg per day of caffeine for three consecutive weeks prior to an ischemic insult (chronic caffeine group). Rats in the control group exhibited enhanced magnetic resonance image intensity in the striatum 24 h after ischemia which increased in the striatum and also appeared in the hippocampus after 48 h, and which began to resolve in both regions by 72 h post-ischemia. Histopathological analysis of each rat following the final magnetic resonance examination showed that ischemic neuronal injury was strictly confined to the brain regions showing magnetic resonance image changes. Acute caffeine rats showed accelerated changes in the magnetic resonance images, with increased hippocampal intensity appearing at 24 h post-ischemia. Although there was magnetic resonance evidence of accelerated injury, quantitative analysis of the histopathological data at 72 h showed no significant difference in the extent of neuronal injury in any brain region between control-ischemic and acute caffeine rats. Nine out of 11 rats in the chronic caffeine group showed no magnetic resonance image changes over the three study days. Chronic caffeine rats had significantly less neuronal damage in all vulnerable brain regions than either of the other groups of ischemic rats. The accelerated ischemic injury in rats treated with an acute dose of caffeine may occur secondary to antagonism of adenosine receptors, whereas protection from ischemic injury following chronic administration of caffeine may be mediated by up-regulation of adenosine receptors.

Delayed AMPA receptor blockade reduces cerebral infarction induced by focal ischemia.

The potent and selective AMPA receptor antagonist NBQX was tested for cytoprotective properties in an adult rat model of transient focal neocortical ischemia. Nineteen spontaneously hypertensive rats sustained 2 h of middle cerebral artery occlusion, followed by 22 h of recirculation. Ninety minutes following the onset of ischemia, at the time of, and 30 min following reperfusion, they received i.p. injections of either saline (n = 10) or 30 mg kg-1 of NBQX (n = 9). Saline-treated rats had a mean volume of neocortical infarction ( +/- s.d.) of 181 +/- 31 mm3, while NBQX-treated rats sustained significantly less damage, 125 +/- 19 mm3 (p less than 0.001). Regional cerebral blood flows during ischemia and reperfusion were not affected by the drug. We suggest that the AMPA receptor may play an important role in ischemic cerebral infarction.

The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury.

Mechanisms responsible for anoxic/ischemic cell death in mammalian CNS grey and white matter involve an increase in intracellular Ca2+, however the routes of Ca2+ entry appear to differ. In white matter, pathological Ca2+ influx largely occurs as a result of reversal of Na+-Ca2+ exchange, due to increased intracellular Na+ and membrane depolarization. Na+ channel blockade has therefore been logically and successfully employed to protect white matter from ischemic injury. In grey matter ischemia, it has been traditionally presumed that activation of agonist (glutamate) operated and voltage dependent Ca2+ channels are the primary routes of Ca2+ entry. Less attention has been directed towards Na+-Ca2+ exchange and Na+ channel blockade as a protective strategy in grey matter. This study investigates mexiletine, a use-dependent sodium channel blocker known to provide significant ischemic neuroprotection to white matter, as a grey matter protectant. Pentobarbital (65 mg/kg) anesthetized, mechanically ventilated Sprague-Dawley rats were treated with mexiletine (80 mg/kg, i.p.). Then 25 min later the animals were subjected to 10 min of bilateral carotid occlusion plus controlled hypotension to 50 Torr by temporary partial exsanguination. Animals were sacrificed with perfusion fixation after 7 days. Ischemic and normal neurons were counted in standard H&E sections of hippocampal CA1 and the ratio of ischemic to total neurons calculated. Mexiletine pre-treatment reduced hippocampal damage by approximately half when compared to control animals receiving saline alone (45 vs. 88% damage, respectively; P<0.001). These results suggest that mexiletine (and perhaps other drugs of this class) can provide protection from ischemia to grey matter as well as white matter.

Intracranial suprasellar angiolipoma: ultrastructural and immunohistochemical features.

The authors present ultrastructural and immunohistochemical characteristics of an intracranial suprasellar tumor displaying features of cavernous angioma with islets of adipose tissue. Electron microscopy revealed thin-walled vessels separated by a loose collagenous stroma containing nests of mature adipocytes as well as fibroblasts, myofibroblasts, mast cells, and a few macrophages. Intracytoplasmic lipid droplets were also identified in scattered pericytes and smooth muscle cells of vascular walls and in the transitional cells resembling smooth muscle cells and adipocytes. Many adipose tissue cells were positive for S-100 protein with polyclonal antibodies. Other lipidized tumor cells were immunoreactive for some or all of the following: smooth muscle-specific actin, factor XIIIa, vimentin, and, occasionally, for desmin. Ultrastructure and immunohistochemistry indicate that in addition to typical adipocytes, lipidized cells of another nature contribute to the characteristic appearance of the adipose tissue component of angiolipoma.

Magnetic resonance imaging and 31P magnetic resonance spectroscopy study of the effect of temperature on ischemic brain injury.

Transient forebrain ischemia was induced in rats whose brain temperature was 31, 33, 35, 38, or 40 degrees C. The development of regional injury was followed using magnetic resonance (MR) imaging, with the ultimate extent of neuronal injury quantified histopathologically. Animals in the hypothermic groups showed minimal changes in MR images over 4 days; normothermic animals showed intensity enhancement attributed to progressive edema developing in the striatum and, later, in the hippocampus. Ischemia at 40 degrees C resulted in widespread edema formation by 1 day post-ischemia; animals in this group did not survive beyond 30 hours. Histopathological analysis at 4 days (1 day for the hyperthermic group) post-ischemia showed that neuronal damage in the normothermic group was confined to the hippocampus and striatum. Minimal damage was found in the hypothermic groups; damage in the hyperthermic group was severe throughout the forebrain. There were no differences in the pre-ischemia 31P MR spectra for the different groups. During ischemia, the increase in intensity of the Pi peak and the fall in tissue pH increased with temperature in the order hypothermic less than normothermic less than hyperthermic group of animals. Post-ischemia energy recovery was similar in all groups, while pH recovered more rapidly in hypothermic animals.

False aneurysm of the cavernous carotid artery: a complication of transsphenoidal surgery.

Although excellent results currently are being achieved with transsphenoidal surgery, life-threatening complications may occasionally result from this approach. We present a patient with carotid injury sustained during transsphenoidal surgery, who presented 6 weeks postoperatively with a large false aneurysm in the cavernous part of the right internal carotid artery. This lesion was successfully treated by trapping. The pathogenesis of this complication is discussed and the relevant literature is reviewed.

Effect of mannitol, nimodipine, and indomethacin singly or in combination on cerebral ischemia in rats.

The effects of mannitol, nimodipine, and indomethacin on ischemic neuronal injury were examined in 45 rats divided equally into nine groups subjected to 10 minutes of forebrain ischemia. Of two control groups, one received maintenance fluids while the other received a normal saline bolus. In the remaining seven groups, mannitol, nimodipine, and indomethacin were administered singly or in combination 5 minutes before forebrain ischemia. Seven days after ischemia, the brains were perfusion-fixed, sectioned coronally into 2.8-mm slices, and stained with hematoxylin and eosin. Ischemic neurons were directly counted on predetermined regions of standardized serial sections. Considerable amelioration of ischemic injury (ischemic neurons/total neurons) was observed with mannitol (ischemic injury, 7 +/- 5% in the hippocampal CA1/CA2 sectors and 28 +/- 17% in the CA3 sector). This is in contrast to control values of 64 +/- 11% and 80 +/- 6%, respectively, and those obtained in the normal saline group of 70 +/- 10% and 59 +/- 13%, respectively. The beneficial effect with nimodipine reached significance in only the hippocampal CA3 sector (ischemic injury, 35 +/- 21%). Indomethacin showed no significant benefit. Combining the agents resulted in significantly reduced neuronal injury compared with control groups, although the effect was not greater than that achieved with mannitol alone. The degree of ischemic injury was least when all three agents were used in combination (ischemic injury, 12 +/- 12% in the hippocampal CA1/CA2 sectors and 4 +/- 4% in the CA3 sector). Our data support the concept that successfully blocking the ischemic cascade with a single, diversely acting agent or multiple agents will evoke the best beneficial response.

Experimental cerebral ischemia studied using nuclear magnetic resonance imaging and spectroscopy.

The effects of short-duration forebrain ischemia on cerebral metabolism in the rat have been studied using several nuclear magnetic resonance (NMR) techniques. In vivo phosphorus-31 (31P) NMR spectroscopy showed that the model produces rapid cerebral energy failure and acidosis. Reperfusion was accompanied by recovery of high-energy metabolites in about 30 minutes, with a slower recovery of pH. Proton (1H) NMR spectra of perchloric acid extracts of selected brain regions showed that levels of alanine and gamma-aminobutyric acid (GABA) were elevated and the level of glutamate was depressed immediately after the ischemic insult, returning to normal by 24 hours. The lactate level remained elevated for up to 7 days after ischemia, suggesting ongoing abnormal mitochondrial function. Postischemic cerebral glucose metabolism was monitored using carbon-13 (13C)-labelled glucose as an NMR probe. Glycolysis was impaired immediately after the ischemic insult, resulting in accumulation of glucose in the tissue and reduced formation of amino acids and tricarboxylic acid cycle intermediates. Glycolysis recovered by 1 hour, but underwent a secondary decrease at 24 hours, the time at which neuronal injury became manifest histologically and physiologically. Nuclear magnetic resonance imaging was used to follow the regional development of tissue injury in selectively vulnerable brain regions. Striatal changes were evident by 24 hours after reperfusion, increasing in intensity and accompanied by hippocampal changes by 48 hours, then becoming less pronounced by 72 hours. Histologic analysis of regional neuronal injury correlated well with the imaging results, establishing NMR imaging as a noninvasive method of visualizing the regional development of ischemic tissue injury.