Background and Purpose— For a biomarker to serve as an auxiliary or surrogate outcome measure, it must be tightly correlated with and causally related to functional clinical outcome. Vessel recanalization is a potential surrogate outcome marker for functional outcome in trials of thrombolytic and mechanical recanalization therapies in acute stroke, but the correlation of recanalization and clinical outcome has not been previously systematically reviewed. Methods— Through Medline search, we identified and abstracted recanalization and outcome data from all articles published between 1985 and 2002 that assessed vessel recanalization, either spontaneous or therapeutically induced, in acute ischemic stroke. Results— Fifty-three studies encompassing 2066 patients reported recanalization rates. Recanalization rates categorized according to intervention were: spontaneous (24.1%), intravenous fibrinolytic (46.2%), intra-arterial fibrinolytic (63.2%), combined intravenous–intra-arterial (67.5%), and mechanical (83...

The Impact of Recanalization on Ischemic Stroke Outcome A Meta-Analysis

Evidence from animal experiments shows that the brain stem is involved in the pathophysiology of migraine. To investigate human migraine, we used positron emission tomography to examine the changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. During the attacks, increased blood flow was found in the cerebral hemispheres in cingulate, auditory and visual association cortices and in the brain stem. However, only the brain stem activation persisted after the injection of sumatriptan had induced complete relief from headache and phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control.

Brain stem activation in spontaneous human migraine attacks.

Background Calcitonin gene–related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks. Methods In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed. Results The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; th...

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Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine.

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

Pathophysiology of Migraine: A Disorder of Sensory Processing

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

Calcitonin Gene-Related Peptide: Physiology and Pathophysiology

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.

CGRP may play a causative role in migraine

Background and Purpose [123I]Iomazenil is a specific radioligand for the central benzodiazepine receptor that may be useful as an indicator of the intactness of cortical neurons after focal cerebral ischemia. We evaluated the binding of this receptor in reperfused cortex among patients with ischemic stroke to detect viable neurons in cortex that appeared structurally intact on conventional neuroimaging studies. Methods Fourteen patients were selected by (1) angiography within 24 hours of onset showing embolic occlusion of an intracranial artery, (2) cerebral blood flow showing ischemia of moderate severity in 12 cases and spontaneous reflow in 2 cases, and (3) thrombolysis with reperfusion within 24 hours in most cases. Thirty reperfused cortical areas that remained structurally intact, 7 infarcted cortical areas, and 6 contralateral cerebellar areas with reduced blood flow were selected as regions of interest to estimate receptor binding 5 days to 23 months after the stroke. A two-compartment model was u...

Incomplete brain infarction of reperfused cortex may be quantitated with iomazenil

Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment of migraine attacks. It is therefore important to investigate its mechanism of action in patients with migraine. We here investigate the effects of intravenous human alpha-CGRP (hαCGRP) on intracranial hemodynamics. In a double-blind, cross-over study, the effect of intravenous infusion of hαCGRP (2 μg/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (Vmean) in the middle cerebral artery (MCA), as well as the heart rate and blood pressure, were the outcome parameters. No change of rCBF was observed at the end of infusion [1.2% ± 1.7 with hαCGRP, vs. −1.6% ± 3.1 with placebo (mean ± SD)] (P = 0.43). Vmean in MCA decreased to 13.5% ± 3.6 with hαCGRP versus 0.6% ± 1.8 with placebo (P < 0.005). Since rCBF was unchanged, this indicates a dilation of the MCA. hαCGRP induced a decrease in MAP (12%) (P < 0.005) and an increase in heart rate (58%) (P < 0.0001). CGRP dilates cerebral arteries, but the effect is so small that it is unlikely to be the only mechanism of CGRP-induced migraine.

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Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients.

W e want to report an error in interpreting d,l-hexamethylpropylene amine oxime (HMPAO) tomograms as cerebral blood flow (CBF) in subacute ischemic stroke cases. By simultaneously studying CBF by `33Xe dynamic single-photon emission computed tomography (SPECT), an obvious discrepancy was noted in that the HMPAO tomograms grossly exaggerated the reflow hyperemia following spontaneous reperfusion. To interpret 'Tc-HMPAO images in terms of CBF distribution, it is essential that the same or almost the same fraction of locally supplied tracer is fixed in the various regions, healthy as well as diseased, at the time imaging is performed. This fixation is due to extraction across the blood-brain barrier (BBB) and to retention of the extracted tracer molecules, a retention caused by chemical conversion to a hydrophilic metabolite that is unable to cross cell membranes as well as the BBB. A constant degree of fractional fixation in all brain regions of 40-50% has been found in humans.1 A few series comparing 'Tc-HMPAO images with CBF tomography obtained by `33Xe as well as with C1502 positron emission tomography images have consistently shown a good agreement in normal humans and in various disease states including acute ischemic stroke,2-4 but the number of such comparisons is rather limited. Nevertheless, the impression gained from this factual basis is that 9Tc-HMPAO can be trusted to image CBF distribution after correction for a minor nonlinearity due to back-diffusion in the first few minutes.5 The fidelity of 9`Tc-HMPAO to map CBF has been taken for granted to such an extent that it has been used as a \"gold standard\" of CBF distribution in comparative studies with other SPECT tracers of CBF such as N-isopropyl-p-(1231)iodoamphetamine (123I-IMP)6 or 99mTc-N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester (`9Tc-ECD).7 We report here three cases of focal hyperfixation of 9`Tc-HMPAO in patients with subacute stroke (2-3 weeks) with evidence of infarct reperfusion. By hyperfixation we mean a higher counting rate over the infarct (relative to that of the opposite side) than can be explained by CBF as measured by 133Xe tomography at the same time. This can only occur if the fractional fixation exceeds the normal level of 40-50%. In case 1, on October 26, 1992, a 62-year-old man suddenly developed massive right-sided hemiparesis and aphasia. On day 3, SPECT with 'Tc-HMPAO showed massive reduction of tracer uptake in the anterior half of the left middle cerebral artery (MCA) distribution territory. When restudied on day 15, we first measured CBF by 133Xe tomography. As shown in Figure 1, the infarct

Hyperfixation of HMPAO in subacute ischemic stroke leading to spuriously high estimates of cerebral blood flow by SPECT.

Objective: To determine the incidence, time course, and clinical importance of spontaneous reperfusion of cerebral infarcts in patients with acute stroke. Design: Prospective, community based. Setting: Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark. Patients: Included in the incidence and time course study were 354 unselected patients with acute ischemic stroke. Clinical outcome was studied in a subgroup of 36 patients admitted on the day of stroke onset and in whom it was known whether spontaneous reperfusion occurred within the first week after stroke onset. Measurements: Computed tomography and single photon emission computed tomography, with technetium Tc 99m exametazime used as a flow tracer. The Scandinavian Stroke Scale neurologic score was determined on admission, 1 and 2 weeks after stroke, and at discharge. Results: The incidence of spontaneous reperfusion was 77% in patients with cortical infarcts. The frequency of reperfusion increased rapidly from zero at the time of onset to 60% on day 7 after stroke, reaching a maximum on day 14, at which time 77% showed reperfusion. Marked clinical improvement was observed in patients with spontaneous reperfusion ( P =.001), while no improvement occurred in patients without reperfusion. Reperfusion was not observed in subcortical infarcts. Conclusions: The rate of spontaneous reperfusion increases gradually with time and occurs within the first 2 weeks after stroke onset in approximately four of five patients with cortical infarcts. Spontaneous reperfusion seemed to improve clinical outcome.

Spontaneous Reperfusion of Cerebral Infarcts in Patients With Acute Stroke: Incidence, Time Course, and Clinical Outcome in the Copenhagen Stroke Study

B Sperling

Papers

CGRP may play a causative role in migraine

Incomplete brain infarction of reperfused cortex may be quantitated with iomazenil

Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients.

Hyperfixation of HMPAO in subacute ischemic stroke leading to spuriously high estimates of cerebral blood flow by SPECT.

Spontaneous Reperfusion of Cerebral Infarcts in Patients With Acute Stroke: Incidence, Time Course, and Clinical Outcome in the Copenhagen Stroke Study