• Background and Purpose We tested the hypothesis that cerebral hypoperfusion after experimental global cerebral ischemia is caused by plugging of the microcirculation with activated leukocytes using in vivo microscopic observation of the behavior of leukocytes in the cortical microcirculation during the transition from postischemic hyperperfusion to hypoperfusion.Methods Anesthetized and ventilated rats (n=24) were equipped with a closed cranial window. Physiological variables and cortical regional cerebral blood flow (laser-Doppler flowmetry) were measured continuously. Leukocytes were labeled intravitally with rhodamine 6G and visualized in the microcirculation of the brain surface and outer layers of the cortex with confocal laser scanning microscopy from preischemia to 4 hours after reperfusion that followed 10 minutes of global cerebral ischemia (rCBF<10% of control).Results In controls (n=8), there were no signs of leukocyte activation over the 4-hour observation period. In ischemic rats (n=16), during the transition from hyperperfusion to hypoper-S evere transient global forebrain ischemia leads to a characteristic pattern of cerebral blood flow (CBF) changes in several species: After recirculation a short period of hyperperfusion develops, followed by prolonged hypoperfusion. -2 The factors causing this blood flow pattern and its consequences for ischemic damage are not fully understood.Generally, hyperperfusion is attributed to maximal vasodilation caused by the accumulation of vasodilator metabolic products, such as H + ,K + , nitric oxide, adenosine, etc, 2 -4 although neurogenic mechanisms may be involved as well.5 It is less clear what causes hypoperfusion. The concept of a mechanical obstruction of the postischemic microcirculation with subsequent hypoperfusion 6 or "no-reflow" 7 by leukocytes ("leukocyte plugging" 8 ) has received much attention. 910 Leukocytes may be activated during ischemia, and activated leukocytes interact with the vascular endothelium, possibly resulting in microvascular obstruction. 10 In skeletal muscle, Harris and Skalak" demonstrated that even a few activated leukocytes may have a profound impact on the resistance of microvascular networks and therefore blood flow.Received April 5, 1993; final revision received October 28, 1993; accepted January 5, 1994.From the Department of Neurology, Humboldt University, Berlin, Germany.Correspondence to Dr Ulrich Dirnagl, Department of Neurology, Humboldt University, Schumannstr 20/21, 10098 Berlin, Germany.fusion there was no change in the behavior of leukocytes. Most notably, no capillary pluggers were seen. In the postischemic period only a slight increase of the number of leukocytes rolling along or sticking to the venular endothelium was seen, and very few capillaries were plugged by leukocytes. Extravasation of leukocytes into the brain tissue was observed in 8 rats beginning 2 hours after ischemia with a variable degree between animals.Conclusions Because there was only mild activation of leukocyte-endothelium interaction w...

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OBJECTIVE:to assess migraine outcome following twelve months treatment with erenumab and compare patients who underwent three months erenumab discontinuation following the first treatment cycle to those who continued monthly administrations.METHODS:this is a multicentric observational study in migraine patients in treatment with erenumab. Following a full 12 months treatment cycle (T12) patients could either continue or discontinue erenumab for at least three months. Patients who underwent treatment discontinuation were assessed following three months (T15) to decide whether to start re-treatment. Patients were then assessed following at T16 and T18.RESULTS:Thirty consecutive patients were enrolled. Nineteen patients underwent treatment suspension at T12 up to T15, whereas 11 continued phrophylaxis. At T15, patients who discontinued treatment documented significantly more migraine days (17.06±6.5 vs 4.8±2.5; p < 0.0001) and analgesics consumption (14.8±9.2 vs 4.6±2.5; p = 0.002), compared to those who continued treatment. Following re-treatment, at T16, patients who had previously undergone discontinuation documented a significant improvement in terms of migraine days (9.01±4.4 vs 17.06±6.5; p < 0.0001) and analgesics consumption (9.6±7.3 vs 14.8±9.2; p = 0.004). Such improvement was even greater at T18, comparable to T12.CONCLUSIONS:Following treatment discontinuation, a rapid migraine worsening was found, despite the high clinical response during treatment and at re-treatment, which might be secondary to an untimely interruption of a potentially disease modifying pharmacological intervention. Although clinical improvement was documented following retreatment, given the high frequency and degree of worsening during discontinuation, it seems plausible – even ethical – to re-evaluate current timing of discontinuation.CLASSIFICATION OF EVIDENCE:This study provides class III evidence that people with migraine discontinuing erenumab migraine prophylaxis after 12 months were more likely to have an increase in non-responder status and migraine days than those who continued treatment.