Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

Neurodegenerative diseases and oxidative stress.

L'incidence annuelle du syndrome de Guillain-Barre est de 1,5/100000 habitants La mortalite actuelle est estimee a environ 5 % d'apres des essais therapeutiques recents, bien conduits Dix pour cent des malades gardent des sequelles motrices tres invalidantes un an apres le debut des premiers signes neurologiques La prise en charge de ces malades necessite des equipes entrainees, multidisciplinaires, pouvant pratiquer l'ensemble des therapeutiques specifiques La corticotherapie per os'ou par voie intraveineuse est inefficace Les echanges plasmatiques sont le premier traitement dont l'efficacite a ete demontree par rapport a un groupe controle Les indications sont maintenant mieux connues Les formes benignes (marche possible) beneficient de 2 echanges plasmatiques; 2 echanges supplementaires sont realises en cas d'aggravation Dans les formes intermediaires (marche impossible) et les formes severes (recours a la ventilation mecanique), 4 echanges plasmatiques sont conseilles Il n'est pas utile d'augmenter leur nombre dans les formes severes ou en cas d'absence d'amelioration De fortes doses d'immunoglobulines donnees par voie intraveineuse (lq IV) [0,4 g/kg/j pendant 5 jours] sont aussi efficaces que les echanges plasmatiques dans les formes intermediaires et severes Dans ces formes, le choix entre Ig IV et echanges plasmatiques depend des contre-indications respectives de ces traitements et de leur faisabilite Les travaux en cours ont comme objectif de mieux preciser les indications respectives des echanges plasmatiques et des lq IV dans des formes de gravite differente, leur morbidite comparee, la dose optimale des lq IV

[Guillain-Barré syndrome].

Classification and epidemiology of MCI.

Background and Purpose— Acute rates of recanalization after intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in proximal vessel occlusion have been estimated sparingly, typically using transcranial Doppler (TCD). We aimed to study acute recanalization rates of IV rt-PA in CT angiogram-proven proximal (internal carotid artery [ICA], M1 middle cerebral artery [MCA], M2-MCA, and basilar artery) occlusions and their effects on outcome. Materials and Methods— The CT angiogram database of the Calgary stroke program was reviewed for the period 2002 to 2009. All patients with proximal vessel occlusions receiving IV rt-PA who were assessed for recanalization by TCD or angiogram (for acute endovascular treatment) were included for analysis. Rates of acute recanalization as observed on TCD/first run of angiogram and postendovascular therapy recanalization rates were noted. Modified Rankin Scale score ≤2 at 3 months was used as a good outcome. Results— Among 1341 patients in the CT angiogram database, 388 patients with proximal occlusion were identified. Of these, 216 patients had received IV rt-PA; 127 patients underwent further imaging to assess recanalization. Among the patients undergoing TCD (n=46) and cerebral angiogram (n=103), only 27 (21.25%) patients had acute recanalization. By occlusion subtype, the rates of recanalization were: distal ICA (with or without ICA neck occlusion or stenotic disease) 1 of 24 (4.4%); M1-MCA (with or without ICA neck occlusion or stenotic disease) 21 of 65 (32.3%); M2-MCA 4 of 13 (30.8%); and basilar artery 1 of 25 (4%). Onset to rt-PA time was comparable in patients with and without recanalization. Recanalization ( P Conclusions— A low rate of acute recanalization was observed with IV rt-PA in proximal vessel occlusions identified by baseline CT angiogram. Recanalization was the strongest predictor of good outcome.

Low Rates of Acute Recanalization With Intravenous Recombinant Tissue Plasminogen Activator in Ischemic Stroke. Real-World Experience and a Call for Action

Background and Purpose— Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Sys...

Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke

Editors' Note: Dr. Rosenberg questions whether the resolution of the mild cognitive impairment in the study by Drs. Koepsell and Monsell was not in fact caused by a statistical phenomenon—regression to the mean—which can make natural variation in repeated …

https://n.neurology.org/content/neurology/80/19/1818.1.full.pdf

Reversion from mild cognitive impairment to normal or near-normal cognition: Risk factors and prognosis

Background: To evaluate the time course of major vessel recanalization under IV thrombolysis in relation to functional outcome in acute ischemic stroke. Methods: A total of 99 patients with an acute anterior circulation vessel occlusion who underwent IV thrombolysis were included. All patients had a standardized admission and follow-up procedure. Color-coded duplex sonography was performed on admission, 30 minutes after thrombolysis, and at 6 and 24 hours after onset of symptoms. Recanalization was classified as complete, partial, and absent. Functional outcome was rated with the modified Rankin Scale on day 30. Results: Complete recanalization occurred significantly more frequently in patients with multiple branch occlusions compared to those with mainstem occlusion (OR 5.33; 95% CI, 2.18 to 13.05; p p p = 0.002) was significantly associated with a favorable outcome. Multivariate analysis revealed recanalization at any time within 24 hours and NIHSS scores on days 1 and 7 together explaining 75% of the functional outcome variance 30 days after stroke. Conclusions: Complete recanalization up to 24 hours after stroke onset is significantly associated with the short-term clinical course and functional outcome 30 days after acute stroke.

Recanalization after intravenous thrombolysis: does a recanalization time window exist?

Background and Purpose—DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke. Methods—One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed. Results—No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99– and 75 placebo-treated patients in the intent-to-treat cohort was (meanSD) 12.24.0 and 12.63.3, respectively; the time to needle (meanSD) was 6:361:47 and 6:281:33 hours, respectively; and the age (meanSD) was 73.39.9 and 72.09.6 years, respectively. The 90-day median change from baseline (the primary end point) was 6.0 and 5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (P0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (P0.03). Conclusions—In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex. (Stroke. 2008; 39:1774-1778.)

DP-b99, a Membrane-Activated Metal Ion Chelator, as Neuroprotective Therapy in Ischemic Stroke

Disturbance in metallochemical reactions and metal-protein association are associated with chronic neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, as well as with neurodegeneration triggered by acute cerebral ischaemia. Many neurological diseases have been linked directly or indirectly to perturbed homeostasis of Ca, Fe, Zn, or Cu ions. Consequently, acute or chronic neurodegenerative disorders represent excellent targets for exploiting metal ion chelator approaches. Drug Dev. Res. 56: 300–309, 2002. © 2002 Wiley-Liss, Inc.

Metal ion chelation in neurodegenerative disorders

Background and Purpose—DP-b99, a lipophilic moderate-affinity chelator of zinc, was postulated to improve recovery after acute ischemic stroke. We evaluated the safety and therapeutic effects of DP-b99 in patients with acute hemispheric ischemic stroke. Methods—The Membrane-Activated Chelator Stroke Intervention trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of intravenous DP-b99 administered for 4 consecutive days (NCT00893867). Acute ischemic stroke patients within 9 hours of onset, but untreated by alteplase, with a baseline National Institutes of Health Stroke Scale score of 10 to 16, and evidence of language dysfunction, visual field defect, and neglect were eligible. The primary efficacy analysis compared distributions of functional status measured by modified Rankin score in the intent-to-treat population of patients with any post-treatment outcome, adjusted for initial severity. Functional and neurological recovery were secondary measures. Home time was...

Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke

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