K. Hajjar

Timing of Conditioned Eyeblink Responses Is Impaired in Cerebellar Patients

In the present study, timing of conditioned eyeblink responses (CRs) was investigated in cerebellar patients and age-matched controls using a standard delay paradigm. Findings were compared with previously published data of CR incidences in the same patient population (Gerwig et al., 2003; Timmann et al., 2005). Sixteen patients with pure cortical cerebellar degeneration (spinocerebellar ataxia type 6 and idiopathic cerebellar ataxia), 14 patients with lesions within the territory of the superior cerebellar artery, and 13 patients with infarctions within the territory of the posterior inferior cerebellar artery were included. The affected cerebellar lobules and possible involvement of cerebellar nuclei were determined by three-dimensional magnetic resonance imaging (MRI) in patients with focal lesions (n = 27). Based on a voxel-by-voxel analysis, MRI lesion data were related to eyeblink conditioning data. CR incidence was significantly reduced, and CRs occurred significantly earlier in patients with cortical cerebellar degeneration and lesions of the superior cerebellum compared with controls. Incidence and timing of CRs was not impaired in patients with lesions restricted to the posterior and inferior cerebellum. Voxel-based MRI analysis revealed that cortical areas within the anterior lobe (Larsell lobule HV) were most significantly related to timing deficits, whereas reduced CR incidences were related to more caudal parts (lobule HVI) of the superior cerebellar cortex. The present data suggest that different parts of the superior cerebellar cortex may be involved in the formation of the stimulus association and appropriate timing of conditioned eyeblink responses in humans. Extracerebellar premotoneuronal disinhibition, however, is another possible explanation for changes in CR timing.

Robotic Measurement of Arm Movements After Stroke Establishes Biomarkers of Motor Recovery

Background and Purpose— Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. Methods— In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. Results— Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R2 of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). Conclusions— These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.

Extinction of conditioned eyeblink responses in patients with cerebellar disorders.

Extinction of conditioned eyeblink responses (CRs) was analyzed in sixteen patients with pure cortical cerebellar degeneration, 14 patients with lesions within the territory of the superior cerebellar artery (SCA), 13 patients with infarctions within the territory of the posterior inferior cerebellar artery (PICA) and 45 age-matched controls. Three-dimensional (3D) magnetic resonance (MRI) data sets were acquired in patients with focal lesions to identify affected cerebellar lobules and possible involvement of nuclei. Eyeblink conditioning was performed using a standard delay protocol. At the end of the experiment 10 CS-alone trials were presented as extinction trials. Controls showed significant effects of extinction that is a significant decline comparing CR-incidences in the extinction trials and the last block of 10 trials of the paired trials. In the group of all cerebellar patients, however, no significant effects of extinction were observed. In patients with unilateral lesions effects of extinction were present on the unaffected, but not on the affected side. Deficits of extinction were observed in PICA and SCA patients both with and without involvement of cerebellar nuclei. Extending previous reports in cerebellar patients the present findings show that the ipsilateral cerebellar hemisphere contributes to extinction of conditioned eyeblink responses in humans. It cannot be ruled out, however, that impaired acquisition affected the extinction results.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

Background Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. Methods We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran–Mantel–Haenszel test. Results Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43–1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18–1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90–1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. Conclusion Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

New anticoagulants for stroke prevention in atrial fibrillation

ZusammenfassungPatienten mit Vorhofflimmern haben ein hohes Schlaganfallrisiko. Dieses Risiko kann durch Vitamin-K-Antagonisten wie Phenprocoumon oder Warfarin sowohl in der Primär- als auch in der Sekundärprävention, verglichen mit Placebo, um 60–70% reduziert werden. Vitamin-K-Antagonisten haben allerdings eine Vielzahl von Problemen in der praktischen Anwendung, was die relativ geringe Einnahmefrequenz bei Patienten mit Vorhofflimmern erklärt. Neue orale Antikoagulanzien wie direkte Thrombininhibitoren (Dabigatran) oder direkte Faktor-Xa-Hemmer wie Rivaroxaban und Apixaban zeigten eine im Vergleich zu Warfarin mindestens ebenbürtige wenn nicht höhere Wirksamkeit und zum Teil auch eine niedrigere Inzidenz an schwerwiegenden Blutungskomplikationen. Die neuen Substanzen sind sowohl in der Sekundär- als auch in der Primärprävention von Schlaganfällen bei Patienten mit Vorhofflimmern wirksam. Apixaban ist auch deutlich wirksamer als Azetylsalizylsäure bei Patienten, die für eine Behandlung mit Warfarin nicht geeignet sind, bei vergleichbarer Rate an schwerwiegenden Blutungskomplikationen.AbstractOral anticoagulation with vitamin K antagonists (warfarin, phenprocoumon) is successful in both primary and secondary stroke prevention for patients with atrial fibrillation (AF), yielding a 60–70% relative reduction in stroke risk compared with placebo and a mortality reduction of 26%. However, these agents have a number of well documented shortcomings. This review describes the current landscape and developments in stroke prevention in patients with AF with special reference to secondary prevention. A number of new drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists are under investigation. These include direct factor Xa inhibitors and direct thrombin inhibitors. Recent studies (RE-LY, ROCKET-AF, AVERROES, ARISTOTLE) provide promising results for these new agents including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF. The new anticoagulants add to the therapeutic options for patients with AF and offer a number of advantages over warfarin for both clinician and patient, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants will improve clinical decision-making.Oral anticoagulation with vitamin K antagonists (warfarin, phenprocoumon) is successful in both primary and secondary stroke prevention for patients with atrial fibrillation (AF), yielding a 60-70% relative reduction in stroke risk compared with placebo and a mortality reduction of 26%. However, these agents have a number of well documented shortcomings. This review describes the current landscape and developments in stroke prevention in patients with AF with special reference to secondary prevention. A number of new drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists are under investigation. These include direct factor Xa inhibitors and direct thrombin inhibitors. Recent studies (RE-LY, ROCKET-AF, AVERROES, ARISTOTLE) provide promising results for these new agents including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF. The new anticoagulants add to the therapeutic options for patients with AF and offer a number of advantages over warfarin for both clinician and patient, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants will improve clinical decision-making.

Neue Antikoagulanzien zur Schlaganfallprävention bei Vorhofflimmern

ZusammenfassungPatienten mit Vorhofflimmern haben ein hohes Schlaganfallrisiko. Dieses Risiko kann durch Vitamin-K-Antagonisten wie Phenprocoumon oder Warfarin sowohl in der Primär- als auch in der Sekundärprävention, verglichen mit Placebo, um 60–70% reduziert werden. Vitamin-K-Antagonisten haben allerdings eine Vielzahl von Problemen in der praktischen Anwendung, was die relativ geringe Einnahmefrequenz bei Patienten mit Vorhofflimmern erklärt. Neue orale Antikoagulanzien wie direkte Thrombininhibitoren (Dabigatran) oder direkte Faktor-Xa-Hemmer wie Rivaroxaban und Apixaban zeigten eine im Vergleich zu Warfarin mindestens ebenbürtige wenn nicht höhere Wirksamkeit und zum Teil auch eine niedrigere Inzidenz an schwerwiegenden Blutungskomplikationen. Die neuen Substanzen sind sowohl in der Sekundär- als auch in der Primärprävention von Schlaganfällen bei Patienten mit Vorhofflimmern wirksam. Apixaban ist auch deutlich wirksamer als Azetylsalizylsäure bei Patienten, die für eine Behandlung mit Warfarin nicht geeignet sind, bei vergleichbarer Rate an schwerwiegenden Blutungskomplikationen.AbstractOral anticoagulation with vitamin K antagonists (warfarin, phenprocoumon) is successful in both primary and secondary stroke prevention for patients with atrial fibrillation (AF), yielding a 60–70% relative reduction in stroke risk compared with placebo and a mortality reduction of 26%. However, these agents have a number of well documented shortcomings. This review describes the current landscape and developments in stroke prevention in patients with AF with special reference to secondary prevention. A number of new drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists are under investigation. These include direct factor Xa inhibitors and direct thrombin inhibitors. Recent studies (RE-LY, ROCKET-AF, AVERROES, ARISTOTLE) provide promising results for these new agents including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF. The new anticoagulants add to the therapeutic options for patients with AF and offer a number of advantages over warfarin for both clinician and patient, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants will improve clinical decision-making.Oral anticoagulation with vitamin K antagonists (warfarin, phenprocoumon) is successful in both primary and secondary stroke prevention for patients with atrial fibrillation (AF), yielding a 60-70% relative reduction in stroke risk compared with placebo and a mortality reduction of 26%. However, these agents have a number of well documented shortcomings. This review describes the current landscape and developments in stroke prevention in patients with AF with special reference to secondary prevention. A number of new drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists are under investigation. These include direct factor Xa inhibitors and direct thrombin inhibitors. Recent studies (RE-LY, ROCKET-AF, AVERROES, ARISTOTLE) provide promising results for these new agents including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF. The new anticoagulants add to the therapeutic options for patients with AF and offer a number of advantages over warfarin for both clinician and patient, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants will improve clinical decision-making.

New aspects of stroke medicine

ZusammenfassungDie systemische Thrombolyse mit „recombinant tissue-type plasminogen activator“ (rt-PA) bleibt weiterhin die einzige wirksame und zugelassene medikamentöse Behandlung des akuten ischämischen Insults. Eine Vielzahl von Studien belegt, wie wichtig die möglichst schnelle Rekanalisation ist. Die Wirksamkeit der Thrombektomie ist bisher in randomisierten Studien nicht ausreichend belegt. Deswegen ist die Aufnahme von geeigneten Patienten in die derzeit laufenden randomisierten Therapiestudien von hoher Bedeutung. Die frühe Gabe von Magnesium beim ischämischen Insult auch außerhalb des Krankenhauses war nicht neuroprotektiv wirksam. Für die Prävention von tiefen Beinvenenthrombosen und Lungenembolien hat sich die intermittierende pneumatische Kompression der unteren Extremitäten bei immobilisierten Patienten mit Schlaganfall als wirksam erwiesen. Die Kombination von Acetylsalicylsäure (ASS) und Clopidogrel ist der ASS-Monotherapie bei Patienten mit lakunärem Schlaganfall nicht überlegen und führt zu vermehrten Blutungskomplikationen. Die neuen oralen Antikoagulanzien (NOAK) sind auch in der Sekundärprävention besser wirksam als Warfarin und haben insgesamt ein erniedrigtes Risiko intrakranieller sowie systemischer schwerwiegender Blutungskomplikationen. In neuen Studien soll untersucht werden, ob Dabigatran und Rivaroxaban in der Schlaganfallprävention bei Patienten mit kryptogenem Schlaganfall einer ASS-Monotherapie überlegen sind.SummarySystemic thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains the only effective and approved medical treatment of acute ischemic stroke. Several studies have demonstrated the importance of rapid recanalization. The efficacy of thrombectomy has so far not been sufficiently shown in randomized clinical trials; therefore, inclusion of suitable patients in one of the currently ongoing randomized trials is of great importance. The early treatment with magnesium after acute ischemic stroke during the pre-hospital phase did not prove to be neuroprotective. Intermittent pneumatic compression of the lower extremities in immobilized stroke patients effectively prevents deep venous thrombosis and pulmonary embolism. In patients with lacunar stroke the combination of aspirin and clopidogrel is not superior to aspirin alone and causes more bleeding complications. The novel oral anticoagulants are superior to warfarin in secondary prevention and carry a lower risk of intracranial and systemic bleeding complications. New studies will investigate whether dabigatran or rivaroxaban are superior to aspirin in secondary prevention after cryptogenic stroke.Systemic thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains the only effective and approved medical treatment of acute ischemic stroke. Several studies have demonstrated the importance of rapid recanalization. The efficacy of thrombectomy has so far not been sufficiently shown in randomized clinical trials; therefore, inclusion of suitable patients in one of the currently ongoing randomized trials is of great importance. The early treatment with magnesium after acute ischemic stroke during the pre-hospital phase did not prove to be neuroprotective. Intermittent pneumatic compression of the lower extremities in immobilized stroke patients effectively prevents deep venous thrombosis and pulmonary embolism. In patients with lacunar stroke the combination of aspirin and clopidogrel is not superior to aspirin alone and causes more bleeding complications. The novel oral anticoagulants are superior to warfarin in secondary prevention and carry a lower risk of intracranial and systemic bleeding complications. New studies will investigate whether dabigatran or rivaroxaban are superior to aspirin in secondary prevention after cryptogenic stroke.

Neues aus der Schlaganfallmedizin@@@New aspects of stroke medicine

ZusammenfassungDie systemische Thrombolyse mit „recombinant tissue-type plasminogen activator“ (rt-PA) bleibt weiterhin die einzige wirksame und zugelassene medikamentöse Behandlung des akuten ischämischen Insults. Eine Vielzahl von Studien belegt, wie wichtig die möglichst schnelle Rekanalisation ist. Die Wirksamkeit der Thrombektomie ist bisher in randomisierten Studien nicht ausreichend belegt. Deswegen ist die Aufnahme von geeigneten Patienten in die derzeit laufenden randomisierten Therapiestudien von hoher Bedeutung. Die frühe Gabe von Magnesium beim ischämischen Insult auch außerhalb des Krankenhauses war nicht neuroprotektiv wirksam. Für die Prävention von tiefen Beinvenenthrombosen und Lungenembolien hat sich die intermittierende pneumatische Kompression der unteren Extremitäten bei immobilisierten Patienten mit Schlaganfall als wirksam erwiesen. Die Kombination von Acetylsalicylsäure (ASS) und Clopidogrel ist der ASS-Monotherapie bei Patienten mit lakunärem Schlaganfall nicht überlegen und führt zu vermehrten Blutungskomplikationen. Die neuen oralen Antikoagulanzien (NOAK) sind auch in der Sekundärprävention besser wirksam als Warfarin und haben insgesamt ein erniedrigtes Risiko intrakranieller sowie systemischer schwerwiegender Blutungskomplikationen. In neuen Studien soll untersucht werden, ob Dabigatran und Rivaroxaban in der Schlaganfallprävention bei Patienten mit kryptogenem Schlaganfall einer ASS-Monotherapie überlegen sind.SummarySystemic thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains the only effective and approved medical treatment of acute ischemic stroke. Several studies have demonstrated the importance of rapid recanalization. The efficacy of thrombectomy has so far not been sufficiently shown in randomized clinical trials; therefore, inclusion of suitable patients in one of the currently ongoing randomized trials is of great importance. The early treatment with magnesium after acute ischemic stroke during the pre-hospital phase did not prove to be neuroprotective. Intermittent pneumatic compression of the lower extremities in immobilized stroke patients effectively prevents deep venous thrombosis and pulmonary embolism. In patients with lacunar stroke the combination of aspirin and clopidogrel is not superior to aspirin alone and causes more bleeding complications. The novel oral anticoagulants are superior to warfarin in secondary prevention and carry a lower risk of intracranial and systemic bleeding complications. New studies will investigate whether dabigatran or rivaroxaban are superior to aspirin in secondary prevention after cryptogenic stroke.Systemic thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains the only effective and approved medical treatment of acute ischemic stroke. Several studies have demonstrated the importance of rapid recanalization. The efficacy of thrombectomy has so far not been sufficiently shown in randomized clinical trials; therefore, inclusion of suitable patients in one of the currently ongoing randomized trials is of great importance. The early treatment with magnesium after acute ischemic stroke during the pre-hospital phase did not prove to be neuroprotective. Intermittent pneumatic compression of the lower extremities in immobilized stroke patients effectively prevents deep venous thrombosis and pulmonary embolism. In patients with lacunar stroke the combination of aspirin and clopidogrel is not superior to aspirin alone and causes more bleeding complications. The novel oral anticoagulants are superior to warfarin in secondary prevention and carry a lower risk of intracranial and systemic bleeding complications. New studies will investigate whether dabigatran or rivaroxaban are superior to aspirin in secondary prevention after cryptogenic stroke.

Neues aus der Schlaganfallmedizin

ZusammenfassungDie systemische Thrombolyse mit „recombinant tissue-type plasminogen activator“ (rt-PA) bleibt weiterhin die einzige wirksame und zugelassene medikamentöse Behandlung des akuten ischämischen Insults. Eine Vielzahl von Studien belegt, wie wichtig die möglichst schnelle Rekanalisation ist. Die Wirksamkeit der Thrombektomie ist bisher in randomisierten Studien nicht ausreichend belegt. Deswegen ist die Aufnahme von geeigneten Patienten in die derzeit laufenden randomisierten Therapiestudien von hoher Bedeutung. Die frühe Gabe von Magnesium beim ischämischen Insult auch außerhalb des Krankenhauses war nicht neuroprotektiv wirksam. Für die Prävention von tiefen Beinvenenthrombosen und Lungenembolien hat sich die intermittierende pneumatische Kompression der unteren Extremitäten bei immobilisierten Patienten mit Schlaganfall als wirksam erwiesen. Die Kombination von Acetylsalicylsäure (ASS) und Clopidogrel ist der ASS-Monotherapie bei Patienten mit lakunärem Schlaganfall nicht überlegen und führt zu vermehrten Blutungskomplikationen. Die neuen oralen Antikoagulanzien (NOAK) sind auch in der Sekundärprävention besser wirksam als Warfarin und haben insgesamt ein erniedrigtes Risiko intrakranieller sowie systemischer schwerwiegender Blutungskomplikationen. In neuen Studien soll untersucht werden, ob Dabigatran und Rivaroxaban in der Schlaganfallprävention bei Patienten mit kryptogenem Schlaganfall einer ASS-Monotherapie überlegen sind.SummarySystemic thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains the only effective and approved medical treatment of acute ischemic stroke. Several studies have demonstrated the importance of rapid recanalization. The efficacy of thrombectomy has so far not been sufficiently shown in randomized clinical trials; therefore, inclusion of suitable patients in one of the currently ongoing randomized trials is of great importance. The early treatment with magnesium after acute ischemic stroke during the pre-hospital phase did not prove to be neuroprotective. Intermittent pneumatic compression of the lower extremities in immobilized stroke patients effectively prevents deep venous thrombosis and pulmonary embolism. In patients with lacunar stroke the combination of aspirin and clopidogrel is not superior to aspirin alone and causes more bleeding complications. The novel oral anticoagulants are superior to warfarin in secondary prevention and carry a lower risk of intracranial and systemic bleeding complications. New studies will investigate whether dabigatran or rivaroxaban are superior to aspirin in secondary prevention after cryptogenic stroke.Systemic thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) remains the only effective and approved medical treatment of acute ischemic stroke. Several studies have demonstrated the importance of rapid recanalization. The efficacy of thrombectomy has so far not been sufficiently shown in randomized clinical trials; therefore, inclusion of suitable patients in one of the currently ongoing randomized trials is of great importance. The early treatment with magnesium after acute ischemic stroke during the pre-hospital phase did not prove to be neuroprotective. Intermittent pneumatic compression of the lower extremities in immobilized stroke patients effectively prevents deep venous thrombosis and pulmonary embolism. In patients with lacunar stroke the combination of aspirin and clopidogrel is not superior to aspirin alone and causes more bleeding complications. The novel oral anticoagulants are superior to warfarin in secondary prevention and carry a lower risk of intracranial and systemic bleeding complications. New studies will investigate whether dabigatran or rivaroxaban are superior to aspirin in secondary prevention after cryptogenic stroke.

Stärken und Grenzen der neuen Antikoagulanzienhofflimmern

Vorhofflimmern ist die häufigste Form der kardialen Arrhythmie im Alter und ein wichtiger unabhängiger Risikofaktor für ischämische Insulte. In der Vergangenheit wurden Patienten mit Vorhofflimmern mit Vitamin-K-Antagonisten antikoaguliert. Damit konnte das Schlaganfallrisiko um 60–70% reduziert werden. Die neuen Antikoagulanzien haben den Vorteil, dass sie in einer fixen Dosis gegeben werden und dass keine Kontrolle der Gerinnungshemmung notwendig ist.