Special topic section: linkages among cerebrovascular, cardiovascular, and cognitive disorders: Preventing dementia by preventing stroke: The Berlin Manifesto.

The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action. © 2019 the Alzheimer's Association and the World Stroke Organisation. Published by Elsevier Inc. All rights reserved.

Preventing dementia by preventing stroke: The Berlin Manifesto.

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.

Changing the mindset in life sciences toward translation: a consensus.

Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.

Lumbar spinal stenosis: syndrome, diagnostics and treatment.

Lumbar spinal stenosis (LSS) comprises narrowing of the spinal canal with subsequent neural compression, and is frequently associated with symptoms of neurogenic claudication. To establish a diagnosis of LSS, clinical history, physical examination results and radiological changes all need to be considered. Patients who exhibit mild to moderate symptoms of LSS should undergo multimodal conservative treatment, such as patient education, pain medication, delordosing physiotherapy and epidural injections. In patients with severe symptoms, surgery is indicated if conservative treatment proves ineffective after 3-6 months. Clinically relevant motor deficits or symptoms of cauda equina syndrome remain absolute indications for surgery. The first randomized, prospective studies have provided class I-II evidence that supports a more rapid and profound decline of LSS symptoms after decompressive surgery than with conservative therapy. In the absence of a valid paraclinical diagnostic marker, however, more evidence-based data are needed to identify those patients for whom the benefit of surgery would outweigh the risk of developing complications. In this Review, we briefly survey the underlying pathophysiology and clinical appearance of LSS, and explore the available diagnostic and therapeutic options, with particular emphasis on neuroradiological findings and outcome predictors.

ESPRIT study design and outcomes--a critical appraisal.

Evidence is needed to guide therapeutic decisions on patients who had ischaemic cerebral events. The recently published European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), an open-label randomised controlled study, compared long-term treatment of patients randomised to aspirin 30-325 mg daily with (n = 1363) or without (n = 1376) dipyridamole 200 mg twice daily. The study found the combination to be superior to aspirin alone (13% vs. 16% events in a composite endpoint of vascular death, non-fatal stroke, non-fatal myocardial infarction, or major bleeding; hazard ratio 0.8; 95% confidence interval 0.66-0.98). In the interpretation of the results, criticism has been raised related to the study design (open-label, change during the study), the study conduct (half of the aspirin patients underdosed, 33% drop-out rate in the combination group, missing information on potential confounders such as protective concomitant medication), and the outcomes (lack of differences in the efficacy outcomes between the intent-to-treat and the on-treatment populations, lack of differences in minor bleedings between treatment groups, borderline statistical significance of primary study endpoint). Further studies are needed to determine the place of aspirin/dipyridamole combinations in the secondary prevention of stroke.

Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO.

In rats, cortical spreading hyperaemia is coupled to a spreading neuroglial depolarization wave (spreading depression) under physiological conditions, whereas cortical spreading ischaemia is coupled to it if red blood cell products are present in the subarachnoid space. Spreading ischaemia has been proposed as the pathophysiological correlate of the widespread cortical infarcts abundantly found in autopsy studies of patients with subarachnoid haemorrhage. The purpose of the present study was to investigate whether the extracellular ion changes associated with the depolarization wave may cause the vasoconstriction underlying spreading ischaemia. We induced spreading ischaemia in vivo with the nitric oxide (NO) scavenger oxyhaemoglobin and an elevated K+ concentration in the subarachnoid space while slow potential, pH, extracellular volume and concentrations of K+, Na+, Ca2+ and Cl- were measured in the cortex with microelectrodes. We then extraluminally applied an ionic cocktail (cocktail(SI)) to the isolated middle cerebral artery in vitro, matching the ionic composition of the extracellular space as measured during spreading ischaemia in vivo. Extraluminal application of cocktail(SI) caused middle cerebral artery dilatation in the absence and constriction in the presence of NO synthase inhibition in vitro, corresponding with the occurrence of spreading hyperaemia in the presence and spreading ischaemia in the absence of NO in vivo. The L-type Ca2+ inhibitor nimodipine caused the cocktail(SI)-induced vasoconstriction to revert to vasodilatation in the absence of NO in vitro similar to the reversal of spreading ischaemia to spreading hyperaemia in response to nimodipine in vivo. We found that K+ was the predominant vasoconstrictor contained in cocktail(SI). Its vasoconstrictor action was augmented by NO synthase inhibition. Our results suggest that, under elevated baseline K+ as a hallmark of any condition of energy deficiency, the extracellular ion changes represent the essential mediator of the vascular response to spreading neuroglial depolarization. In the presence of NO they mediate vasodilatation and in its absence they mediate constriction.

Timing the valve replacement in infective endocarditis involving the brain.

Neurological complications are very frequent in patients with infective endocarditis (20-40 %). In these patients it is unclear at what time a valve replacement should be performed. In order to develop a data based recommendation we studied 12 patients of our own and analyzed 228 patients from the literature. We included patients with valve replacement after a neurological complication of endocarditis and documented the time between manifestation and operation and the outcome. Based on these 240 patients we calculated the risk of neurological deterioration after the valve replacement. After brain infarction this risk is 20% within three days, 20-50% between day 4 and 14, but declines to < 10% after 14 days and < 1% after 4 weeks. Valve replacement within the first four weeks after intracranial hemorrhage has been reported to be successful only in individual cases. The risk of deteriorating declines later to 15%. Based on these limited data we suggest that valve replacement in patients with brain infarction should be considered within the first 72 hours if they have severe heart failure, otherwise after four weeks. Only a few selected patients with intracranial hemorrhage and progressive heart failure might benefit from valve replacement within the first four weeks. For all other neurological complications there are no reliable data. We propose a structured approach depending on cardiac and neurological complications and the time course of the disease.

Delayed occlusion after internal carotid artery dissection under heparin.

Internal carotid artery dissection (ICAD) is a frequent etiology of stroke in the young. Immediate anticoagulation with unfractionated heparin is the most frequent treatment. A theoretical side effect of unfractionated heparin is an increase in the intramural hematoma resulting in hemodynamic cerebral infarction. We studied 20 patients with ICAD. All patients were immediately treated with unfractionated heparin. Activated partial thromboplastin time (aPTT) ratios were measured twice daily. We prospectively monitored the course of ICAD with repeated ultrasound in hospital. Unexpectedly, delayed ICA occlusion was noted in 5 patients under treatment. One of these developed a watershed infarct. We then analyzed the aPTT ratios over the first 6 days after diagnosis. Patients with delayed occlusion had significantly higher aPTT ratios (2.6 +/- 0.4 vs. 2.0 +/- 0.5, p < 0.05). Within the limits of a partially retrospective design, our study seems to support the notion that unfractionated heparin can increase the intramural hematoma. Our findings further justify a randomized clinical trial to resolve the anticoagulant/antiplatelet debate.

Rhabdomyolysis and paraneoplastic stiff-man syndrome with amphiphysin autoimmunity.

Stiff-Man syndrome (SMS) is a rare disease of the central nervous system characterized by chronic muscle rigidity and autoimmunity directed against synaptic antigens. In a subset of patients, generally positive for antiamphiphysin autoantibodies, SMS has an autoimmune paraneoplastic origin. Amphiphysin isoforms are expressed at high levels in brain and skeletal muscle and often are overexpressed in breast cancer. We report here the occurrence of rhabdomyolysis in a patient with SMS, breast cancer, and antibodies that recognize both brain and muscle amphiphysin isoforms. Immunotherapy induced a remission of both rhabdomyolysis and SMS symptoms. Autoimmune rhabdomyolysis may represent a paraneoplastic complication of cancer patients with amphiphysin autoimmunity.

Ischemia triggered by spreading neuronal activation is induced by endothelin-1 and hemoglobin in the subarachnoid space.

Delayed cerebral vasospasm has a major impact on the outcome of subarachnoid hemorrhage. Two important candidates to cause the arterial spasm are the red blood cell product oxyhemoglobin and the vasoconstrictor endothelin-1, although oxyhemoglobin alone is not sufficient to induce cerebral ischemia and endothelin-1 leads to ischemia only at relatively high concentrations. In this study, we demonstrated that the combination of oxyhemoglobin and endothelin-1 triggered spreading neuronal activation in rat cortex in vivo. In contrast with the expected transient increase of regional cerebral blood flow during spreading depression, however, cerebral blood flow decreased profoundly and was long-lasting, paralleled by delayed repolarization of the steady (direct current) potential. These changes are characteristic of cortical spreading ischemia. Replacing oxyhemoglobin for the nitric oxide synthase inhibitor Nomega-nitro-L-arginine mimicked these effects, implicating nitric oxide scavenging functions of oxyhemoglobin. Furthermore, the effect of endothelin-1 was related to a reduction of Na(+)-/K(+)-ATPase activity rather than solely to its vasoconstrictive properties. In conclusion, the threshold concentration of endothelin-1 that induces cerebral ischemia is profoundly reduced via a complex interaction between the neuronal/astroglial network and the cortical microcirculation if nitric oxide availability declines. The results may have implications for the understanding of subarachnoid hemorrhage-related cortical lesions.

The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors.

BACKGROUND AND PURPOSE: The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke. The study was also designed to provide an estimate of the number of cases required to perform a larger phase III efficacy study. METHODS: Five hundred patients were recruited in a prospective, double-blind, placebo-controlled, randomized, multicenter phase II study. RESULTS: This safety trial was stopped prematurely when 342 patients (339 valid) had been randomized because of an imbalance in end points. Demographic data, cardiovascular risk factors, and blood pressure on admission, on study onset, and within the whole study period were not significantly different between the 2 groups. However, the cumulative 12-month mortality and the number of vascular events differed significantly in favor of the candesartan cilexetil group (odds ratio, 0.475; 95% CI, 0.252 to 0.895). There were no significant differences in concomitant medication and in number or type of side effects. CONCLUSIONS: Although the mechanisms by which angiotensin type 1 (AT1) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar beneficial effects in cerebral and in myocardial ischemia. The fact that no cardiovascular or cerebrovascular event occurred as a result of hypotension is of significant clinical importance. When there is need for or no contraindication against early antihypertensive therapy, candesartan cilexetil is a safe therapeutic option according to the ACCESS results.

Deep brain stimulation in dystonia.

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.

Migraine aggravation caused by cephalic venous congestion.

BACKGROUND: Cerebral venous distension is thought by some to serve as a source of migraine pain. Previous investigators have tried to modify pain intensity by induction of additional venous congestion via compression of both internal jugular veins (Queckenstedt's maneuver). The magnitude of blood flow within the internal jugular veins depends markedly on body position, and inconsistencies in positioning may have influenced their results. OBJECTIVE: To investigate the effect of Queckenstedt's maneuver, performed both in the upright and in the supine body position, in migraineurs during an acute attack. METHODS: Twenty-five patients (18 women, 7 men; mean age +/- SD, 35.4 +/- 13.3 years) with International Headache Society-defined migraine without aura were evaluated. Queckenstedt's maneuver was performed in both body positions during an acute migraine attack, involving constant application of manual pressure to both internal jugular veins for 30 seconds. Headache intensity was rated before, during, and after Queckenstedt's maneuver on a scale extending from 1 (mild) to 10 (intolerable). RESULTS: Seventeen patients (68%) reported an increase of headache intensity in the supine position during Queckenstedt's maneuver. In the sitting position, pain increase was observed only in 6 patients (24%). The magnitude of pain increase was significantly greater in the supine position compared to the upright position (P=.02). CONCLUSIONS: Our results support a role for cerebral venous congestion in the generation of migraine pain and suggest body position may influence the clinical expression of that process.

Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats.

OBJECTIVE: It has been proposed that delayed ischemic neurological deficits are induced by red blood cell (RBC) products after subarachnoid hemorrhage. Prophylactic treatment with the Ca2+ antagonist nimodipine or prevention of systemic volume contraction reduces the occurrence of delayed ischemic neurological deficits. To gain insight into the underlying mechanism, we studied the effects of nimodipine or volume expansion on ischemic events induced by RBC products in rats. METHODS: A cranial window was implanted in 52 rats. At the window, cerebral blood flow (measured with laser Doppler flowmetry) and the subarachnoid direct current potential were recorded; the cortical surface was superfused with artificial cerebrospinal fluid. A spreading neuronal/astroglial depolarization wave was triggered at a remote site, from which it traveled to the cranial window. RESULTS: In 16 rats, the depolarization wave triggered an ischemic event at the cranial window when artificial cerebrospinal fluid containing the RBC product hemoglobin and elevated K+ levels was superfused. In contrast, in animals receiving intravenously administered nimodipine (n = 12) or moderate volume expansion/hemodilution with hydroxyethyl starch (6% hydroxyethyl starch 200/0.5) (n = 10), the depolarization wave triggered brief initial hypoperfusion, followed by brief hyperemia, in the cortical area exposed to the RBC products. Under physiological conditions, the depolarization wave triggered brief hyperemia (n = 14). CONCLUSION: Spreading ischemia induced by RBC products is antagonized by measures known to be beneficial in the prophylaxis of delayed ischemic neurological deficits. Our findings suggest that a mechanism involving the cortical microcirculation might underlie the therapeutic effects of nimodipine and volume expansion.

Treatment of acute cluster headache with 20 mg sumatriptan nasal spray--an open pilot study.

We investigated the efficacy and tolerability of 20 mg sumatriptan nasal spray in the acute treatment of cluster headache attacks in an open-label study. 10 patients met the criteria of the International Headache Society (IHS) for episodic or chronic cluster headache and were enrolled in our study. The primary efficacy measure was "pain free" 30 minutes after treatment. Secondary end-points included "headache response" (defined as headache improvement from "very severe", "severe" or moderate" pain to "mild" or "no" pain) 15, 30, 45 and 60 minutes after treatment. We also assessed the participant's overall treatment satisfaction at the end of the study. Sumatriptan nasal spray was applied in 154 "moderate" to "very severe" cluster headache attacks. 30 minutes after nasal spray application, 50% of attacks were completely aborted and 58% of attacks responded to treatment. The overall efficacy of sumatriptan nasal spray was considered "excellent" in two, "good" in four, "reasonable" in two and "poor" in two patients. Eight patients indicated their intention to treat further attacks with intranasal sumatriptan. Seven patients were interviewed after a follow-up period of six months. Four patients continued to treat all cluster headache attacks with the intranasal sumatriptan formula, two patients had switched to subcutaneous sumatriptan and one patient was in remission since the end of the study. We conclude that 20 mg sumatriptan nasal spray might be an alternative therapy for the treatment of cluster headache attacks, but double-blind studies are needed to further evaluate its efficacy.

Endothelin-1 potently induces Leão's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura?

According to the 'neuronal' theory, cortical spreading depression (CSD) is the pathophysiological correlate of migrainous aura. However, the 'vascular' theory has implicated altered vascular function in the induction of aura symptoms. The possibility of a vascular origin of aura symptoms is supported, e.g. by the clinical observation that cerebral angiography frequently provokes migrainous aura. This suggests that endothelial irritation may somehow initiate one of the pathways resulting in migrainous aura. Up to now, an endothelium-derived factor has never been shown to trigger CSD. Here, for the first time, we demonstrate and characterize the ability of the vasoconstrictor and astroglial/neuronal modulator endothelin-1 to trigger Leão's 'spreading depression of activity' in vivo in rats. At a concentration range between 10 nM and 1 microM, endothelin-1 induced changes characteristic of CSD with regard to the rate of propagation, steady (direct current) potential and extracellular K(+)-concentration. A spreading hyperaemia followed by oligaemia was observed similar to those in K(+)-induced CSD. Endothelin-1 did not provoke changes characteristic of a terminal depolarization. The mechanism by which endothelin-1 generated CSD involved the N-methyl-D-asparate receptor. Cerebral blood flow decreased slightly, but significantly, before endothelin-1 generated CSD. A vasodilator (NO*-donor) shifted the threshold for CSD induction to higher concentrations of endothelin-1. Endothelin-1, in contrast to K(+), did not induce CSD in rat brain slices suggesting indirectly that endothelin-1 may require intact perfusion to exert its effects. In conclusion, endothelin-1 was found in the experiment to be the most potent inducer of CSD currently known. We propose endothelin-1 as a possible candidate for the yet enigmatic link between endothelial irritation and migrainous aura.