Raf Brouns

The complexity of neurobiological processes in acute ischemic stroke

There is an urgent need for improved diagnostics and therapeutics for acute ischemic stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on current knowledge of disease mechanisms underlying acute focal cerebral ischemia. Insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future diagnostic and therapeutic approaches. In this review, we summarize the actual knowledge on the pathophysiology of acute ischemic stroke. We focus on the ischemic cascade, which is a complex series of neurochemical processes that are unleashed by transient or permanent focal cerebral ischemia and involves cellular bioenergetic failure, excitotoxicity, oxidative stress, blood-brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells.

Neurological complications in renal failure: a review

Neurological complications whether due to the uremic state or its treatment, contribute largely to the morbidity and mortality in patients with renal failure. Despite continuous therapeutic advances, many neurological complications of uremia, like uremic encephalopathy, atherosclerosis, neuropathy and myopathy fail to fully respond to dialysis. Moreover, dialytic therapy or kidney transplantation may even induce neurological complications. Dialysis can directly or indirectly be associated with dialysis dementia, dysequilibrium syndrome, aggravation of atherosclerosis, cerebrovascular accidents due to ultrafiltration-related arterial hypotension, hypertensive encephalopathy, Wernickes encephalopathy, hemorrhagic stroke, subdural hematoma, osmotic myelinolysis, opportunistic infections, intracranial hypertension and mononeuropathy. Renal transplantation itself can give rise to acute femoral neuropathy, rejection encephalopathy and neuropathy in graft versus host disease. The use of immunosuppressive drugs after renal transplantation can cause encephalopathy, movement disorders, opportunistic infections, neoplasms, myopathy and progression of atherosclerosis. We address the clinical, pathophysiological and therapeutical aspects of both central and peripheral nervous system complications in uremia.

Intravenous Thrombolysis with Recombinant Tissue Plasminogen Activator in a Stroke Patient Treated with Dabigatran

Apixaban is increasingly used in clinical practice (1), but data on the bleeding risk in patients treated with recombinant tissue plasminogen activator (rt-PA) while taking apixaban are nonexistent. A 74-year-old right-handed man presented with abrupt onset of global aphasia. He was known with a partial right hemianopsia secondary to a left occipital intracerebral hemorrhage five-years earlier and with paroxysmal nonvalvular atrial fibrillation treated with apixaban 5 mg bid. The National Institutes of Health Stroke Scale (NIHSS) score was 8. Noncontrast computed tomography (CT) of the brain showed no signs of acute intracranial pathology. Perfusion-CT revealed hypoperfusion in the territory of the left middle cerebral artery (Fig. 1a). An ostial stenosis of the left internal carotid artery was diagnosed on CT angiography (Fig. 1b). After informed consent by proxy, i.v. rt-PA therapy (0·9 mg/kg; total dose 81 mg) was administered at 4·5 h after symptom onset and 8·5 h after apixaban intake. Platelet count, prothrombin time, activated partial thromboplastin time, and fibrinogen levels were normal, as was creatinine clearance. The patient experienced an excellent recovery (NIHSS score 1) without signs of new infarction or intracranial hemorrhage on repeat CT. As apixaban is commonly used in patients with elevated stroke risk (1), therapeutic decision-making with regard to thrombolytic therapy may not uncommonly pose problems in the near future. Our case report illustrates that further study on the safety of rt-PA in this patient population is justified. Ann De Smedt*, Melissa Cambron, Koenraad Nieboer, Maarten Moens, Robbert-Jan Van Hooff, Laetitia Yperzeele, Kristin Jochmans, Jacques De Keyser, and Raf Brouns

Belgian Fabry Study Prevalence of Fabry Disease in a Cohort of 1000 Young Patients With Cerebrovascular Disease

Background and Purpose— Data on the prevalence of Fabry disease in patients with central nervous system pathology are limited and controversial. In this study, we assessed the prevalence of Fabry disease in young patients presenting with cerebrovascular disease in Belgium. Methods— In this national, prospective, multicenter study, we screened for Fabry disease in 1000 patients presenting with ischemic stroke, transient ischemic attack, or intracranial hemorrhage; unexplained white matter lesions; or vertebrobasilar dolichoectasia. In male patients, we measured &agr;-galactosidase A (&agr;-GAL A) activity in dried blood spots. Female patients were screened for mutations by exonic DNA sequencing of the &agr;-GAL A gene. Results— &agr;-GAL A activity was deficient in 19 men (3.5%), although all had normal &agr;-GAL A gene sequences. Enzymatic deficiency was confirmed on repeat assessment in 2 male patients (0.4%). We identified missense mutations in 8 unrelated female patients (1.8%): Asp313Tyr (n=5), Ala143Thr (n=2), and Ser126Gly (n=1). The pathogenicity of the 2 former missense mutations is controversial. Ser126Gly is a novel mutation that can be linked to late-onset Fabry disease. Conclusion— &agr;-GAL A deficiency may play a role in up to 1% of young patients presenting with cerebrovascular disease. These findings suggest that atypical variants of Fabry disease with late-onset cerebrovascular disease exist, although the clinical relevance is unclear in all cases.

Neurobiochemical Markers of Brain Damage in Cerebrospinal Fluid of Acute Ischemic Stroke Patients

BACKGROUND Ischemic injury to the central nervous system causes cellular activation and disintegration, leading to release of cell-type-specific proteins into the cerebrospinal fluid (CSF). We investigated CSF concentrations of myelin basic protein (MBP), glial fibrillary astrocytic protein (GFAP), the calcium-binding protein S100B, and neuron-specific enolase (NSE) in acute ischemic stroke patients and their relation to initial stroke severity, stroke location, and long-term stroke outcome. METHODS CSF concentrations of MBP, GFAP, S100B, and NSE were assessed in 89 stroke patients on admission (mean 8.7 h after stroke onset) and in 35 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIH Stroke Scale [NIHSS] score on admission, infarct volume), (b) stroke location, and (c) stroke outcome (modified Rankin Scale [mRS] score at month 3). RESULTS MBP concentration was significantly higher in subcortical than in cortical infarcts (median MBP, 1.18 vs 0.66 microg/L, P < 0.001). GFAP and S100B concentrations correlated with the NIHSS score on admission (GFAP, R = 0.35, P = 0.001; S100B, R = 0.29, P = 0.006), infarct volume (GFAP, R = 0.34, P = 0.001; S100B, R = 0.28, P = 0.008), and mRS score at month 3 (R = 0.42, P < 0.001 and R = 0.28, P = 0.007). Concentrations of NSE did not correlate with stroke characteristics. CONCLUSIONS MBP, GFAP, S100B, and NSE display relevant differences in cellular and subcellular origins, which are reflected in their relation to stroke characteristics. MBP is a marker for infarct location. GFAP and S100B correlate with stroke severity and outcome.

Middelheim Fabry Study (MiFaS): a retrospective Belgian study on the prevalence of Fabry disease in young patients with cryptogenic stroke.

OBJECTIVE To assess the prevalence of Fabry disease in young patients with cryptogenic stroke. PATIENTS AND METHODS We retrospectively assessed the prevalence of Fabry disease in patients aged 16-60 years that were admitted to ZNA Middelheim Hospital from January 1, 2000 to December 31, 2004 for cryptogenic stroke. We screened for Fabry disease by measurement of alpha-galactosidase A and beta-glucuronidase activity on blood spot. In all patients with abnormal enzymatic activity and in all female patients with low normal values, genetic sequencing of the alpha-GAL-gene was performed. RESULTS In a population of 103 young patients with cryptogenic stroke that met the in- and exclusion criteria, we were unable to identify any patient with Fabry disease. CONCLUSION Based on the results of alpha-galactosidase A and beta-glucuronidase activity, genetic sequencing and the low prevalence of clinical signs and symptoms of Fabry disease in this population, we believe that the true prevalence of Fabry disease in patients with cryptogenic stroke may be less than currently accepted in literature.

Risk Factors for Poststroke Depression: Identification of Inconsistencies Based on a Systematic Review

Objective: Depression after stroke or poststroke depression (PSD) has a negative impact on the rehabilitation process and the associated rehabilitation outcome. Consequently, defining risk factors for development of PSD is important. The relationship between stroke and depression is described extensively in the available literature, but the results are inconsistent. The aim of this systematic review is to outline conflicting evidence on risk factors for PSD. Methods: PubMed, Medline, and Web of Knowledge were searched using the keywords “stroke,” “depression,” and “risk factor” for articles published between January 01, 1995, and September 30, 2012. Additional articles were identified and obtained from a hand search in related articles and reference lists. Results: A total of 66 article abstracts were identified by the search strategy and 24 articles were eligible for inclusion based on predefined quality criteria. The methodology varies greatly between the various studies, which is probably responsible for major differences in risk factors for PSD reported in the literature. The most frequently cited risk factors for PSD in the literature are sex (female), history of depression, stroke severity, functional impairments or level of handicap, level of independence, and family and social support. Conclusions: Many risk factors are investigated over the last 2 decades and large controversy exists concerning risk factors for development of PSD. These contradictions may largely be reduced to major differences in clinical data, study population, and methodology, which underline the need for more synchronized studies.

Evaluation of lactate as a marker of metabolic stress and cause of secondary damage in acute ischemic stroke or TIA

BACKGROUND Accumulation of lactate in ischemic regions has been documented in acute stroke. We evaluated the relation between lactate levels in blood and cerebrospinal fluid (CSF) and ischemic stroke evolution and outcome. METHODS Lactate was measured in blood of 187 acute ischemic stroke and TIA patients at admission, 24 h, 72 h and 7 days after stroke onset. In a subpopulation of 85 stroke patients and in 51 controls, lactate was measured in CSF. Stroke evolution was evaluated by change in the NIHSS score within the first 72 h and by occurrence of progressing stroke. At 3 months after stroke, outcome was assessed on the basis of mortality rate and the modified Rankin Scale. RESULTS We found no relation between lactate levels in blood and stroke evolution or outcome. Lactate in CSF was higher in stroke patients than in controls and correlated with stroke evolution and outcome. Multivariate regression analyses showed that CSF lactate levels, age and stroke severity are independent predictors for stroke evolution and outcome. CONCLUSIONS Lactate levels in CSF, but not in blood, are a reliable marker for metabolic crisis in acute ischemic stroke and correlate with the stroke evolution in the subacute phase and with long-term outcome.

Insulin-Like Growth Factor I Serum Levels Influence Ischemic Stroke Outcome

Background and Purpose— Insulin-like growth factor I (IGF-I) is neuroprotective in animal models of stroke. We investigated whether serum IGF-I levels in patients with acute ischemic stroke influence stroke severity and outcome. Methods— Concentrations of IGF-I and IGF binding protein 3 were measured in serum samples obtained within 6 hours after stroke onset from 255 patients who took part in the placebo arm of the United States and Canadian Lubeluzole in Acute Ischemic Stroke Study. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Multivariate analysis was performed to assess the overall shift in modified Rankin Scale score and changes in the National Institutes of Health Stroke Scale score at 3 months. Survival curves were plotted using the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. Results— After controlling for statistically relevant risk factors, subjects with high IGF-I levels or IGF-I/IGF binding protein 3 ratios had a better neurological and functional outcome at 3 months. Baseline stroke severity was not different between high and low IGF-I groups. In contrast to the low IGF-I group, neurological symptoms gradually improved from Day 3 in the high IGF-I group. Conclusions— Our results suggest that high serum IGF-I levels just after ischemic stroke onset are associated with neurological recovery and a better functional outcome.

Decrease in uric acid in acute ischemic stroke correlates with stroke severity, evolution and outcome.

Abstract Background: Although uric acid (UA) is one of the most important antioxidants in plasma and appears to be neuroprotective in animal models, results from human studies are controversial. In this study, we investigated the kinetics of serum UA concentrations in the acute, subacute and chronic phase of ischemic stroke and its relation with initial stroke severity, stroke evolution in the subacute phase and long-term stroke outcome. Methods: Serum concentrations of UA were measured in 199 stroke patients at admission (median, 2.8 h after stroke onset), at 24 h, 72 h, day 7, month 1 and month 3 after onset of stroke. We evaluated the relationship between changes in UA concentrations and (a) stroke severity [patients with transient ischemic attack (TIA) vs. stroke patients, National Institutes of Health Stroke Scale (NIHSS) score at admission], (b) stroke evolution (stroke progression, infarct volume at 72 h), and (c) stroke outcome [modified Rankin scale (mRS) score at month 3, mortality]. Results: UA concentrations decreased significantly during the first 7 days after stroke onset before returning to baseline (p<0.001). Mean plasma UA concentrations decreased from 336.66±113.01 μmol/L at admission to 300.37±110.04 μmol/L at day 7 (p<0.001) in patients with stroke, but did not change significantly in patients with TIA. Changes in UA concentrations from admission to day 7 (ΔUAday 7) correlated with the NIHSS score (ρ=0.32; p<0.001), stroke progression (ρ=0.29; p=0.001), infarct volume (ρ=0.37; p<0.001), mRS score (ρ=0.28; p=0.001) and mortality (p=0.010). Conclusions: Decreases in UA during the first week after onset of stroke correlates with more severe stroke, unfavorable stroke evolution, and poor long-term stroke outcome. Clin Chem Lab Med 2010;48:383–90.