Correlations of health status indicators with perceived neuropsychological impairment and cognitive processing speed in multiple sclerosis.

BACKGROUND: Comorbidity and health behaviours may explain heterogeneity regarding cognitive performance in multiple sclerosis. Patient-reported cognitive difficulties have impact but do not consistently correlate with objective cognitive performance. Our study aims to investigate whether health status indicators including comorbidities, body mass index, physical activity, smoking, sleeping behaviour and consumption patterns for fish, alcohol and caffeinated drinks are associated with measures of subjective and objective cognitive performance. METHODS: Survey data on self-reported cognitive performance, assessed with the MS Neuropsychological Screening Questionnaire (MSNQ), were related to the presence of arterial hypertension, diabetes mellitus, cardiovascular and chronic renal diseases, hypercholesterolemia, depression based on 2-question screening tool, health and consumption behaviors. We included the Symbol Digit Modalities Test when available within 6 months as an objective, performance-based metric of cognitive processing speed. We investigated the interrelation between all variables with a Spearman correlation matrix and corrected for multiple testing. Regression models were built and controlled for age, sex and phenotype. RESULTS: We used available data from 751 patients with definite MS, including 290 SDMT scores within a time window of 6 months, to study relations between variables. MSNQ and SDMT scores were not significantly correlated. Correlation patterns for subjective and objective performance differed. Age, disease duration and physical disability correlated with SDMT scores only. Regression analyses could be performed for MSNQ scores in 595/751 (79.2%) and for SDMT scores in 234/751 (31.2%) participants. After restricting variables to avoid collinearity and adjusting for the number of variables, regression models explained 15% of the variance for subjective and 14% of the variance for objective cognitive performance. A higher number of physical comorbidities, reporting depressive symptoms, sleeping 9 h or more and daily use of sleeping medication were associated with lower subjective cognitive performance, whereas increasing age was associated with reduced processing speed. These associations persisted after correction for multiple testing. CONCLUSION: Increasing age is associated with reduced cognitive processing speed whereas comorbidities and sleep behaviors contribute to subjective cognitive performance.

Modulation of Cytokine-Induced Astrocytic Endothelin-1 Production as a Possible New Approach to the Treatment of Multiple Sclerosis.

Background: In the human central nervous system (CN), resting astrocytes do not visually show endothelin-1 (ET-1)-like immunoreactivity. In patients with multiple sclerosis (MS), an inflammatory disorder of the CNS, high levels of ET-1 are found in reactive astrocytes in demyelinated plaques. ET-1 may contribute to the pathology of MS by interrupting the blood-brain-barrier, enhancing inflammatory responses, excitotoxicity and reducing cerebral blood flow. Methods: We used the human astrocytoma cell line 1321N1 to investigate the role of inflammatory cytokines involved in MS lesions (IL-1ß, TNF-α, IFN-γ, LPS, IL-10, TGF-ß) on astrocytic ET-1 upregulation. Prucalopride, rolipram, fenofibrate, fluoxetine, simvastatin, daglutril, and resveratrol were investigated as potential candidate drugs to suppress cytokine-induced astrocytic ET-1 production. Effects on ET-1 production were measured using both ELISA and RT-qPCR. Results and Conclusions: ET-1 secretion by astrocytoma cells was only stimulated by the pro-inflammatory cytokines IL-1ß and TNF-α. Fluoxetine, simvastatin, and resveratrol significantly inhibited this IL-1ß- and TNF-α-induced ET-1 production. Simvastatin and resveratrol significantly reduced ET-1 mRNA levels, indicating an effect at the level of transcription. Fluoxetine significantly reduced endothelin converting enzyme-1 mRNA levels, suggesting and effect at the level of protein-processing. The required concentrations of simvastatin (>0.1 µM) and resveratrol (>10 µM) cannot be achieved in humans using pharmacologically accepted doses. Fluoxetine exerted a significant inhibitory effect on ET-1 secretion at a concentration of 5 µM, which is pharmacologically achievable in human brain, but the effect was modest (<50% suppression) and probably not sufficient to obtain a clinically relevant ET-1 effect. Our in vitro model can be a useful screening tool in the development of new drugs to suppress astrocytic ET-1 production. The effect of simvastatin was for the most part mediated via the mevalonate pathway, suggesting that this might be an interesting target for further drug development.

Post-stroke treatment with 17ß-estradiol exerts neuroprotective effects in both normotensive and hypertensive rats.

Although ischemic stroke is a major cause of death worldwide and the predominant cause of acquired disability, the only effective drug therapy that has been developed thus far is reperfusion by tissue plasminogen activator. Since most patients do not qualify for this treatment, new methods have to be developed. It is well known that estradiol (E2) exerts neuroprotective effects in different models of cerebral ischemia, but post-stroke treatment after an acute stroke has hardly been investigated. As many patients with an acute ischemic stroke have arterial hypertension, it is also of interest to evaluate the influence of this co-morbidity on the treatment efficacy of E2. The effects of E2 administered 30min after a transient middle cerebral artery occlusion (tMCAO) induced by an intracerebral injection of endothelin-1 were assessed in male normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Treatment with E2 reduced infarct size in both WKY and SHRs and decreased the number of degenerating neurons, indicating that acute treatment with E2 is indeed neuroprotective. To address the role of glia in neuroprotection, the effects of E2 on the activation of microglia and astrocytes was determined. It appeared that E2 had no effect on microglial activation, but reduced the activation of astrocytes in SHRs but not in the normotensive controls. We conclude that post-stroke E2 treatment in both normotensive and hypertensive rats is neuroprotective. Although the presence of hypertension changed the astrocytic response to E2, it did not affect treatment efficacy.

Absence of system xc- on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. METHODS: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT-/-) mice and irradiated mice reconstituted in xCT-/- bone marrow (BM), to their proper wild type (xCT+/+) controls. RESULTS: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT-/- mice were equally susceptible to EAE, whereas mice transplanted with xCT-/- BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. CONCLUSIONS: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc- on immune cells invading the CNS participates to EAE. Since a total loss of system xc- had no net beneficial effects, these results have important implications for targeting system xc- for treatment of MS.

The pathophysiological role of astrocytic endothelin-1.

In the normal central nervous system, endothelin-1 (ET-1) is found in some types of neurons, epithelial cells of the choroid plexus, and endothelial cells of microvessels, but it is usually not detectable in glial cells. However, in different pathological conditions, astrocytes adapting a reactive phenotype express high levels of ET-1 and its receptors, mainly the ETB receptor. ET-1 released by reactive astrocytes appears mainly to have neurodeleterious effects by mechanisms that include constriction of cerebral arterioles leading to impairment of the cerebral microcirculation, increase of blood brain barrier permeability, inflammation, excitotoxicity, impairment of fast axonal transport, and astrogliosis. A few studies in rodents found that ET-1 increased the astrocytic expression of brain-derived neurotrophic factor, glial cell-line derived neurotrophic factor and neurotropin-3, and the production of endocannabinoids. However, whether this occurs in physiological or pathological conditions is unclear. This review summarizes current knowledge about the role of the astrocytic ET-1 system in acute and chronic neurological conditions, including multiple sclerosis, ischemic stroke and hypoxic/ischemic brain injury, traumatic brain injury, subarachnoid hemorrhage, Alzheimer's disease, Binswanger's disease and post-stroke dementia, amyotrophic lateral sclerosis, and CNS infections. Counteracting the harmful effects of astrocytic ET-1 may represent a promising therapeutic target for mitigating secondary brain damage in a variety of neurological diseases. We also briefly address the role of astrocytic ET-1 in astrocytic tumors and pain.

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.

SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.

Autonomic dysfunction in acute ischemic stroke: an underexplored therapeutic area?

Impaired autonomic function, characterized by a predominance of sympathetic activity, is common in patients with acute ischemic stroke. This review describes methods to measure autonomic dysfunction in stroke patients. It summarizes a potential relationship between ischemic stroke-associated autonomic dysfunction and factors that have been associated with worse outcome, including cardiac complications, blood pressure variability changes, hyperglycemia, immune depression, sleep disordered breathing, thrombotic effects, and malignant edema. Involvement of the insular cortex has been suspected to play an important role in causing sympathovagal imbalance, but its exact role and that of other brain regions remain unclear. Although sympathetic overactivity in patients with ischemic stroke appears to be a negative prognostic factor, it remains to be seen whether therapeutic strategies that reduce sympathetic activity or increase parasympathetic activity might improve outcome.

ß2-adrenergic agonists modulate TNF-α induced astrocytic inflammatory gene expression and brain inflammatory cell populations.

BACKGROUND: The NF-κB signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic ß2-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic ß2-adrenergic receptors and the TNF-α induced inflammatory gene program. METHODS: Proinflammatory conditions were generated by the administration of TNF-α. Genes that are susceptible to astrocytic crosstalk between ß2-adrenergic receptors (stimulated by clenbuterol) and TNF-α were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-α in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-α administration. RESULTS: Parallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic ß2-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of ß2-adrenergic receptor agonists and TNF-α on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-α co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance. CONCLUSIONS: Our results show that astrocytic ß2-adrenergic receptors are potent regulators of astrocytic TNF-α-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic ß2-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis.

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in ß(2) adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

Interleukin-6, a mental cytokine.

Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence implicating IL-6 in brain-related processes originated from its dysregulated expression in several neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. In addition, IL-6 was shown to be involved in multiple physiological CNS processes such as neuron homeostasis, astrogliogenesis and neuronal differentiation. The molecular mechanisms underlying IL-6 functions in the brain have only recently started to emerge. In this review, an overview of the latest discoveries concerning the actions of IL-6 in the nervous system is provided. The central position of IL-6 in the neuroinflammatory reaction pattern, and more specifically, the role of IL-6 in specific neurodegenerative processes, which accompany Alzheimer's disease, multiple sclerosis and excitotoxicity, are discussed. It is evident that IL-6 has a dichotomic action in the CNS, displaying neurotrophic properties on the one hand, and detrimental actions on the other. This is in agreement with its central role in neuroinflammation, which evolved as a beneficial process, aimed at maintaining tissue homeostasis, but which can become malignant when exaggerated. In this perspective, it is not surprising that 'well-meant' actions of IL-6 are often causing harm instead of leading to recovery.

Cerebral autoregulation in stroke: a review of transcranial Doppler studies.

BACKGROUND AND PURPOSE: Cerebral autoregulation may become impaired after stroke. To provide a review of the nature and extent of any autoregulation impairment after stroke and its course over time, a technique allowing repeated bedside measurements with good temporal resolution is required. Transcranial Doppler (TCD) in combination with continuous blood pressure measurements allows noninvasive continuous bedside investigation with high temporal resolution of the dynamic and the steady-state components of cerebral autoregulation. Therefore, this review focuses on all TCD studies on cerebral autoregulation in the setting of documented ischemic stroke. METHODS: PubMed and EMBASE were searched for studies of stroke, autoregulation, and TCD. Studies were either acute phase (<96 hours after index stroke) or chronic phase (>96 hours after index stroke) autoregulation studies. Quality of studies was studied in a standardized fashion. RESULTS: Twenty-three studies met the inclusion criteria. General agreement existed on cerebral autoregulation being impaired, even after minor stroke. Bilateral impairment of autoregulation was documented, particularly after lacunar stroke. Studies showed progressive deterioration of cerebral autoregulation in the first 5 days after stroke and recovery over the next 3 months. Impaired cerebral autoregulation as assessed by TCD was related to neurological deterioration, the necessity for decompressive surgery, and poor outcome. Synthesis of the data of various studies was, however, limited by studies not meeting key methodological criteria for observational studies. CONCLUSIONS: TCD in combination with continuous blood pressure measurement offers a method with a high temporal resolution feasible for bedside evaluation of cerebral autoregulation in the stroke unit. TCD studies have shown impairment of cerebral autoregulation in various subtypes of ischemic stroke. To improve the synthesis of data from various research groups, there is urgent need for standardization of methodology of TCD studies in cerebral autoregulation.

Delayed akinetic catatonic mutism following methadone overdose.

A 49-year-old woman developed a catatonic mute state a few weeks after methadone overdose. Clinical, radiological and histological findings were consistent with toxic spongiform leukoencephalopathy, which adds a potentially deadly side-effect to a generally considered safe substitution for heroin.

Reduced creatine kinase B activity in multiple sclerosis normal appearing white matter.

BACKGROUND: Two studies using (31)P-magnetic resonance spectroscopy (MRS) reported enhanced phosphocreatine (PCr) levels in normal appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but this finding could not be properly explained. METHODOLOGY/PRINCIPAL FINDINGS: We performed (31)P-MRS and (1)H-MRS in the NAWM in 36 subjects, including 17 with progressive MS, 9 with benign MS, and 10 healthy controls. Compared to controls, PCr/beta-ATP and PCr/total (31)P ratios were significantly increased in subjects with progressive MS, but not with benign MS. There was no correlation between PCr ratios and the N-acetylaspartate/creatine ratio, suggesting that elevated PCr levels in NAWM were not secondary to axonal loss. In the central nervous system, PCr is degraded by creatine kinase B (CK-B), which in the white matter is confined to astrocytes. In homogenates of NAWM from 10 subjects with progressive MS and 10 controls without central nervous system disease, we measured CK-B levels with an ELISA, and measured its activity with an enzymatic assay kit. Compared to controls, both CK-B levels and activity were decreased in subjects with MS (22.41 versus 46.28 microg/ml; p = 0.0007, and 2.89 versus 7.76 U/l; p<0.0001). CONCLUSIONS/SIGNIFICANCE: Our results suggest that PCr metabolism in the NAWM in MS is impaired due to decreased CK-B levels. Our findings raise the possibility that a defective PCr metabolism in astrocytes might contribute to the degeneration of oligodendrocytes and axons in MS.

Progesterone and dexamethasone differentially regulate the IGF-system in glial cells.

IGF-1 is an important factor for myelin synthesis and hence possesses therapeutic potential in treating demyelinating disease such as multiple sclerosis. However, IGF-1 poorly crosses the blood-brain barrier. In this study, we investigated the effects of the sex steroid progesterone and the glucocorticoid dexamethasone on regulation of the IGF-system in glial cells. By means of quantitative PCR analysis, we demonstrate that progesterone upregulates IGF-1, the type 1 IGF receptor and IGFBP-2 in primary rat astrocytes and both IGF-1 and IGFBP-6 in OLN-93 oligodendroglial progenitor cells. In contrast, dexamethasone showed a negative effect on expression of IGF-1, the type 1 IGF receptor and the respective IGF binding proteins in both cell types. In oligodendrocytes, the differentiation marker CNPase was positively regulated by progesterone and negatively regulated by dexamethasone. Further, oligodendroglial cell migration was enhanced approximately 4-fold by progesterone. This study implicates progesterone as a positive regulator of IGF-system in glial cells and demonstrates a further biological function of progesterone in oligodendrocyte biology, namely stimulation of progenitor cell migration. Dexamethasone, on the other hand, is a negative regulator of the IGF-system in glial cells.

Risk factors for cerebral venous thrombosis and deep venous thrombosis in patients aged between 15 and 50 years.

Cerebral venous thrombosis (CVT) and deep vein thrombosis or pulmonary embolism (DVT/PE) are associated with many risk factors. It is unclear why CVT occurs less often than DVT/PE. Age dependent risk factors may play a role. The aim of our study was to compare risk factors in a uniform age group of CVT and DVT/PE patients aged between 15 and 50 years. Thrombophilic markers and clinical risk factors of 79 CVT patients and 173 DVT/PE patients aged 15-50 years were compared. Multivariable logistic regression analysis was performed to investigate if risk factors were independently associated with CVT or DVT/PE. Cerebral venous thrombosis patients were younger (median age 30 years vs. 42 years; p<0.001) and more often female (82% vs. 52%; p<0.001). There were no differences in thrombophilic markers. Cerebral venous thrombosis was less often associated with trauma, immobilisation or surgery than DVT/PE (6% vs. 21%; adjusted OR 0.29; 95%CI 0.10-0.82). In women, CVT was more frequently associated with oral contraceptive use, pregnancy or puerperium (82% vs. 53%; adjusted OR 2.34; 95%CI 1.03-5.32). This study demonstrated no differences in thrombophilic markers between CVT patients and DVT/PE patients aged between 15 and 50 years, while the frequency of some transient risk factors was different. Cerebral venous thrombosis was relatively more common in women and hormonal factors may predispose to CVT compared to DVT/PE, while trauma, immobilisation and surgery may be less important in the pathophysiology of CVT.

IGF-1 regulates cAMP levels in astrocytes through a beta2-adrenergic receptor-dependant mechanism.

We have recently demonstrated that neonatal astrocytes derived from mice lacking beta-2 adrenergic receptors (beta(2)AR) possess higher proliferation rates, as compared to wild-type cells, an attribute that was shown to involve insulin-like growth factor (IGF) signaling. In the present study, we demonstrate that basal cAMP levels in beta(2)AR knockout astrocytes were significantly lower than in wild type cells. Furthermore, treatment with IGF-1 reduced intracellular cAMP levels in wild type astrocytes, yet had no effects on cAMP levels in beta(2)AR deficient astrocytes. Our data suggests that IGF-1 treatment influences cAMP production through a beta(2)AR-dependant mechanism in astrocytes. A deficit of beta(2)AR on astrocytes, as previously reported in multiple sclerosis, may influence cell proliferation, an action which could have implications in processes involved in astrogliosis.

Trismus as manifestation of bilateral internal capsule genu infarction.

Acute trismus can have different causes. We describe the presentation, course and radiological findings of a 34-year-old man who developed acute trismus and MRI findings consistent with the combination of an old and fresh infarction in the genu of the internal capsule. We believe it is important to consider stroke as a cause of acute trismus.

Cigarette smoking and progression in multiple sclerosis.

OBJECTIVE: To investigate the influence of cigarette smoking on progression and disability accumulation in multiple sclerosis (MS). METHODS: Information on past and present smoking of 364 patients with MS was obtained through a structured questionnaire survey. We used Kaplan-Meier analyses and Cox regression models to evaluate the influence of smoking on the development and age at onset of secondary progression, on the age at onset of progression in patients with primary progressive MS, and on the time from disease onset to Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0 in all patients. We also investigated the correlation between smoked pack-years and EDSS scores and the rate of progression as measured with the Multiple Sclerosis Severity Score. RESULTS: We found no significant associations between cigarette smoking and any of the used measures. CONCLUSION: Our data suggest that cigarette smoking has no influence on disease progression or accumulation of disability in multiple sclerosis.

Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations.

BACKGROUND AND PURPOSE: Because of the risk of hemorrhage, especially in the brain, thrombolytic therapy with intravenous alteplase is restricted by guidelines, and only a small number of selected patients are being treated. Findings from metaanalyses, post hoc analyses of the randomized trials, and postlicensing experience suggest that more subjects, who otherwise have a poor predicted outcome without treatment, might benefit from intravenous alteplase. Summary of Review- There is a strong indication that treatment may still be beneficial beyond 3 hours up until 4.5 hours. The risk of symptomatic intracerebral hemorrhage is not increased in patients aged 80 years or older. Excluding patients with severe stroke or with early ischemic changes in more than one third of the middle cerebral artery territory on baseline CT scan is probably not necessary when treatment is started <3 hours of symptom onset. Patients with minor or improving symptoms can also benefit. Intravenous thrombolysis appears appropriate as first line therapy for posterior circulation stroke. Alteplase can be given to patients with cervical artery dissection, seizure at onset and evidence of acute ischemia on brain imaging, and after carefully weighing risk and benefit in pregnancy and during menstruation. There are anecdotal reports on its use in children, patients with recent myocardial infarction, cardiac embolus, intracranial aneurysm or arteriovenous malformation, prior stroke and recent surgery. There appears to be a substantially increased risk of symptomatic cerebral hemorrhage in hyperglycemic stroke patients. The combined intravenous and intraarterial approach to recanalization appears safe and is currently under investigation in a randomized trial. CONCLUSIONS: This document does not intend to change the guidelines but reviews the literature on the use of intravenous alteplase for stroke beyond guidelines and in particular conditions.