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No side effects after low-dose amphetamine administration in stroke rehabilitation [5]

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mean6SD age 36.7612.8 years), from the same ethnic back- ground. The frequency of factor V Leiden and of the MTHFR in patients with CVT were 10% (1/10) and 33.3% (3/10), respec- tively, ie, twice as much as that found in controls (5.8% (15/259) and 17.4% (45/259), respectively). Two patients had the MTHFR genotype and the G20210A PRTH variant simultaneously; 1 carried the PRTH and the factor V Leiden variants. On the whole, 3 patients (33.3%) showed the coexistence of 2 throm- bophilic genes; this was significantly different from the preva- lence of the coexistence among healthy subjects (5/259, 1.9%; P50.0019). Three CVT patients had a family history of venous thromboembolism; all were heterozygous for the G20210A PRTH variant. Four patients showed recurrent venous thrombo- embolism; among them, 3 carried the G20210A PRTH variant and 2 showed the association of the latter with factor V Leiden or with the MTHFR 677TT genotype. In our female patients, 2 of 6 experienced CVT while using oral contraceptives; none of the polymorphisms was present in both cases. The coexistence of PRTH and factor V mutation has been strongly associated with juvenile and recurrent venous thrombo- embolism.6,7 The MTHFR variant increases the risk of deep-vein thrombosis in factor V Leiden carriers.8 Despite the limitations of the sample size, these data confirm the role of the G20210A PRTH variant as a predisposing factor for CVT. Our data also indicate that thrombophilic genes often coexist in patients with CVT. Whether (and the extent towhich) thrombosis at this unusual site reflects a sustained hypercoagulable state needs to be further evaluated.

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... 26 Amphetamine, which increases the brain and spinal cord levels of norepinephrine, has been shown to promote recovery of function in animal models of brain injury. The eectiveness in humans is still unknown but we know that low doses of amphetamine can be used without serious side eects in stroke subjects 27 and need to be investigated in SCI subjects. Rossignol et al 13 recently showed that norepinephrine but not clonidine enhanced locomotor activity in incomplete spinal cats. ...
... serotonergic) and/ or in combination with other locomotor training strategies such as functional electrical stimulation. 27 Finally, it will be important to identify features of SCI subjects that may predict who will bene®t from such therapy. ...
Article
Clonidine, a noradrenergic agonist has been associated with improved walking in both spinal cat and spinal cord injured (SCI) subjects. The objective of this brief review is to compare the effects of clonidine on walking capabilities in SCI subjects with functionally complete and incomplete spinal cord injuries. Both oral administration and intrathecal injection of clonidine were investigated. A motorized treadmill was used and harness support provided in most of the SCI subjects as no walking capabilities could be observed overground. A single subject design was used in these chronic SCI subjects. Canada and France. In complete SCI subjects while receiving clonidine, none of the subjects was able to initiate independent stepping. In contrast, the greatest effects were found in SCI subjects with injuries that are incomplete but still severely disabling while minimal effects could be observed in the more functional SCI subjects. These effects on walking are observed in measures of walking speed, and electromyographic and kinematic patterns. Regardless of effects on walking, however, a consistent decrease of the flexor reflex amplitude could be observed in all SCI subjects independent of the severity of the lesion. This review demonstrated that clonidine could be a powerful anti-spasmodic drug in addition to improving locomotion in a limited number of SCI subjects. The mechanism, significance and implications of these results will be discussed.
... Stimulant therapy with amphetamine, believed to result in enhanced neural plasticity in the subacute time period postinjury, has demonstrated significant benefit in aphasia patients within 45 days of ischemic stroke (Walker-Batson et al., 2001). There were no problems with tolerability (Unwin & Walker-Batson, 2000), and the benefit did not appear to simply be the result of a general hemodynamic effect (Unwin & Walker-Batson, 2000). This benefit, though, did not occur for patients over a year after their stroke (Walker-Batson, 1999). ...
... Stimulant therapy with amphetamine, believed to result in enhanced neural plasticity in the subacute time period postinjury, has demonstrated significant benefit in aphasia patients within 45 days of ischemic stroke (Walker-Batson et al., 2001). There were no problems with tolerability (Unwin & Walker-Batson, 2000), and the benefit did not appear to simply be the result of a general hemodynamic effect (Unwin & Walker-Batson, 2000). This benefit, though, did not occur for patients over a year after their stroke (Walker-Batson, 1999). ...
Article
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Previous research suggests that the noradrenergic system modulates flexibility of access to the lexical-semantic network, with propranolol benefiting normal subjects in lexical-semantic problem solving tasks. Patients with Broca's aphasia with anomia have impaired ability to access appropriate verbal output for a given visual stimulus in a naming task. Therefore, we tested naming in a pilot study of chronic Broca's aphasia patients with anomia after propranolol and after placebo in a double-blinded crossover manner. Naming was better after propranolol than after placebo, suggesting a potential benefit from propranolol in chronic Broca's aphasia with anomia. Larger follow-up studies are necessary to further investigate this effect.
... Mild headache that completely resolved after 325 mg of acetaminophen use was reported in two subjects after both experiments. At the first couple of minutes of tDCS application, mild to 25 Unexpectedly, we observed a significant decrease in heart rates during the placebo experiment (9.6 [7.10], P = 0.002), but no significant change was noted during the active experiment (P = 0.38). [15.10], ...
Article
There is a growing need for various effective adjunctive treatment options for speech recovery after stroke. A pharmacological agent combined with noninvasive brain stimulation has not been previously reported for poststroke aphasia recovery. In this "proof of concept" study, we aimed to test the safety of a combined intervention consisting of dextroamphetamine, transcranial direct current stimulation, and speech and language therapy in subjects with nonfluent aphasia. Ten subjects with chronic nonfluent aphasia underwent two experiments where they received dextroamphetamine or placebo along with transcranial direct current stimulation and speech and language therapy on two separate days. The Western Aphasia Battery-Revised was used to monitor changes in speech performance. No serious adverse events were observed. There was no significant increase in blood pressure with amphetamine or deterioration in speech and language performance. Western Aphasia Battery-Revised aphasia quotient and language quotient showed a statistically significant increase in the active experiment. Comparison of proportional changes of aphasia quotient and language quotient in active experiment with those in placebo experiment showed significant difference. We showed that the triple combination therapy is safe and implementable and seems to induce positive changes in speech and language performance in the patients with chronic nonfluent aphasia due to stroke.
... noteworthy that patients enrolled into this dextroamphetamine protocol suffered no adverse reactions, a finding that we have previously reported. 28 This study is limited because of the small group of aphasic subjects and may not represent all stroke patients. However, because many of the patients we studied had severe aphasic deficits at entry, effects in this small sample would appear to be meaningful. ...
Article
Background and Purpose — A number of studies suggest that drugs which increase the release of norepinephrine promote recovery when administered late (days to weeks) after brain injury in animals. A small number of clinical studies have investigated the effects of the noradrenergic agonist dextroamphetamine in patients recovering from motor deficits following stroke. To determine whether these findings extend to communication deficits subsequent to stroke, we administered dextroamphetamine, paired with speech/language therapy, to patients with aphasia. Methods — In a prospective, double-blind study, 21 aphasic patients with an acute nonhemorrhagic infarction were randomly assigned to receive either 10 mg dextroamphetamine or a placebo. Patients were entered between days 16 and 45 after onset and were treated on a 3-day/4-day schedule for 10 sessions. Thirty minutes after drug/placebo administration, subjects received a 1-hour session of speech/language therapy. The Porch Index of Communicative Ability was used at baseline, at 1 week off the drug, and at 6 months after onset as the dependent language measure. Results — Although there were no differences between the drug and placebo groups before treatment ( P =0.807), by 1 week after the 10 drug treatments ended there was a significant difference in gain scores between the groups ( P =0.0153), with the greater gain in the dextroamphetamine group. The difference was still significant when corrected for initial aphasia severity and age. At the 6-month follow-up, the difference in gain scores between the groups had increased; however, the difference was not significant ( P =0.0482) after correction for multiple comparisons. Conclusions — Administration of dextroamphetamine paired with 10 1-hour sessions of speech/language therapy facilitated recovery from aphasia in a small group of patients in the subacute period after stroke. Neuromodulation with dextroamphetamine, and perhaps other drugs that increase central nervous system noradrenaline levels, may facilitate recovery when paired with focused behavioral treatment.
... 242,243 The safety of dextroamphetamine in a stroke population has been tested in a small series. 244 Limited data support the use of other neurotransmitter-releasing agents to promote stroke recovery, including methylphenidate, 245 levodopa, 246 and L-threo-3,4dihydroxyphenyl serine (L-DOPS). 247 Fluoxetine in nondepressed patients in a small RCT appeared to have a small benefit in motor recovery independent of the treatment of depression. ...
... Es handelt sich hierbei um direkte und indirekte noradrenerge Substanzen wie Noradrenalin und Amphetamine. Im Tierexperiment bewirkten diese Substanzen eine Zunahme der kortikalen neuronalen mRNA-Expression und der Synapsen- dichte [86, 87, 90, 91]. Die Erhöhung der Synapsendichte geht dabei mit der Funktionsverbesserung im Verhalten einher [81] . ...
Article
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Statistical learning is a basic mechanism of information processing in the human brain. The purpose lies in the extraction of probabilistic regularities from the multitude of sensory inputs.Principles of statistical learning contribute significantly to language acquisition and presumably also to language recovery following stroke.The empirical database presented in this manuscript demonstrates that the process of word segmentation, acquisition of a lexicon, and acquisition of simple grammatical rules can be entirely explained through statistical learning.Statistical learning is mediated by changes in synaptic weights in neuronal networks.The concept therefore stands at the transition to molecular biology and pharmacology of the neuronal synapse. It still remains to be shown if all aspects of language acquisition can be explained through statistical learning and which regions of the brain are involved in or capable of statistical learning.Principles of effective language training are obvious already. Most important is the massive, repeated interactive exposure.Conscious processing of the stimulus material may not be essential.The crucial principle is a high cooccurrence of language and corresponding sensory processes.This requires a more intense training frequency than traditional aphasia treatment programs provide.
... Patients with uncontrolled hypertension of 160/100 mmHg or more were excluded from entry into the study. 69 Insomnia occurred in one patient who received a higher dose (15 mg) of amphetamine. 64 In addition to amphetamine, methylphenidate has recently been tried in a similar fashion in a small, randomized, controlled trial of poststroke rehabilitation. ...
Article
Despite much progress in stroke prevention and acute intervention, recovery and rehabilitation have traditionally received relatively little scientific attention. There is now increasing interest in the development of stroke recovery drugs and innovative rehabilitation techniques to promote functional recovery after completed stroke. Experimental work over the past two decades indicates that pharmacologic intervention to enhance recovery may be possible in the subacute stage, days to weeks poststroke, after irreversible injury has occurred. This paper discusses the concept of "rehabilitation pharmacology" and reviews the growing literature from animal studies and pilot clinical trials on noradrenergic pharmacotherapy, a new experimental strategy in stroke rehabilitation. Amphetamine, a monoamine agonist that increases brain norepinephrine levels, is the most extensively studied drug shown to promote recovery of function in animal models of focal brain injury. Further research is needed to investigate the mechanisms and clinical efficacy of amphetamine and other novel therapeutic interventions on the recovery process.
... noteworthy that patients enrolled into this dextroamphetamine protocol suffered no adverse reactions, a finding that we have previously reported. 28 This study is limited because of the small group of aphasic subjects and may not represent all stroke patients. However, because many of the patients we studied had severe aphasic deficits at entry, effects in this small sample would appear to be meaningful. ...
Article
Full-text available
A number of studies suggest that drugs which increase the release of norepinephrine promote recovery when administered late (days to weeks) after brain injury in animals. A small number of clinical studies have investigated the effects of the noradrenergic agonist dextroamphetamine in patients recovering from motor deficits following stroke. To determine whether these findings extend to communication deficits subsequent to stroke, we administered dextroamphetamine, paired with speech/language therapy, to patients with aphasia. In a prospective, double-blind study, 21 aphasic patients with an acute nonhemorrhagic infarction were randomly assigned to receive either 10 mg dextroamphetamine or a placebo. Patients were entered between days 16 and 45 after onset and were treated on a 3-day/4-day schedule for 10 sessions. Thirty minutes after drug/placebo administration, subjects received a 1-hour session of speech/language therapy. The Porch Index of Communicative Ability was used at baseline, at 1 week off the drug, and at 6 months after onset as the dependent language measure. Although there were no differences between the drug and placebo groups before treatment (P=0.807), by 1 week after the 10 drug treatments ended there was a significant difference in gain scores between the groups (P=0.0153), with the greater gain in the dextroamphetamine group. The difference was still significant when corrected for initial aphasia severity and age. At the 6-month follow-up, the difference in gain scores between the groups had increased; however, the difference was not significant (P=0.0482) after correction for multiple comparisons. Administration of dextroamphetamine paired with 10 1-hour sessions of speech/language therapy facilitated recovery from aphasia in a small group of patients in the subacute period after stroke. Neuromodulation with dextroamphetamine, and perhaps other drugs that increase central nervous system noradrenaline levels, may facilitate recovery when paired with focused behavioral treatment.
... A follow-up to this study showed there were no adverse reactions to the administration of 10 mg of damphetamine to patients in a typical stroke population. The medication was administered 30 minutes prior to relevant therapies for a total of 10 sessions [30]. In a larger, double-blind, placebo-controlled study, these findings were challenged. ...
Article
Full-text available
There is increasing evidence that environmental and neuropharmacologic treatments enhance stroke recovery. Functional magnetic resonance imaging and transcranial magnetic stimulation have significantly broadened our understanding of the neuroanatomic relationships involved in recovery from brain injury due to stroke. These tools have also demonstrated the role for pharmacologic enhancement of cortical plasticity coupled with behavioral interventions. Robot-assisted therapy and partial body weight-supported treadmill gait training have demonstrated the role for technologic intervention in the modern neuro-rehabilitation setting. Current research using hemi-field ocular prisms and patching techniques suggest a role in the rehabilitation of hemianopsia and visual neglect. Finally, many advances have been made in the understanding of common stroke complications, such as depression, dysphagia, venous thromboembolic disease, incontinence, and spasticity.
... The increases in BP and heart rate are in agreement with the sympathomimetic properties of amphetamines, but they have not previously been described in studies providing information on treatment safety in stroke patients. 10,11,15,27 Our study differs from earlier studies in a number of ways. Walker-Batson et al 11,12 started treatment 16 to 45 days after stroke onset, administered 10 mg d-amph at an interval of 3 to 4 days, and excluded patients with uncontrolled hypertension (Ͼ160/110 mm Hg), whereas we started d-amph treatment within 72 hours, administered 5 to 20 mg d-amph twice daily, and included patients with hypertension. ...
Article
Amphetamine is reported to enhance recovery after experimental stroke, but results from the first few trials in humans are inconclusive. Limited information is available on treatment safety. This study intended to investigate the safety and tolerability of dexamphetamine in patients with acute cerebral ischemia. Forty-five patients with cerebral ischemia were enrolled within 72 hours after onset of symptoms. Patients were randomized to 1 of 3 dose levels (2.5, 5, or 10 mg orally twice daily) or placebo for 5 consecutive days. Adverse events, blood pressure, heart rate, body temperature, consciousness level, and functional outcome measures were followed up daily during treatment. Follow-ups were made at day 7 and 1 and 3 months after stroke. Mean systolic and diastolic blood pressures and heart rate increased 14 mm Hg, 8 mm Hg, and 9 bpm, respectively, with dexamphetamine treatment compared with placebo (P< or =0.01). There was no difference between dexamphetamine and placebo regarding adverse events, body temperature, or consciousness level. During treatment, there was a benefit of dexamphetamine in neurological and functional outcome (P<0.05), but differences were not maintained at follow-up. Overall, dexamphetamine was safe and well tolerated by patients with acute cerebral ischemia, but blood pressure and heart rate increased during treatment in comparison to placebo. These observations may be important in the future planning of amphetamine trials because changes in these variables have been observed to interfere with clinical outcome. The suggestions of improvement in outcome must be confirmed in further studies.
... 3,81 Unwin and Walker-Batson reported no events in their experience of 50 patients poststroke, but subjects with known cardiac disease were excluded. 82 Martinsson demonstrated a dosedependent increase in systolic and diastolic blood pressure and pulse rate. 38 Hypertensive patients were included in this study, but there appeared to be no increase in adverse events attributable to these drug-related haemodynamic changes. ...
Article
Reducing disability and dependency after a stroke is an important clinical objective. We examine what is known about the use of dexamphetamine in patients recovering from an acute stroke, and consider whether further clinical studies should be undertaken. Dexamphetamine has repeatedly been shown to enhance recovery after experimental brain injury in animals, the best effects being seen when dexamphetamine is combined with lesion-specific motor training or sensory stimulation. Postulated mechanisms for these beneficial effects in animals are in keeping with contemporary theories of neurophysiological rehabilitation in man. There have been few clinical studies of dexamphetamine during rehabilitation after an acute stroke. Four controlled trials demonstrated a tendency to an improved outcome when dexamphetamine was paired with therapy and administered 3-30 days after an ischaemic stroke. However, clinical studies to date have been small, included only highly selected patients, and have not addressed possible confounding effects of the drug on mood and untreated depression. Dexamphetamine has previously been used under supervision in medically ill patients and appears to be safe and well-tolerated. There is a need for well-designed studies to assess further the safety and efficacy of dexamphetamine in rehabilitation after stroke.
... 242,243 The safety of dextroamphetamine in a stroke population has been tested in a small series. 244 Limited data support the use of other neurotransmitter-releasing agents to promote stroke recovery, including methylphenidate, 245 levodopa, 246 and L-threo-3,4dihydroxyphenyl serine (L-DOPS). 247 Fluoxetine in nondepressed patients in a small RCT appeared to have a small benefit in motor recovery independent of the treatment of depression. ...
Article
Stroke is a leading cause of disability in the United States.1 The Veterans Health Administration (VHA) of the Department of Veterans Affairs (VA) estimates that 15 000 veterans are hospitalized for stroke each year (VA HSR&D, 1997). Forty percent of stroke patients are left with moderate functional impairments and 15% to 30% with severe disability.2 Effective rehabilitation interventions initiated early after stroke can enhance the recovery process and minimize functional disability. Improved functional outcomes for patients also contribute to patient satisfaction and reduce potential costly long-term care expenditures. There are only 45 rehabilitation bed units (RBUs) in the VA today. Many veterans who have a stroke and are admitted to a VA Medical Center will find themselves in a facility that does not offer comprehensive, integrated, multidisciplinary care. In a VA rehabilitation field survey published in December 2000, more than half of the respondents reported that the “rehabilitative care of stroke patients was incomplete, fragmented, and not well coordinated” at sites lacking a RBU (VA Stroke Medical Rehabilitation Questionnaire Results, 2000). In Department of Defense (DoD) medical treatment facilities, approximately 20 000 active-duty personnel and dependents were seen in 2002 for stroke and stroke-related diagnoses according to ICD-9 coding.3 Comprehensive treatment for stroke patients in DoD medical facilities is given primarily at medical centers. Smaller DoD community hospitals may have limited resources to see both inpatients and outpatients, relying more on the TRICARE network for ongoing stroke rehabilitation services. A growing body of evidence indicates that patients do better with a well-organized, multidisciplinary approach to post-acute rehabilitation after a stroke.4–6 The VA/DoD Stroke Rehabilitation Working Group only focused on the post–acute stroke rehabilitation care. Duncan and colleagues7 found that greater adherence to post-acute stroke rehabilitation guidelines was associated with improved patient outcomes and concluded “compliance …
... In response to the concern that the drug may be toxic, Walker-Batson et al. conducted a follow-up study on a larger patient pool, within 16-42 days of stroke onset, and treated 28 patients with D-amphetamine and 16 patients with placebo 30 min before physiotherapy session on an alternating cycle of every third/fourth day for 10 sessions. 13 The data revealed that the drug was well tolerated during the 12-month course of the study. A parallel study by the same group revealed that such D-amphetamine paired with physical therapy accelerates recovery of stroke patients from aphasia. ...
Article
Journal of Human Hypertension is exclusively concerned with all clinical aspects of human hypertension. The journal publishes fully refereed original research papers from around the world.
Article
Importance Data from animal models show that the administration of dextroamphetamine combined with task-relevant training facilitates recovery after focal brain injury. Results of clinical trials in patients with stroke have been inconsistent. Objectives To collect data important for future studies evaluating the effect of dextroamphetamine combined with physiotherapy for improving poststroke motor recovery and to test the efficacy of the approach. Design, Setting, Participants This pilot, double-blind, block-randomized clinical trial included patients with cortical or subcortical ischemic stroke and moderate or severe motor deficits from 5 rehabilitation hospitals or units. Participants were screened and enrolled from March 2001 through March 2003. The primary outcome was assessed 3 months after stroke. Study analysis was completed December 31, 2015. A total of 1665 potential participants were screened and 64 were randomized. Participants had to begin treatment 10 to 30 days after ischemic stroke. Data analysis was based on intention to treat. Interventions Participants were allocated to a regimen of 10 mg of dextroamphetamine (n = 32) or placebo (n = 32) combined with a 1-hour physical therapy session beginning 1 hour after drug or placebo administration every 4 days for 6 sessions in addition to standard rehabilitation. Main Outcomes and Measures The primary outcome was the difference between groups in change in Fugl-Meyer motor scores from baseline to 3 months after stroke (intention to treat with dextroamphetamine). Secondary exploratory measures included the National Institutes of Health Stroke Scale, Canadian Neurological Scale, Action Research Arm Test, modified Rankin Scale score, Functional Independence Measure, Ambulation Speed and Distance, Mini-Mental State Examination, Beck Depression Inventory, and Stroke Impact Scale. Results Among the 64 patients randomized to dextroamphetamine vs placebo (55% men; median age, 66 years; age range, 27-91 years), no overall treatment-associated difference in the mean (SEM) change in Fugl-Meyer motor scores from baseline to 3 months after stroke was noted (−18.65 [2.27] points with dextroamphetamine vs −20.83 [2.94] points with placebo; P = .58). No overall treatment-associated differences in any of the study’s secondary measures and no differences in subgroups based on stroke location or baseline severity were found. No adverse events were attributed to study treatments. Conclusions and Relevance Treatment with dextroamphetamine combined with physical therapy did not improve recovery of motor function compared with placebo combined with physical therapy as assessed 3 months after hemispheric ischemic stroke. The studied treatment regimen was safe. Trial Registration ClinicalTrials.gov identifier: NCT01905371
Findings from a growing number of studies indicate that patients with aphasia frequently have concomitant impairments of working memory, attention, or both that may negatively affect their language comprehension and production skills (e.g., Caspari, Parkinson, LaPointe, & Katz 1998; Murray, 2002). In contrast, how these cognitive deficits might be remediated or accommodated for has been the subject of relatively few investigations. The purpose of this article is to review critically initial research findings pertaining to treating working memory and attention in patients with aphasia. First, evidence supporting the coexistence of attention and working memory problems in aphasia is reviewed briefly. Next, previous results pertaining to the direct behavioral treatment of attention and working memory impairments in patients with aphasia are described and evaluated. Finally, suggestions are provided to spur further empirical investigation of behavioral and pharmacologic treatments for nonlinguistic deficits associated with aphasia.
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Neuromodulation with pharmacological agents, including drugs of abuse such as amphetamine, when paired with behavioral experience, has been shown to positively modify outcomes in animal models of stroke. A number of clinical studies have tested the efficacy of a variety of drugs to enhance recovery of language deficits post stroke. The purpose of this paper is to : (1) present pertinent animal studies supporting the use of dextro-amphetamine sulphate (AMPH) to enhance recovery after experimental lesions with emphasis on the importance of learning dependent activity for lasting recovery; (2) briefly review neuropharmacological explorations in the treatment of aphasia; (3) present a pilot study in aphasia exploring a drug combination of AMPH and donepezil hydrochloride paired with behavioral treatment to facilitate recovery; and (4) conclude with comments regarding the role of adjunctive pharmacotherapy in the rehabilitation of aphasia, particularly AMPH. Copyright © 2015. Published by Elsevier Inc.
Recovery following stroke has two distinct periods: the immediate recuperative phase taking effect within the first few days, and the delayed phenomenon occurring several days later. The first phase is thought to be a secondary to resolution of brain edema and diaschisis, while the latter phase is believed to be due to neural plasticity. Neural plasticity comprises primarily neurite growth and synaptogenesis. While there have been controversial studies regarding the existence and exact nature of neural plasticity, several researchers have established behavioral recovery after stroke as a function of neuronal remodeling, that would include dendritic growth and increase in synaptic population. Nororepinephrine plays a key role in both phases of stroke recovery. Antagonist such as clonidine and alpha-1 agonists impair functional recovery when administered in the immediate post-stroke period. Sympathomimetic drugs such as amphetamines have been shown to increase functional performance that correlates with neuronal (and synaptic) growth in the brain. Most of these studies have been performed on rats, with limited work performed on human subjects. The exact dosage and timing of administration of amphetamines in the post-stroke period remains to be defined. Nonetheless, amphetamines remain a viable and exciting option for in the post-stroke "recovery" period.
Article
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The administration of numerous facilitatory drugs in combination with appropriate physiotherapeutic approaches is reported to facilitate neurorehabilitation. First evidence of the possible beneficial influence of facilitatory drugs in neurorehabilitation arose from studies investigating the pharmacology of learning in healthy humans. Amphetamine, for example, has shown to improve performance of different somatosensory and motor skills. Paired with physical therapy in stroke patients, it also increases the rate and extent of motor recovery and supports treatment of aphasia. Amphetamine is however known as a "dirty drug", because it acts non-specifically by increasing centrally the levels of dopamine, serotonin, and noradrenaline. Thus, first approaches intend to scrutinize the role of more specifically acting pharmacological agents on learning and neurorehabilitation. In this review, focus is placed on two main topics: (i) studies that aimed to investigate the pharmacological basis of motor and sensory skills in healthy humans and (ii) studies investigating whether the same drugs may also support neurorehabilitation. First, different sensorimotor paradigms are discussed, which were introduced to investigate basic influences of facilitatory pharmaceuticals on cortical plasticity. Then, emphasis is placed on the role of these drugs acting to gate synaptic plasticity in neurorehabilitation. It is concluded that further studies in large populations should focus on more specifically acting pharmaceuticals, their side effects and their capacity in supporting different patterns of physical therapy.
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Traumatic brain injury is the leading cause of death in young patients and stroke is the leading cause of major disability in elderly patients. Both injuries are often followed by cerebral plasticity changes and increased intracerebral pressure (ICP). Aim of the review is to present current knowledge about amphetamines and other therapeutics concerning the recovery of brain injury based on contemporary findings. On the one hand beneficial effects for cognitive and physical outcome after brain injury by coupling amphetamine with physical therapy could be demonstrated; on the other hand its efficacy was shown in only two out of 10 clinical trials. Impairment after brain injury is reduced if adequate early treatment is established. On the basis of current findings amphetamine after brain injury cannot be recommended. In patients with an increased ICP the maintenance of an adequate cerebral perfusion pressure is required. In patients with increased ICP under controlled ventilation, the combination of ketamine with, for example, a short-acting benzodiazepine and opioid or methohexital is equally well tolerated. Ketamine decreases ICP without lowering blood pressure and cerebral perfusion pressure. Its neuroprotective property might reduce the exacerbation of brain injury following N-methyl-D-aspartate-receptor activation, neuronal apoptosis and systemic inflammatory responses.
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Major therapeutic advances in the rehabilitation of subacute stroke are lacking. One promising approach is treatment with amphetamine in combination with physiotherapy so as to promote motor function. In a randomized, double-blind, placebo-controlled clinical trial, the effect of 10 sessions with 10 mg of amphetamine combined with physiotherapy during a 5-week period was investigated in 39 geriatric patients who had been admitted to a stroke rehabilitation unit. Motor function (Fugl-Meyer motor performance score) and activities of daily living (ADL; Barthel's index) were assessed at baseline and at the end of treatment. All patients improved significantly over the intervention period. Amphetamine-treated patients did not show any increase in motor function or ADL as compared to the control group. Rehabilitation with amphetamine at this dosage and interval, combined with physiotherapy, did not promote motor recovery or functional capacity in patients suffering from stroke.
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Recent studies demonstrate that neurological patients show great potential for recovery in both the early and late stages following injury. Enhancement of the recovery process could be achieved with new rehabilitation approaches alone or in combination with pharmacological intervention. These new approaches have evolved from fundamental advances in both animal and human studies. To date few randomized clinical trials have addressed the efficacy or effectiveness of these new approaches. In this paper, important quantitative studies will be reviewed and discussed in relation to the important mechanisms of locomotor control and plasticity that take place following lesions of the central nervous system.
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D-amphetamine has been shown to affect early stages of stroke recovery, and may have a beneficial effect on functions when administered later after stroke. To test D-amphetamine effects on skill acquisition after the acute or subacute stages of stroke, when lesion-related structural changes have consolidated. Sixteen healthy subjects were treated with D-amphetamine during a 4-week training of tactile frequency discrimination in a placebo-controlled, double-blind design. All subjects improved significantly in tactile temporal acuity. However, improvement did not differ in subjects treated with or without D-amphetamine. No beneficial effect of D-amphetamine on somatosensory training improvements was found in healthy subjects.
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Over the past two decades, experimental studies following brain injury have shown that the central nervous system is dynamic and malleable to internal and external inputs. Neuromodulation and/or direct manipulation of motor and sensory experience can modify brain plasticity and functional outcome after experimental lesions. Specifically, pharmacologic modulation has been found to facilitate recovery of various behavioral deficits following occlusive injury. Additionally, the behavioral experience that induces long-term plasticity in motor and sensory maps after injury appears to be limited to those that entail the development of new skills. These data have strong application to human rehabilitation. This review will: (1) overview critical experimental studies that show that pharmacologic manipulation and/or specific behavioral experience may modify the functional organization of the injured brain and (2) review beginning studies which are exploring the application of this knowledge clinically.
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Clinical trials of pharmacological agents in stroke have mainly focused on events that need to be modified in the very acute stage, such as restoration of blood flow with thrombolytic therapy or reducing the effects of ischaemia with neuroprotective therapy. Thrombolytic therapy is, however, only effective within the first few hours of stroke onset and so far, no neuroprotective therapy has proven to be efficacious in humans. Thus, there is a great need for new pharmacological strategies to improve outcome after stroke. Accumulating evidence supports the assumption that the brain is plastic and improvements can be expected after permanent injuries. Acute and chronic alterations in neurotransmitter regulation after injury affects plasticity and may thus provide a basis for new pharmacological targets for stroke recovery. The search for pharmacological therapies that affect the recovery process after a permanent injury has been intensified during the last decade. Amphetamines, in combination with training, are currently one of the most promising pharmacological strategies studied for recovery after stroke. Several non-mutually exclusive hypotheses, more or less supported by experimental studies, have tried to explain the mechanisms underlying the facilitation of recovery of function with amphetamine treatment. Amphetamines are believed to hasten the processes in the brain, such as plasticity mechanisms and resolution of diaschisis. The combination of amphetamine and task-specific training seems to be of importance to the outcome. Results from animal studies are consistent between different models and species, and mainly show an increased rate of recovery but there are a few exceptions, with some studies reporting no effect or even a decreased recovery rate. In humans the number of randomised controlled studies of amphetamines is growing rapidly. Results from a Cochrane systematic review indicate a faster motor and language recovery rate with treatment, but the number of studies is too few and studies are too small to draw definite conclusions about the effect on recovery of stroke. Data in the systematic review also indicate that the mortality rate is higher in amphetamine-treated patients compared with placebo-treated patients. However, this is most likely because of baseline imbalances between the treatment groups with patients with more severe strokes being allocated to amphetamine treatment. Further clinical trials are justified, but at present amphetamines should not be used in clinical practice.
Article
Animal research shows that treatment with amphetamines improves recovery after focal cerebral ischaemia. If the effects are similar in humans, amphetamine treatment could have a major impact on recovery from stroke. To assess the effects of amphetamine treatment in patients with stroke. We searched the Cochrane Stroke Group Trials Register (last searched January 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to January 2006), EMBASE (1980 to January 2006), CINAHL (1982 to January 2006), CINAHL (1982 to January 2006), Science Citation Index (1992 to March 2005) and registers of ongoing trials. We also checked the reference lists of all relevant articles and reviews, and contacted researchers in the field. Randomized unconfounded trials comparing amphetamine with placebo. Two review authors independently selected trials for inclusion and assessed trial quality; one extracted the data. Ten studies involving 287 patients were included, but not all trials contributed data to each outcome examined in this review. The quality of the trials varied but was generally high. Based on three trials (106 patients) there was no evidence that amphetamine treatment reduced death or dependence (Peto's odds ratio (Peto OR) 1.5, 95% confidence interval (CI) 0.6 to 3.3). Imbalances at baseline with more serious stroke allocated to amphetamine may account for the trend for more deaths at the end of follow up among amphetamine-allocated patients (Peto OR 2.8, 95% CI 0.9 to 8.6). Based on two trials (73 patients) systolic (weighted mean difference (WMD) 8.4 mm Hg, 95% CI 1.6 to 15.2) and diastolic (WMD 4.9 mm Hg, 95% CI 1.1 to 8.8) blood pressure, as well as heart rate, increased (WMD 10.6 bpm, 95% CI 3.3 to 17.8) in amphetamine-allocated patients. Based on six studies (176 patients) there was evidence of a better relative change from baseline to last follow up in motor function (WMD -6.1 points; 95% CI -10.4 to -1.9) Different results with different analysis approaches emphasize caution in the interpretation of the results. At present, too few patients have been studied to draw any definite conclusions about the effects of amphetamine treatment on recovery from stroke. The suggested benefits on motor function and the non-significant trend towards increased risk of death could be related to imbalances in prognostic variables or other bias in the studies. Further research is therefore justified.
Article
Aphasia recovery has often been attributed to a combination of "spontaneous recovery" and rehabilitation. However, a variety of new pharmacological, surgical, and interventional neuroradiology procedures have been developed that can complement rehabilitation in the first days to weeks after stroke by restoring blood flow to dysfunctional but salvageable brain tissue. This paper will review the medical and surgical interventions to improve regional cerebral blood flow that recently have been shown to (1) augment aphasia recovery by improving tissue function, and (2) prevent expansion of the stroke that would otherwise impede recovery. Success with such treatments facilitates aphasia rehabilitation by improving the baseline language performance that must be improved further with language therapy.
Article
Experimental animal research shows that treatment with amphetamines improves recovery after focal cerebral ischaemia. If the effect were similar in humans, amphetamine treatment could have a major impact on recovery from stroke. The objective of this review was to assess the effects of amphetamine treatment in patients with stroke. We searched the Cochrane Stroke Group Trials Register (last searched November 2002). In addition, we searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 4 2002), MEDLINE (1966-September 2002), EMBASE (1980-November 2002), and Science Citation Index (1992-December 2002). The reference lists of all relevant articles and reviews were checked, and we contacted researchers in the field to identify further published and unpublished studies. Randomized unconfounded trials comparing amphetamine with placebo. Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. Seven studies involving 172 patients were included. The quality of the trials varied but was generally high. Based on two trials (85 patients) there was no evidence that amphetamine treatment reduced death or dependence (Peto's odds ratio, [Peto OR] 1.54; 95% Confidence Interval [CI] 0.64 to 3.73). In these two trials, there were imbalances at baseline, with more serious strokes allocated to amphetamine. This imbalance may account for the trend for more deaths at the end of follow-up among amphetamine allocated patients (Peto OR 3.33; 95% CI 0.99 to 11.24). Based on 4 studies (95 patients) there was evidence of a better relative change in motor function according to the Fugl-Meyer motor scale (Weighted Mean Difference, [WMD] -8.17 points; 95% CI -13.58 to -2.76) and based on 1 study (21 patients) there was evidence of a better change in language function as assessed by the Porch Index of Communicative Ability score (WMD -7.51 points; 95% CI -14.42 to -0.60) in amphetamine allocated patients. At present, too few patients have been studied to draw any definite conclusions about the effects of amphetamine treatment on recovery from stroke. The suggested benefits on motor and language function, and the non-significant trend towards increased risk of death, could be related to imbalances in prognostic variables or other bias in studies. Further research in this area is therefore justified.
Article
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Previous studies have shown that carotid endarterectomy in patients with symptomatic severe carotid stenosis (defined as stenosis of 70 to 99 percent of the luminal diameter) is beneficial up to two years after the procedure. In this clinical trial, we assessed the benefit of carotid endarterectomy in patients with symptomatic moderate stenosis, defined as stenosis of less than 70 percent. We also studied the durability of the benefit of endarterectomy in patients with severe stenosis over eight years of follow-up. Patients who had moderate carotid stenosis and transient ischemic attacks or nondisabling strokes on the same side as the stenosis (ipsilateral) within 180 days before study entry were stratified according to the degree of stenosis (50 to 69 percent or <50 percent) and randomly assigned either to undergo carotid endarterectomy (1108 patients) or to receive medical care alone (1118 patients). The average follow-up was five years, and complete data on outcome events were available for 99.7 percent of the patients. The primary outcome event was any fatal or nonfatal stroke ipsilateral to the stenosis for which the patient underwent randomization. Among patients with stenosis of 50 to 69 percent, the five-year rate of any ipsilateral stroke (failure rate) was 15.7 percent among patients treated surgically and 22.2 percent among those treated medically (P=0.045); to prevent one ipsilateral stroke during the five-year period, 15 patients would have to be treated with carotid endarterectomy. Among patients with less than 50 percent stenosis, the failure rate was not significantly lower in the group treated with endarterectomy (14.9 percent) than in the medically treated group (18.7 percent, P=0.16). Among the patients with severe stenosis who underwent endarterectomy, the 30-day rate of death or disabling ipsilateral stroke persisting at 90 days was 2.1 percent; this rate increased to only 6.7 percent at 8 years. Benefit was greatest among men, patients with recent stroke as the qualifying event, and patients with hemispheric symptoms. Endarterectomy in patients with symptomatic moderate carotid stenosis of 50 to 69 percent yielded only a moderate reduction in the risk of stroke. Decisions about treatment for patients in this category must take into account recognized risk factors, and exceptional surgical skill is obligatory if carotid endarterectomy is to be performed. Patients with stenosis of less than 50 percent did not benefit from surgery. Patients with severe stenosis (> or =70 percent) had a durable benefit from endarterectomy at eight years of follow-up.
Article
Background and Purpose Indications for carotid endarterectomy have engendered considerable debate among experts and have resulted in publication of retrospective reviews, natural history studies, audits of community practice, position papers, expert opinion statements, and finally prospective randomized trials. The American Heart Association assembled a group of experts in a multidisciplinary consensus conference to develop this statement. Methods A conference was held July 16-18, 1993, in Park City, Utah, that included recognized experts in neurology, neurosurgery, vascular surgery, and healthcare planning. A program of critical topics was developed, and each expert presented a talk and provided the chairman with a summary statement. From these summary statements a document was developed and edited onsite to achieve consensus before final revision. Results The first section of this document reviews the natural history, methods of patient evaluation, options for medical management, results of surgical management, data from position statements, and results to date of prospective randomized trials for symptomatic and asymptomatic patients with carotid artery disease. The second section divides 96 potential indications for carotid endarterectomy, based on surgical risk, into four categories: (1) Proven: This is the strongest indication for carotid endarterectomy; data are supported by results of prospective contemporary randomized trials. (2) Acceptable but not proven: a good indication for operation; supported by promising but not scientifically certain data. (3) Uncertain: Data are insufficient to define the risk/benefit ratio. (4) Proven inappropriate: Current data are adequate to show that the risk of surgery outweighs any benefit. Conclusions Indications for carotid endarterectomy in symptomatic good-risk patients with a surgeon whose surgical morbidity and mortality rate is less than 6% are as follows. (1) Proven : one or more TIAs in the past 6 months and carotid stenosis ≥ 70% or mild stroke within 6 months and a carotid stenosis ≥ 70%; (2) acceptable but not proven : TIAs within the past 6 months and a stenosis 50% to 69%, progressive stroke and a stenosis ≥ 70%, mild or moderate stroke in the past 6 months and a stenosis 50% to 69%, or carotid endarterectomy ipsilateral to TIAs and a stenosis ≥ 70% combined with required coronary artery bypass grafting; (3) uncertain : TIAs with a stenosis <50%, mild stroke and stenosis <50%, TIAs with a stenosis <70% combined with coronary artery bypass grafting, or symptomatic, acute carotid thrombosis; (4) proven inappropriate: moderate stroke with stenosis <50%, not on aspirin; single TIA, <50% stenosis, not on aspirin; high-risk patient with multiple TIAs, not on aspirin, stenosis <50%; high-risk patient, mild or moderate stroke, stenosis <50%, not on aspirin; global ischemic symptoms with stenosis <50%; acute dissection, asymptomatic on heparin. Indications for carotid endarterectomy in asymptomatic good-risk patients performed by a surgeon whose surgical morbidity and mortality rate is less than 3% are as follows. (1) Proven: none. As this statement went to press, the National Institute of Neurological Disorders and Stroke issued a clinical advisory stating that the Institute has halted the Asymptomatic Carotid Atherosclerosis Study (ACAS) because of a clear benefit in favor of surgery for patients with carotid stenosis ≥60% as measured by diameter reduction. When the ACAS report is published, this indication will be recategorized as proven. (2) acceptable but not proven : stenosis >75% by linear diameter; (3) uncertain : stenosis >75% in a high-risk patient/surgeon (surgical morbidity and mortality rate >3%), combined carotid/coronary operations, or ulcerative lesions without hemodynamically significant stenosis; (4) proven inappropriate : operations with a combined stroke morbidity and mortality >5%.
Article
Patients carrying the FV Leiden or the FII A20210 mutation have a high risk of venous thromboembolism. Among 542 patients with a documented diagnosis of deep venous thrombosis in one leg consecutively referred for a thrombophilic work-up, we have retrospectively assessed the rate of objectively documented previous recurrence in carriers of both FV Leiden and FII A20210 mutations. Eighty-two patients had experienced 115 episodes of recurrent venous thromboembolism. The rate of recurrent venous thromboembolism was 29.2% among subjects with and 14.5% in those without deficiencies of natural anticoagulant proteins (p = 0.055), and 24.6% among patients with and 14.0% in those without antiphospholipid antibodies (p = 0.036). The frequency of having a recurrent thromboembolism was 16.2%, 20.0%, and 36.4% among carriers of FV Leiden, FII A20210 mutation, or both gene defects, respectively, and 12.8% in subjects carrying neither mutation (p for trend = 0.004). When adjusted for age, sex, and thrombophilic risk factors, the rate was higher among patients with than in those without deficiencies of natural anticoagulant proteins (OR: 3.0; 95% CI: 1.2-7.5), aPL 2.5 (95% CI: 1.3-4.9), or both FV Leiden and FII A20210 gene mutations (OR 4.8; 95% CI: 1.9-12.2). The rate of previous recurrent venous thromboembolism was significantly higher in subjects carrying both FV Leiden and FII 20210 mutations and was comparable to that observed in subjects with deficiencies of natural anticoagulant proteins or antiphospholipid antibodies.
Article
Factor V Leiden and a prothrombin gene variant, G20210A, are mutations associated with a thrombotic risk. The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age. We conducted a case-control study in western Washington state. Case patients were women aged 18 to 44 years with a first stroke (n = 106). Control subjects were women without stroke recruited from the same region by use of random-digit telephone dialing (n = 391). All were interviewed and provided blood specimens, which were genotyped for these mutations. Factor V Leiden was found in 0.9% of case patients, a single patient with a subarachnoid hemorrhage, and in 4.1% of control subjects. The odds ratio (OR) for any stroke was 0.2 (95% confidence interval [CI], 0.03 to 1.7). The prothrombin variant was found in 1.9% of case patients, 1 with a venous stroke and 1 with an ischemic stroke, and in 1.6% of control subjects. The OR for any stroke was 1.48 (95% CI, 0.14 to 9.17). ORs for stroke types were also not statistically significant. In this study, neither factor V Leiden nor the prothrombin variant (G20210A) was an important risk factor for stroke in young women. In this setting, screening for these mutations cannot be recommended. Unanswered by this study is whether screening would be useful in select patients, such as those with a strong family history of thrombophilia or those with venous strokes.
Article
A new model of transient, bilateral hemispheric ischemia in the unanesthetized rat is described. During ether anesthesia the rat's vertebral arteries were electrocauterized through the alar foramina of the first cervical vertebra and reversible clasps placed loosely around the common carotid arteries. Twenty-four hr later, the awake rats were restrained and the carotid clasps tightened to produce 4-vessel occlusion. The carotid clasps were removed after 10, 20 or 30 min of 4-vessel occlusion and the animals killed by perfusion fixation 72 hr later. Rats which convulsed during the ischemic or post-ischemic period were excluded from further study. All rats subjected to 20 or 30 min of 4-vessel occlusion demonstrated ischemic neuronal damage. The H1 and paramedian hippocampus, striatum and layers 3, 5 and 6 of the posterior neocortex were the regions most frequently damaged. The advantages of this model are the ease of preparation of large numbers of animals, a high rate of predictable ischemic neuronal damage, a low incidence of seizures and the absence of anesthesia.
Article
The four-vessel occlusion (4VO) model of Pulsinelli and Brierley (Stroke 1979;10:267-272) has been modified for use in halothane-nitrous oxide-anesthetized, physiologically controlled rats that were ventilating spontaneously. Selection criteria for the classification of severity of ischemia were established by correlating changes in the electroencephalogram and the general physiological status with measurements of regional blood flow and regional energy metabolism. In 13% of animals, 4VO did not cause flattening of the electroencephalogram, and such animals were classified as undergoing only "oligemia." In 65% of rats, the electroencephalogram flattened and blood pressure sharply increased with 4VO, whereas spontaneous respiration continued. This group exhibited almost complete ischemia in autoradiographic blood-flow studies, severe acidosis, and depletion of adenosine 5'-triphosphate and glucose in the forebrain and, hence, was classified as the "ischemia" group. The remaining 22% stopped breathing after vascular occlusion and were rejected for further study. Survival experiments of ischemic animals revealed the typical postischemic sequelae, with primary metabolic recovery after 8 hours of recirculation in all brain structures followed after 8-24 hours by severe biochemical deterioration and neuronal death in the striatum and hippocampus. Postischemic seizure activity was rare. The main advantages of the present modification in comparison with the original method are 1) the application of anesthesia without loss of primary selection criteria, 2) the possibility of invasive physiological monitoring, and 3) the absence of postischemic seizures, which eliminates the necessity for secondary selection criteria.
Article
In a rat 3-day survival model of 10-minute four-vessel occlusion, halothane anesthesia was used to attenuate the ictal blood pressure elevation of the cerebral ischemic response and thereby maintain an isoelectric EEG. Selectively vulnerable regions of the brain were protected by preischemia plus postischemia maintenance treatment with the calcium entry blocker nicardipine. Compared with untreated animals, repeated doses at 500 micrograms/kg IP were markedly more effective than doses of 50 micrograms/kg. Ongoing studies demonstrate a neurocytoprotective action of nicardipine when deferred treatment is given postischemia.
Article
Cerebral ischemia was produced in the rat by simultaneous occlusion of the vertebral and carotid arteries according to the method of Pulsinelli and Brierley (Stroke 10: 267, 1979). Local cerebral blood flow (CBF) was determined by polarographic and autoradiographic techniques. Hydrogen-clearance measurements showed that mean CBF fell in four monitored regions of the hemispheres to between 0.11 and 0.18 ml/g/min, being least in deep rostal gray, intermediate in superficial gray, and greatest in deep caudal gray. However, individual animals had local CBF in excess of 0.20 and even 0.30 ml/g/min, and no animal showed zero CBF. When animals were rendered hypotensive (MABP of 50 Torr) during vascular occlusion, mean CBF ranged between 0.03 and 0.10 ml/g/min in the same regional order. With hypotension, total arrest of flow occurred. Autoradiographic data confirmed the above findings and indicated adequate CBF to the lower brainstem. During vascular occlusion, sufficient CBF may be present ot sustain cerebral tissue as in animals with a well developed spinal circulation or an inadvertently patent vertebral artery.
Article
In animal models of brain injury, administration of numerous pharmaceuticals is reported to facilitate functional recovery. However, only drugs that increase the release of norepinephrine have been shown to promote recovery when administered late (days to weeks) after injury. To determine whether these findings were applicable to humans, we administered the norepinephrine stimulant dextroamphetamine, paired with physical therapy, to hemiplegic stroke patients. Ten hemiplegic patients who suffered an acute ischemic infarction were entered between days 16 and 30 after onset and randomly assigned to receive either 10 mg of dextroamphetamine or a placebo orally every fourth day for 10 sessions paired with physical therapy. The Fugl-Meyer Motor Scale was used at baseline, within each session, and for 12 months after onset as the dependent measure. Confounding medications such as alpha-adrenergic antagonists or agonists were excluded in all subjects. Although there were no differences between the groups at baseline (P = .599), there was a significant (P = .047) difference between the groups when the drug had been discontinued for 1 week and at the 12-month follow-up visit (P = .047). Administration of dextroamphetamine paired with physical therapy increased the rate and extent of motor recovery in a small group of hemiplegic stroke patients. These data support and extend previous findings of the facilitatory aspects of certain types of drugs on recovery from brain injury. The use of neuromodulation may allow the nervous system to adapt previously unused or alternative pathways to relevant external input.
Article
Indications for carotid endarterectomy have engendered considerable debate among experts and have resulted in publication of retrospective reviews, natural history studies, audits of community practice, position papers, expert opinion statements, and finally prospective randomized trials. The American Heart Association assembled a group of experts in a multidisciplinary consensus conference to develop this statement. A conference was held July 16-18, 1993, in Park City, Utah, that included recognized experts in neurology, neurosurgery, vascular surgery, and healthcare planning. A program of critical topics was developed, and each expert presented a talk and provided the chairman with a summary statement. From these summary statements a document was developed and edited onsite to achieve consensus before final revision. The first section of this document reviews the natural history, methods of patient evaluation, options for medical management, results of surgical management, data from position statements, and results to date of prospective randomized trials for symptomatic and asymptomatic patients with carotid artery disease. The second section divides 96 potential indications for carotid endarterectomy, based on surgical risk, into four categories: (1) Proven: This is the strongest indication for carotid endarterectomy; data are supported by results of prospective contemporary randomized trials. (2) Acceptable but not proven: a good indication for operation; supported by promising but not scientifically certain data. (3) Uncertain: Data are insufficient to define the risk/benefit ratio. (4) Proven inappropriate: Current data are adequate to show that the risk of surgery outweighs any benefit. Indications for carotid endarterectomy in symptomatic good-risk patients with a surgeon whose surgical morbidity and mortality rate is less than 6% are as follows. (1) Proven: one or more TIAs in the past 6 months and carotid stenosis > or = 70% or mild stroke within 6 months and a carotid stenosis > or = 70%; (2) acceptable but not proven: TIAs within the past 6 months and a stenosis 50% to 69%, progressive stroke and a stenosis > or = 70%, mild or moderate stroke in the past 6 months and a stenosis 50% to 69%, or carotid endarterectomy ipsilateral to TIAs and a stenosis > or = 70% combined with required coronary artery bypass grafting; (3) uncertain: TIAs with a stenosis < 50%, mild stroke and stenosis < 50%, TIAs with a stenosis < 70% combined with coronary artery bypass grafting, or symptomatic, acute carotid thrombosis; (4) proven inappropriate: moderate stroke with stenosis < 50%, not on aspirin; single TIA, < 50% stenosis, not on aspirin; high-risk patient with multiple TIAs, not on aspirin, stenosis < 50%; high-risk patient, mild or moderate stroke, stenosis < 50%, not on aspirin; global ischemic symptoms with stenosis < 50%; acute dissection, asymptomatic on heparin. Indications for carotid endarterectomy in asymptomatic good-risk patients performed by a surgeon whose surgical morbidity and mortality rate is less than 3% are as follows. (1) Proven: none. (As this statement went to press, the National Institute of Neurological Disorders and Stroke issued a clinical advisory stating that the Institute has halted the Asymptomatic Carotid Atherosclerosis Study (ACAS) because of a clear benefit in favor of surgery for patients with carotid stenosis > or = 60% as measured by diameter reduction. When the ACAS report is published, this indication will be recategorized as proven. (2) acceptable but not proven: stenosis > 75% by linear diameter; (3) uncertain; stenosis > 75% in a high-risk patient/surgeon (surgical morbidity and mortality rate > 3%), combined carotid/coronary operations, or ulcerative lesions without hemodynamically significant stenosis; (4) proven inappropriate: operations with a combined stroke morbidity and mortality > 5%.
Article
Diagnosis of hemorrhagic transformation (HT) could influence the prognosis and the management of acute ischemic stroke. The interobserver reliability of CT-scan HT classification is evaluated in the present study. Fifty 5-day CT scans of patients enrolled in the Multicenter Acute Stroke Trial-Italy (MAST-I) were reviewed independently by two neuroradiologists and one neurologist with CT training. They evaluated the presence and type of intraparenchymal HT (hemorrhagic infarction types I, II, and III and intracerebral hemorrhage) (five-item scale), as well as the presence of intraventricular and/or subarachnoid bleeding according to standardized definitions. Agreement for exclusion of HT and intraventricular/ subarachnoid bleeding was good between the neuroradiologists (kappa = 0.70 and kappa = 0.72) and excellent between the neurologist and each neuroradiologist (kappa = 0.87 and kappa = 0.77, kappa = 0.83, and kappa = 0.81, respectively). The overall agreement for the five-item HT scale between the two neuroradiologists was good (kappa n = 0.65) because of discordance over the last three items. Better overall agreement was obtained with a three-item scale: no hemorrhage, petechial type I hemorrhagic infarction, and other HT (type II and type III hemorrhagic infarction and intracerebral hemorrhage) together (kappa w = 0.82 Exclusion of HT is a reliable CT diagnosis when made by neuroradiologists and also by a neurologist with CT training. Five- and three-item scales of HT types showed good to excellent reliability. The validity of the scale for predicting short- and long-term outcome should be evaluated in future studies.
Article
Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age- and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q506, a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q506; of them, 10 patients and 3 control subjects had isolated factor V:Q506 (adjusted OR = 6.3, 95% CI = 1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR = 17.3, 95% CI = 2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR = 6.0) or multiplicative (OR = 4.4) model. The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q506. Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q506 alone.
Article
Idiopathic cerebral-vein thrombosis can cause serious neurologic disability. We evaluated risk factors for this disorder, including genetic risk factors (mutations in the genes encoding factor V and prothrombin) and nongenetic risk factors (such as the use of oral contraceptive agents). We compared the prevalence of these risk factors in 40 patients with cerebral-vein thrombosis, 80 patients with deep-vein thrombosis of the lower extremities, and 120 healthy controls. The G1691A mutation in the factor V gene and the G20210A prothrombin-gene mutation, which are established genetic risk factors for venous thrombosis, were studied. We also assessed the use of oral contraceptives and other risk factors for thrombosis. The prevalence of the prothrombin-gene mutation was higher in patients with cerebral-vein thrombosis (20 percent) than in healthy controls (3 percent; odds ratio, 10.2; 95 percent confidence interval, 2.3 to 31.0) and was similar to that in patients with deep-vein thrombosis (18 percent). Similar results were obtained for the mutation in the factor V gene. The use of oral contraceptives was more frequent among women with cerebral-vein thrombosis (96 percent) than among controls (32 percent; odds ratio, 22.1; 95 percent confidence interval, 5.9 to 84.2) and among those with deep-vein thrombosis (61 percent; odds ratio, 4.4; 95 percent confidence interval, 1.1 to 17.8). For women who were taking oral contraceptives and who also had the prothrombin-gene mutation (seven patients with cerebral-vein thrombosis but only one control), the odds ratio for cerebral-vein thrombosis rose to 149.3 (95 percent confidence interval, 31.0 to 711.0). Mutations in the prothrombin gene and the factor V gene are associated with cerebral-vein thrombosis. The use of oral contraceptives is also strongly and independently associated with the disorder. The presence of both the prothrombin-gene mutation and oral-contraceptive use raises the risk of cerebral-vein thrombosis further.
Article
It has been recently reported that a G-->A transition at nucleotide position 20210 in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of deep venous thrombosis. To date, it is unknown whether this polymorphism also represents a risk factor for cerebral venous thrombosis (CVT). Venous blood samples were collected from 45 patients with CVT and from 354 healthy blood donors as controls. A second control group consisted of 131 subjects with acute ischemic stroke or transient ischemic attack (TIA). Genomic DNA was isolated from peripheral blood leukocytes. Amplification of DNA was performed by polymerase chain reaction (PCR). The G-->A transition at nucleotide position 20210 of the prothrombin gene was detected by allele-specific restriction digestion. The G20210-->A transition in the prothrombin gene was found in a heterozygous form in 4 of 45 patients with CVT (8.9%) and in 8 of 354 healthy control subjects (2.3%). This difference was statistically significant (P=0.010). The G20210-->A transition increased the relative risk for CVT approximately 5-fold (age-adjusted odds ratio 5.7; 95% CI 1.5 to 21.5). In contrast, in the group of patients with acute cerebral ischemia, only 3 of 131 subjects (2.3%) were heterozygous for the G20210-->A transition, which corresponded to the prevalence in the group of healthy blood donors. The recently described G20210-->A transition in the 3'-untranslated region of the prothrombin gene is an inherited risk factor for CVT but obviously not for acute ischemic stroke or TIA.
Article
BACKGROUND and Different coagulation disorders have been associated with cerebral venous thrombosis (CVT). Until now, fewer than 50 patients have been reported with CVT and the factor V Leiden (FVL) mutation. Although the prevalence of FVL-positive patients with CVT ranged from 10% to 25%, it was as low as 0.5% to 3% in the control groups. Most other studies had not systematically searched for concomitant risk factors or previous thromboembolic events. To better define the relevance of the FVL mutation in conjunction with additional risk factors in CVT, we conducted the present case-control study. Fifty-five patients with CVT were compared with 272 healthy controls. A standardized interview regarding established risk factors for venous thrombosis and the patients' and their families' histories for thromboembolic events was performed. The presence of the FVL mutation was determined by polymerase chain reaction on DNA obtained from peripheral blood leukocytes. Of 55 patients, 8 (14.5%) were heterozygous for the FVL mutation compared with 17 of 272 controls (6.25%). The relative risk for the presence of FVL was 2.55 (95% confidence interval, 1.04 to 6.26; P=0.04). Additional risk factors for CVT were frequently found in both the presence and absence of FVL. Recurrence of venous thromboembolic events was more frequent in patients with the FVL mutation (5 of 8 patients, 62.5%) than in those without this anomaly (8 of 47 patients, 17%; P<0.005). Our study confirms the FVL mutation as the most relevant hereditary risk factor for CVT. Coexisting risk factors are usually involved in the initiation of CVT. Patients with the FVL mutation are at an increased risk for recurrent venous thrombosis.
Article
The detection of asymptomatic embolization with the use of Doppler ultrasound has a number of potential applications in patients with acute stroke. It may provide information on the stroke pathogenesis in individual cases, identify patients with continued embolization, and allow localization of the active embolic source. We recruited 119 patients with acute anterior circulation infarction within 72 hours of stroke onset. Transcranial Doppler recordings were possible in 100 (84.0%). Bilateral 1-hour middle cerebral artery (MCA) recordings were made and saved on digital audiotape for blinded offline analysis. When embolic signals were detected during screening of the first recording, simultaneous recording was performed from the ipsilateral MCA and common carotid artery for an additional 30 minutes. In all patients with embolic signals at screening and in matched negative controls, recordings were repeated on days 4, 7, and 14. Embolic signals were detected in the symptomatic MCA in 16 patients (16%). They were more common in patients with carotid stenosis (P<0.0001), occurring in 50% of this group. They were rare in patients with cardioembolic stroke (4.5%) and were not detected in patients with lacunar stroke. In the 16 patients with embolic signals, the proportion with embolic signals fell over time (P=0. 0025), but they were still present in a third at 2 weeks. In 10 patients, localization of the embolic source was possible by simultaneous recording from the MCA and the ipsilateral common carotid artery. Continued asymptomatic embolization is common after stroke in patients with carotid artery disease and is still present in a significant proportion at 2 weeks. The technique may identify patients at risk of further stroke for more aggressive antiplatelet therapy; this needs to be tested in large prospective studies. The technique may also allow localization of the active embolic source.
Article
Point mutations in the factor V gene (factor V Leiden) and the prothrombin gene (the substitution of A for G at position 20210) are the most common causes of inherited thrombophilia. Whether or not factor V Leiden increases the risk of recurrent deep venous thrombosis is controversial, and there is no information on the risk of recurrence among carriers of both mutations. We studied a retrospective cohort of 624 patients who were referred for a first episode of deep venous thrombosis. After excluding 212 patients with other inherited or acquired causes of thrombophilia, we compared 112 patients who were heterozygous carriers of factor V Leiden with 17 patients who were heterozygous for both factor V Leiden and the prothrombin mutation and 283 patients who had neither mutation. The relative risk of recurrent deep venous thrombosis was calculated with use of a proportional-hazards model. Patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.6; P=0.76). In contrast, patients who were heterozygous for both factor V Leiden and the prothrombin mutation had a higher risk of recurrent thrombosis than did carriers of factor V Leiden alone (relative risk, 2.6; 95 percent confidence interval, 1.3 to 5.1; P=0.002). When the analysis was restricted to patients with spontaneous recurrences (i.e., ones that occurred in the absence of transient risk factors for venous thrombosis), the risk among carriers of both mutations, as compared with carriers of factor V Leiden alone, remained high (relative risk, 3.7; 95 percent confidence interval, 1.7 to 7.7; P<0.001), particularly if the first event had also been spontaneous (relative risk, 5.4; 95 percent confidence interval, 2.0 to 14.1; P<0.001). In contrast, the risk of recurrence in the presence of transient risk factors was similar among carriers of both mutations and carriers of factor V Leiden alone. The risk of recurrent deep venous thrombosis is similar among carriers of factor V Leiden and patients without this mutation. Carriers of both factor V Leiden and the G20210A prothrombin mutation have an increased risk of recurrent deep venous thrombosis after a first episode and are candidates for lifelong anticoagulation.
Article
The clinical correlates of the varying degrees of early hemorrhagic transformation of a cerebral infarct are unclear. We investigated the cohort of a randomized trial of thrombolysis to assess the early and late clinical course associated with different subtypes of hemorrhagic infarction (HI) and parenchymal hematoma (PH) detected within the first 36 hours of an ischemic stroke. We exploited the database of the European Cooperative Acute Stroke Study I (ECASS I), a randomized, placebo-controlled, phase III trial of intravenous recombinant tissue plasminogen activator in acute ischemic stroke. Findings on 24- to 36- hour CT were classified into 5 categories: no hemorrhagic transformation, HI types 1 and 2, and PH types 1 and 2. We assessed the risk of concomitant neurological deterioration and of 3-month death and disability associated with subtypes of hemorrhagic transformation, as opposed to no bleeding. Risks were adjusted for age and extent of ischemic damage on baseline CT. Compared with absence of hemorrhagic transformation, HI1, HI2, and PH1 did not modify the risk of early neurological deterioration, death, and disability, whereas, in both the placebo and the recombinant tissue plasminogen activator groups, PH2 had a devastating impact on early neurological course (odds ratio for deterioration, 32.3; 95% CI, 13. 4 to 77.7), and on 3-month death (odds ratio, 18.0; 95% CI, 8.05 to 40.1). Risk of disability was also higher, but not significantly, after PH2. Risk of early neurological deterioration and of 3-month death was severely increased after PH2, indicating that large hematoma is the only type of hemorrhagic transformation that may alter the clinical course of ischemic stroke.
Article
Patients with recently symptomatic severe carotid stenosis have a high risk of ischemic stroke on medical treatment. The main mechanism of stroke appears to be plaque surface thrombus formation and distal embolism. It is unclear to what extent reduction in blood flow across the stenosis, and the consequent reduction in cerebral perfusion pressure, is also important. Angiographic indices of reduced cerebral perfusion may identify patients at a particularly high risk of stroke who require urgent endarterectomy. The most direct angiographic correlate of poststenotic perfusion pressure is the degree of narrowing of the distal internal carotid artery (ICA) lumen. We sought to develop criteria for the definition of poststenotic narrowing of the ICA and to determine the effect of this and other angiographic characteristics likely to be associated with reduced cerebral perfusion on the risk of ipsilateral ischemic stroke in patients with recently symptomatic carotid stenosis. We studied the carotid angiograms of 3007 patients in the European Carotid Surgery Trial. Poststenotic narrowing of the ICA was defined with use of the ratio of the lumen diameter of the ICA to that of the common carotid artery (CCA). The normal range of the ICA/CCA ratio was defined in 2966 symptomatic or contralateral carotid arteries with 0% to 49% stenosis. Arteries with 70% to 99% symptomatic stenosis and an ICA/CCA ratio below this range were categorized as narrowed. We related the presence of narrowing and other angiographic characteristics to the risk of ipsilateral ischemic stroke on medical treatment. An assessment of the ICA/CCA ratio had good interobserver reproducibility. Poststenotic narrowing of the ICA was defined as an ICA/CCA ratio of <0.42. The 5-year risk of ipsilateral carotid territory ischemic stroke on medical treatment was 8% in patients with 70% to 99% stenosis and narrowing of the ICA versus 25% in patients without narrowing (log rank test, P=0.02). This difference remained after correction for other clinical and angiographic variables (hazard ratio 0.40, 95% CI 0.17 to 0.94, P=0. 03). The other angiographic characteristics did not predict stroke. Poststenotic narrowing of the ICA was associated with a low risk of stroke on medical treatment. This suggests that low flow alone is not usually sufficient to cause ischemic stroke distal to symptomatic carotid stenosis. Poststenotic narrowing may be protective because blood flow distal to the stenosis is insufficient to carry emboli to the brain.
A new model of bilateral hemispheric ischemia in the unanaesthetized rat
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The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and G20210A prothrombin mutation
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