PRE- OR POST-STROKE STATIN USE ‘IMPROVES RECOVERY’

 

Taking statins before or after ischemic stroke has a significant, beneficial effect on short-term outcomes, according to researchers who suggested that the drugs should be administered routinely to those at risk of stroke.

“Statins reduce C-reactive protein (CRP), improve the endothelium, and have an anti-clotting effect," commented lead researcher Majaz Moonis (University of Massachusetts Medical School, Boston, USA), who presented the findings at the American Academy of Neurology Annual Meeting in Miami, Florida, USA, held in April 2005. Given these properties of statins, it seemed reasonable to assume that statins would improve the outcome after stroke.

To test this assumption, Moonis and co-workers examined data on 1618 ischemic stroke patients who were followed up until death or discharge from hospital. Discharge home was defined as a favorable outcome, while discharge to long-term care or death within 45 days was classed as an unfavorable outcome.

The results showed that a favorable outcome was 1.6 times more likely among patients who had been taking statins prior to their stroke than in those who had not been taking the drugs.

Furthermore, those who started taking statins after their stroke were 2.6 times more likely to have a favorable outcome than those not on statins.

Importantly, this association was not affected by stroke severity, which was also correlated with the risk of an unfavorable outcome, the researchers noted.

“These results are very exciting and suggest that, unless contraindicated, all patients at risk for ischemic stroke or recurrent ischemic stroke should probably be treated with statins to reduce their low-density lipoprotein levels," Moonis recommended.

American Academy of Neurology Annual Meeting; Miami , Florida , USA : 9-16 April, 2005

MIGRAINE ALLODYNIA MAY BE PARTLY ATTRIBUTABLE TO TRIPTANS

 

At least some of the temporary sensory symptoms experienced by migraineurs might be attributable to therapy with sumatriptan, according to researchers in Sweden .

Dr. Mattias Linde at the Gothenburg Migraine Clinic and colleagues evaluated the perceptions of tactile and thermal stimuli in 12 migraine patients and 12 healthy controls who received sumatriptan or placebo.

The tests included manual movement of a soft brush back and forth on the dorsal surface of the left hand, and operation by the subjects of a lever that activated a small thermode attached lightly to the hand. The patients were not experiencing migraines during the test periods.

“Twenty minutes after injection, sumatriptan caused a significant increase in brush-evoked feeling of unpleasantness in both groups (p<0.01) (Figure 1), ”Dr.Linde's group reported in the December issue of Cephalalgia. An increase in brush-evoked pain was noted in migraineurs only (Figure 2). All subjects had a reduction of heat pain threshold, and a reduction in cold pain threshold occurred in controls only.

By 40 minutes after injection of the medication, however, all of these differences had resolved.

“The finding that triptans can cause allodynia raises further questions concerning other sensory side effects of triptans and warrants consideration in the interpretation of studies on migraine-induced allodynia," the authors concluded.

Cephalalgia 2004; 24: 1057-66.

ABNORMAL CORTISOL LEVELS LINKED TO INCREASED STROKE MORTALITY

 

Abnormal circulating cortisol levels are a risk factor for death after stroke regardless of whether these levels are high or low, as per recent research.

Elevated cortisol levels are associated with confusion and poor outcome after stroke. Also, dehydroepiandrosterone sulphate (DS), the most abundant androgen, may act as an anti-glucocorticoid. Taking into consideration the fact that dysregulation of these steroids may affect brain function such as neuronal survival, the researchers investigated the relationship between serum cortisol, DS levels and stroke outcomes.

In their study, the researchers examined 88 patients with acute ischemic stroke in terms of serum cortisol and DS levels on day 1 and/or day 4 after hospital admission. Degree of confusion, extent of paresis, and level of functioning were assessed and 28-day and 1-year mortality rates were determined as well.

The study demonstrated that initial cortisol levels were significantly higher in patients with acute disorientation than in those without such symptoms.

In addition, day 1 cortisol levels were independently associated with 28-day and 1-year mortality. Cortisol levels of both less than 270 nmol/L and more than 550 nmol/L were identified as risk factors for death at 1 year. However, DS levels were not associated with cognitive dysfunction.

In summary, hypercortisolism is associated with cognitive dysfunction early after ischemic stroke. High and low circulating cortisol levels are associated with increased mortality after stroke, but DS levels were not associated with clinical outcome.

J Intern Med 2004; 256: 15-21

ERYTHROPOIETIN COULD BE A NOVEL HEMORRHAGIC STROKE TREATMENT

 

The hormone erythropoietin, which stimulates bone marrow to produce red blood cells, could improve functional recovery after intracerebral hemorrhage (ICH), the results of a rat study reveal.

The study authors suggested that their findings may be due to the combined effects of inhibition of apoptosis and suppression of neuroinflammation by the hormone.

“This is the first evidence that erythropoietin has a therapeutic effect in hemorrhagic stroke,” said lead researcher Dong-In Sinn ( Seoul National University Hospital , Korea ).

For their study, Sinn and co-workers induced ICH in adult rats, which were treated with an initial dose of 5000 IU/kg of erythropoietin 20 minutes after stroke, and then daily for 4 to 14 days. The recovery of these animals was compared with that of a control group of rats that received no treatment after ICH.

The scientists discovered that 3 days after stroke, the size of hemorrhage was reduced by 25% in the erythropoietin-treated rats compared with the controls. In addition, the drug significantly reduced the water content in both the damaged and undamaged hemispheres of the brain, and reduced the number of inflammatory cells such as neurotrophils and microglia in the periphery of the hematoma. The activity of capsase-3, which mediates apoptosis, was also decreased in the erythropoietin group compared with the controls.

Furthermore, erythropoietin-treated rats also showed a significantly better recovery in behavioral and functional tests than those that received no treatment.

“Our results suggest that erythropoietin could be a novel drug for treatment of hemorrhagic stroke,” said Sinn. “It not only reduces inflammation, but also improves functional recovery after stroke.”

American Academy of Neurology Annual Meeting in Miami , Florida , USA : 9-16 April, 2005

STROKE AND HYPERTENSION MANAGEMENT

 

Introduction

Each year, stroke occurs in 30.9 million individuals worldwide and is responsible for a pproximately 4 million deaths. Stroke occurs with a greater frequency than myocardial infarction in patients with hypertension. Hypertension is the most prevalent modifiable risk factor for stroke (cerebral infarction/ hemorrhage). Also, hypertension is very common after an acute attack of stroke. This article focuses on the link between stroke and hypertension and how to manage hypertension during an acute attack of stroke.

Hypertension: An important risk factor for stroke

The risk of stroke increases continuously above blood pressure (BP) of approximately 115/75 mmHg. Almost two-thirds of stroke burden globally is attributable to non-optimal BP (i.e. > 115/75 mmHg). Large-scale observational studies have shown that BP is positively and continuously associated with the risk of stroke in a log-linear fashion.

Treatment of hypertension and prevention of stroke
Large randomized controlled trials have demonstrated the benefit of reducing BP for the primary and secondary prevention of stroke.

In India , hypertension is directly responsible for 57% of all stroke deaths.
This fact is important because hypertension is a controllable disease and a 2 mmHg population-wide decrease in BP can prevent 1,51,000 stroke deaths in India .

Thus, BP lowering is an effective measure to reduce the burden of stroke. According to various trials, BP reduction in various high-risk groups reduces the risk of stroke by more than one third. It has now become evident from many studies that not only do hypertensive patients benefit from BP reduction, but high-risk patients with normal BP are also benefited from BP reduction.

Which class of drugs should be used?
Data clearly indicates that treatment with antihypertensive drugs reduces the incidence of all strokes in men, women, elderly individuals, and even in those with a history of stroke/transient ischemic attack (TIA) [Figure 1].

Fifteen trials comparing different antihypertensive agents have been studied recently. In total, there were >96,000 participants and almost 3600 stroke events recorded over a mean follow-up time of 4 to 5 years. Overall the trials indicated that there was little difference between the drug classes, with relative risk reductions of 9% (b-blockers and/or diuretics, versus ACE inhibitors), 8% (b-blockers and/or diuretics versus calcium antagonists) and 11% (calcium antagonists versus ACE inhibitors). The results of Losartan Intervention for Endpoint reduction in hypertension study (LIFE), however indicates that angiotensin receptor blockers may have a greater impact on reduction of stroke than b-blockers. In this study, losartan was associated with a risk reduction in stroke of 24.9% as compared to atenolol. Losartan may offer advantages beyond BP lowering, including attenuation of the central aortic reflected pressure wave and neural-protective influences on brain angiotensin II type 2 receptors.

In general, BP should be reduced to less than 140/90 mmHg. The overall data also suggests that reduction of stroke in persons with hypertension is related more to a reduction in BP than to the type of antihypertensive drug used.

Hypertension in acute ischemic stroke
BP during early hours of stroke and clinical outcomes

Data from 20,000 patients in the International Stroke Trial showed that up to 80% of patients have high BP in the first 48 hours after stroke onset. A transient rise in BP can be found also in previously normotensive patients after an acute ischemic attack.

An elevated BP can result from various causes viz, stress of the stroke, full bladder, pain, pre-existing hypertension, a physiological response to hypoxia and increased intracranial pressure.

Also, BP may decline spontaneously and unpredictably, without intervening medication and the incorrect use of antihypertensive drugs in acute stroke may reduce the pressure - dependent cerebral perfusion to the ischemic penumbra and worsen cerebral damage.

A review of the clinical data of 92 consecutive patients admitted for acute ischemic stroke shows that the neurological outcome differs as per the severity of stroke and the BP during the first 24 hours after stroke onset. It was observed that the best outcome (National Institute of Health Stroke Scale [NIHSS] score, 1-14) was seen in patients who had higher SBP and diastolic BP (DBP) (SBP range; 140-220 mmHg, DBP range; 70-110 mmHg)(Figure 2).

Figure 2. Systolic and diastolic blood pressure (BP) during the hospital stay according to the clinical outcome, as assesed by the National Institutes of Health Stroke Scale (NIH Scale) and mortality at day 7.

Lowering BP immediately after stroke may be harmful
High BP, although the main modifiable risk factor for stroke, may have a beneficial effect in maintaining brain perfusion after acute ischemia.

To test the effect of early BP reduction on prognosis of stroke, 115 consecutive patients admitted in the first 24 hours after stroke onset were evaluated in terms of their modified Rankin and Barthel scales after 3 months. A Rankin score of > 2 or Barthel score < 70 was defined as a poor outcome. The multivariate analysis illustrated that degree of SBP reduction in the first 24 hours was one of the most important predictors for poor outcome (odd ratio = 1.89 per 10% decrease; p=0.047).

Hence, “while lower is better for preventing first and subsequent strokes, there is a growing sentiment that high is good in the acute phase. Blood pressure reduction in the acute phase should be avoided if at all possible,” says Dr. Johnston ( University of Virginia Health System , Virginia ).

Thus, in most circumstances, the BP should generally not be lowered. Situations that might require urgent antihypertensive therapy include hypertensive encephalopathy, aortic dissection, acute renal failure, acute pulmonary edema and acute myocardial infarction.

Theoretical reasons to lower the BP include reducing the formation of brain edema, lessening the risk of hemorrhagic transformation of the infarction, preventing further vascular damage and forestalling early recurrent stroke.

Sublingual use of calcium antagonists like nifedipine should be avoided due to secondary precipitous decline in BP.

As per the American Stroke Association (ASA) guidelines, the consensus is that antihypertensive agents should be withheld unless the DBP is > 120 mmHg or unless the SBP is > 220 mmHg. When treatment is indicated, the BP should be lowered cautiously (Table 1).

 

Hypertension and hemorrhagic stroke

Hemorrhagic stroke, which includes intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), accounts for around 20% of all strokes. The mortality rate has been reported as 40% to 50% for these stroke subtypes, and survivors are often affected by significant morbidity.

The association between hypertension and hemorrhagic stroke is much more steeper as compared to the association of hypertension and ischemic stroke. Studies have also shown that one quarter of hemorrhagic stroke could be prevented if all hypertensive patients were to receive treatment.

In one of the recent study, 549 cases of hemorrhagic stroke were identified. It was observed that as compared to normotensives, untreated hypertension raised the risk of hemorrhagic stroke by 3.5-fold (p<0.0001).

Blood pressure management during hemorrhagic stroke
Most patients are hypertensive after an ICH including, those without a prior history of hypertension. Again, acute normalization of BP is dangerous in this case as well, because a sudden reduction in BP may lead to reduced cerebral perfusion pressure to ischemic levels, and a decreased cerebral blood flow.

However, lowering BP is commonly practised to prevent hematoma enlargement in ICH patients. Evidence from recent studies suggests that high SBP is independently associated with an increased risk of hematoma enlargement. Another study carried out in 76 consecutive patients with hypertensive ICH also suggested that efforts to lower SBP below 150 mmHg may prevent hematoma enlargement.

The use of agents that can increase intracranial pressure (ICP) should be avoided. Agents that produce venodilation, such as nitrates and sodium nitroprusside, should however, not be used in patients with elevated ICP or reduced intracranial compliance, as these venodilators can increase ICP.

There has been a considerable controversy regarding the initial control of BP after the onset of ICH. The American Heart Association (AHA) recommends that patients with SBP > 180 mmHg or DBP > 105 mmHg should receive intravenous antihypertensive agents, although the evidence supporting this guidance is extremely weak.

CONCLUSION

• Hypertension is the most important modifiable risk factor of stroke; BP should be maintained < 140/90 mmHg to reduce the risk of stroke
• There may be no difference between drug classes in BP control for primary and secondary prevention of stroke. However, losartan may offer benefits beyond BP lowering
• BP reduction in the acute phase should be avoided. Antihypertensive agents should be withheld unless DBP is > 120 mmHg or SBP is > 220 mmHg. When treatment is indicated, BP should be lowered cautiously
• In case of hemorrhagic stroke patients, the BP should be maintained below 180/105 mmHg, as per AHA

References

SMELL TEST HELPS DIFFERENTIAL DIAGNOSIS OF PARKINSON'S DISEASE

 

Olfactory function can be used to distinguish between Parkinson's disease and vascular parkinsonism, which occurs in cerebrovascular disease, UK researchers report in the December issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

Dr. R. Katzenschlager of the Reta Lila Weston Institute of Neurological Studies in London , and colleagues note that these conditions can be difficult to differentiate. In fact, a recent study showed that 9 of 17 patients with vascular parkinsonism had been diagnosed as having Parkinson's disease. However, it is known that patients with Parkinson's disease have a markedly impaired sense of smell.

With this in mind, the researchers studied 18 patients with Parkinson's disease, 14 with vascular parkinsonism, and 27 matched controls. They each completed the University of Pennsylvania smell identification test. The test involves sampling of 40 odors which are microencapsulated on paper strips.

Parkinson's disease was associated with significantly lower patient olfactory test scores than vascular parkinsonism. Overall, patients with vascular parkinsonism had scores similar to those of control subjects.

The researchers concluded that such testing "may help in the differential diagnosis between two important causes of parkinsonism in the elderly.”

J Neurol Neurosurg Psychiatry 2004; 75:1749-52

NEW INTRODUCTIONS INTERNATIONALLY

Immunoassay for Alzheimer's NTP biomarker approved in EU

In November 2004, the European Commission approved for use in the European Union a urine neural thread protein (NTP) biomarker test kit (AlzheimAlert, made by Nymox Pharmaceutical Corp.) for use as an aid in the clinical diagnosis of Alzheimer's disease (AD).

The test is a competitive immunoassay that measures NTP levels in urine. NTP has also been identified in brain tissue and cerebrospinal fluid, and there is evidence that the protein is involved in the neuronal cell death and neuritic sprouting that are characteristic of AD.

Elevation of NTP levels occurs early in AD and is positively correlated with the severity of dementia; readings of greater than 18 are considered abnormal and are closely associated with AD and cognitive decline.

The approval was based on the results of clinical studies showing that the biomarker test has a sensitivity of greater than 80% and a specificity of 90% for AD.

The assay is currently under review by the FDA for approval in the U.S.

Rasagiline approved in EU for Parkinson's disease

In February 2005, the European Commission approved for use in the European Union rasagiline 1 mg tablets for use as initial therapy in the treatment of early Parkinson's disease (PD) and as adjunct treatment for moderate to advanced disease. Rasagiline is administered once daily and does not require titration.

Rasagiline is a second-generation selective, irreversible monoamine oxidase type-B inhibitor that blocks the breakdown of dopamine. Its approval was based on the results of studies of more than 1,600 patients showing that rasagiline monotherapy significantly improves motor symptoms and quality of life in patients with early PD. In addition, its adjunctive use in patients with advanced disease significantly reduced "off time" and improved associated motor fluctuations.

Unlike selegiline (which has a similar mechanism of action), rasagiline is not metabolized to amphetamine derivatives. Its main metabolite is aminoindane, which has been shown to improve motor and cognitive functions in experimental models and may contribute to the overall beneficial pharmacological profile of the drug.

ANESTHETIZING HEALTHY HAND AMELIORATES STROKE HEMIPARESIS

Anesthetizing the healthy hand of stroke patients with paralysis on one side may help to improve the function of the paretic hand by changing the balance of somatosensory input to the brain.

Agnes Floel (National Institute of Health, Bethesda , USA ) and colleagues proposed that a reduction of somatosensory input from the healthy hand could influence motor function in the paretic hand of chronic stroke patients with unilateral hand weakness.

To investigate this possibility, the researchers recruited 13 patients who had experienced ischemic stroke at least 1 year prior to enrollment and were still having severe motor paresis. The degree of spasticity and muscle strength in the paretic hand for each patient was assessed using specific tasks, like a series of finger-tapping and wrist-flexion tasks. These tests were also performed during cutaneous anesthesia of the healthy hand and healthy foot as a control.

The researchers observed that performance of the finger-tapping task improved significantly during anesthesia of the healthy hand, but not during control anesthesia of the foot. Moreover, this effect became more pronounced with increasing duration of anesthesia and outlasted the anesthesia period by at least 20 minutes.

Anesthesia had no significant impact on the wrist-flexion task, probably indicating that the improvements are site-specific.

“Our results indicate that somatosensory input originating in the intact hand influences motor function in the paretic hand of patients with chronic stroke and could possibly modulate the beneficial effects of motor training,” said the authors. “These findings may be relevant for the design and optimization of neurorehabilitative strategies after stroke,” they further added.

Ann Neurol 2004; 56: 206-12

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