Atorvastatin is Effective for Stroke Prevention: The SPARCL trial

 

Atorvastatin 80 mg/day significantly reduces the risk of recurrent stroke in patients with recent stroke or transient ischaemic attack (TIA) and without a history of coronary heart disease (CHD), while substantially decreasing the risk of major coronary and CHD events and revascularization procedures, as per the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial presented at the 15th European Stroke Conference (ESC), May 2006.

4,731 patients with documented stroke or TIA within the previous 6 months, with no history of CHD, and with LDL-C between 100 and 190 mg/dl were randomised to either placebo (n = 2,366) or atorvastatin 80 mg/day (n = 2,365) and were followed for 6 years.

The study showed that atorvastatin reduced the following events vs. placebo:

LDL levels in the first month showed 53% reduction with atorvastatin vs. 1% increase in placebo group. Mean on-treatment LDL-C levels were 73 mg/dl for atorvastatin vs. 129 mg/dl for the placebo group.

Atorvastatin was well tolerated with only a slight increase in liver enzymes and no change in musculoskeletal adverse events.

The investigators concluded that these results showed that to prevent a single event of stroke or a major cardiovascular event or a revascularization procedure, a 5-year atorvastatin treatment of 46, 29 and 32 patients, respectively, would be needed.

Thus, the SPARCL study supports the initiation of high dose atorvastatin soon after a stroke or TIA.

15th European Stroke Conference, May 17, 2006

Potential Biomarker of Acute Haemorrhagic Stroke Identified

 

Serum glial fibrillary acidic protein (GFAP) is a promising biomarker for the identification of intracerebral haemorrhage in patients with acute stroke, according to the results of a pilot study published in the March issue of the Journal of Neurology, Neurosurgery and Psychiatry.

Biomarkers of stroke are an evolving field of clinical research. A serum marker which can differentiate between haemorrhagic stroke and ischaemic stroke in the very early phase would help to optimize acute stroke management.

Investigators from Germany determined serum GFAP levels within 6 hours after the onset of stroke in 135 patients. Based on brain imaging, 42 had an intracerebral haemorrhage and 93 had an ischaemic stroke.

GFAP was detectable in the serum of 81% of intracerebral haemorrhage patients but in only 5% of ischaemic stroke patients. Median serum GFAP concentrations in the first 6 hours after symptom onset were significantly elevated in patients with an intracerebral haemorrhage compared with patients with an ischaemic stroke (11 ng/L versus 0 ng/L).

These results indicate that GFAP is not detectable in the serum of the majority of ischaemic stroke patients within the first 6 hours after symptom onset. This finding fits in well with the previous studies reporting a delayed release of astroglial proteins (S100B and GFAP) into the serum in acute ischaemic stroke, reaching maximum concentrations between day 2 and day 4.

Using a cutoff point of 2.9 ng/L, the specificity of GFAP for the identification of intracerebral haemorrhage was high (0.98), with only two false positives, while sensitivity was 0.79, with nine false negatives in the intracerebral haemorrhage group.

The researchers concluded that although GFAP looks a promising marker, further studies are needed to confirm the current results.

J Neurol Neurosurg Psychiatry 2006;77:181-4

Higher Baseline Blood Pressure is Associated With Better Stroke Outcomes

 

Higher baseline systolic and diastolic blood pressures are associated with better outcomes after acute ischaemic stroke, according to findings of a recent study.

Blood pressures are commonly elevated after an acute ischaemic stroke but the prognostic significance of the short-term profile of blood pressure after stroke remains unclear.

Mei Yong, Heinrich Heine University , Dsseldorf , Germany and colleagues investigated the relationship between blood pressure level at admission and variability and outcomes in 615 patients with acute ischaemic stroke.

Higher baseline systolic blood pressure was associated with a 22% higher probability of favorable outcome in 90 days. Similarly, higher baseline diastolic blood pressure was associated with a 22% higher probability of favorable outcome in 90 days.

Decreased variability in diastolic blood pressure independently predicted a more favorable 90-day outcome, but systolic blood pressure variability was not an independent predictor of outcomes.

The findings of the present study suggests that it may be beneficial to keep the blood pressure at a reasonable lower overall level and less variable over time in the early phase after acute stroke. In clinical practice, this means that drugs potentially resulting in a sudden drop in blood pressure or drugs with a short half-life and therefore variable efficacy should be avoided.

The clinical relevance of blood pressure level and variability for the blood pressure management in acute stroke still requires further investigations. These results, as well as others, suggest that the present guidelines for blood pressure treatment and acute stroke may need some revisions, and also that the state of arteries should be taken into consideration.

Stroke 2005;36:2619-25

Obstructive Sleep Apnoea: Impact on Stroke

 

Introduction

Obstructive sleep apnoea (OSA) is defined as sleep disordered breathing (SDB) associated with excessive daytime sleepiness, disruptive snoring, repeated episodes of upper airway obstruction during sleep and nocturnal hypoxaemia.

In urban India , the prevalence of OSA has been reported to be as high as 7.5% while in western countries, up to 5% of adults probably have OSA.

The main pathophysiological event is abnormal narrowing and collapse of the upper airway during sleep due to anatomical narrowing of the upper airway and loss of tone in the pharyngeal muscles, including the genioglossus. The factors important in the progression of disease include baseline obesity, older age and the presence of snoring.

Studies have shown that OSA is associated with an increase in mortality and morbidity in addition to an increased incidence of automobile crashes. A substantial body of evidence has accumulated that OSA is associated with an increased risk of various cardiovascular conditions (Table 1).

Table 1. Cardiovascular conditions associated with OSA

OSA and stroke risk

OSA has been reported to be a risk factor for stroke independently of risk factors like hypertension. The Sleep Health Heart Study demonstrated that OSA was associated with an increased prevalence of stroke. In addition, snoring also has been reported to be associated with stroke.

Complementing the studies on OSA as a risk factor for stroke, other studies have also shown a high prevalence of OSA in stroke patients. In fact, they reported the prevalence of OSA in stroke patients to be at 60% as compared to a prevalence of 4% in the general population.

Possible mechanisms

The various mechanisms which can lead to stroke in OSA include abnormal cerebral hemodynamics, increased platelet aggregability, increased fibrinogen levels, increased blood viscosity and abnormal endothelial function.

Cerebral blood flow has been shown to fluctuate in response to apnoeas and a significant increase in intracranial pressure and a decrease in cerebral perfusion has been shown in different studies. OSA can also confer a hypercoagulable state that can partly mediate the adverse impact on vascular health. In addition, patients with OSA can have an impaired endothelial function and systemic inflammation, both of which can play a pivotal role in the development and progression of atherosclerosis. Lastly, OSA has also been associated with hypertension, coronary artery disease and arrhythmias, all of which are independent risk factors for stroke. The potential mechanisms of vascular disease with OSA are summarized in Table 2.

Table 2. Potential mechanisms of vascular disease associated with OSA

OSA worsens stroke outcome

OSA has also been demonstrated to have an adverse impact on stroke outcome. Severity of upper airway obstruction was found to be associated with a worse functional outcome following stroke, increasing the likelihood of death and dependency. A study in young patients revealed that SDB, 6 weeks after stroke, was independently associated with longer hospital stay and greater long term functional impairment.

Possible mechanisms

Several of the pathophysiological features accompanying OSA have been associated with an adverse outcome in stroke populations. These include:

1. Large fluctuations of blood pressure and the consequent effects on cerebral blood flow: In OSA, repeated elevation of blood pressure, sometimes to an alarming degree, is seen at the termination of each apnoea. In stroke patients, a greater variation in blood pressure correlates with both increased mortality and greater dependency.
2. Baroceptor dysfunction has been reported in OSA. Impaired cardiac baroceptor sensitivity is associated with higher mortality after stroke.
3. Recurrent hypoxaemia associated with frequent apnoeas is another obvious candidate. This might have a critical effect on the ischaemic penumbra surrounding the infarcted brain and might result in extension of the neurological damage.
4. Alternating hypoxaemia and reoxygenation accompanying OSA is associated with increased release of superoxides from neutrophils which might have an adverse effect after stroke.
5. Inflammatory and proinflammatory markers and mediators such as C reactive protein and adhesion molecules are increased in OSA. In stroke, inflammatory changes are increasingly recognized as possibly contributing to injury of vulnerable brain tissue.

Diagnosis of OSA

• The best first step is questioning the spouse or family member of the patient about the symptoms of OSA.
• The gold standard in the diagnosis of OSA is polysomnography. It requires an overnight stay at a sleep laboratory and involves monitoring of oxygen saturation, heart rate, sleep stage by electroencephalography, nasal airflow, oral airflow, jaw muscle tone by electromyography, sleep position and chest and abdominal movement.

Measuring these parameters allows diagnosis of the type of SDB and its severity. An apnoea is a period of time during which breathing stops or is markedly reduced. In simplified terms, an apnoea occurs when a person stops breathing for 10 seconds or more. Apnoeas usually occur during sleep. A hypopnoea is a decrease in breathing that is not as severe as an apnoea. Like apnoeas, hypopnoeas usually disrupt the level of sleep.

Apnoeas are usually measured during sleep (preferably in all stages of sleep) over a 2 hour period. An estimate of the severity of apnoea is calculated by dividing the number of apnoeas by the number of hours of sleep, giving an apnoea index (AI). The greater the AI, the more severe the apnoea.

A hypopnoea index (HI) can be calculated by dividing the number of hypopnoeas by the number of hours of sleep.

The apnoea-hypopnoea index (AHI) is an index of severity that combines apnoeas and hypopnoeas (Table 3). Combining them both gives an overall severity of sleep apnoea including sleep disruptions and desaturations (a low level of oxygen in the blood). The AHI, like the AI and HI, is calculated by dividing the number of apnoeas and hypopnoeas by the number of hours of sleep.

Table 3. AHI and severity of OSA

Management of OSA

The most commonly prescribed treatment for OSA is continuous airway positive pressure (CPAP). The CPAP device keeps the patient's airway open during sleep by producing a positive air pressure. However, it is associated with certain difficulties such as dryness of mouth, rhinorrhea, nasal congestion and dryness, mask discomfort, claustrophobia, irritation from device noise, aerophagy, chest discomfort and partner's intolerance. Another problem is that stroke patients with CPAP present with different degrees of functional disabilities, thereby hindering patient compliance. Studies have shown compliance rate as low as 47 % in patients with a recent ischaemic stroke.

The other therapies that have been used for the management of OSA include:

Behavioral therapy - This includes weight loss and positional therapy. Weight loss may be useful in the short term in some OSA patients while change in the sleeping position may be helpful in patients with mild disease with a positional component.

Pharmacological therapy - Different drugs seem to affect different aspects of sleep apnoea, such as central or obstructive. These include protriptyline, fluoxetine, acetazolamide, theophylline, cilazapril, metoprolol and modafinil. Of these, only modafinil is approved as an adjunctive drug to CPAP in selected patients with OSA who continue to have day-time sleepiness despite use of CPAP.

Mandibular advancement devices - Mandibular advancement devices, which induce protrusion of the mandible during sleep and thereby reduce retroglossal airway collapse, appear to be effective in the treatment of mild apnoea or nonapnoeic snoring and have been shown to improve daytime symptoms and modestly decrease the AHI.

Surgery - The role of surgery in the treatment of OSA remains ill defined and is controversial. The most appropriate indication is clearly reversible causes of upper airway obstruction, such as adenotonsillar hypertrophy or mass lesions.

Summary

• OSA remains an important public health problem because of its neurocognitive sequelae
• There is a body of evidence which shows that OSA is an independent risk factor for stroke
• Further, OSA is also associated with a poor outcome following stroke
• Early diagnosis and management of OSA is hence pivotal in preventing stroke

References:

 

1. Ann Intern Med. 2005;142:187-97
2. Am J Respir Crit Care Med 2001;163:19 - 25
3. N Engl J Med 2005;353:2034-41
4. J Assoc Phy India 2004;52:143-51
5. Mayo Clin Proc 2004;79:1036-46
6. Am J Respir Crit Care Med 2000; 162:2039 - 42
7. Chest 2002;122;852-60
8. Eur Respir J 2001;18: 619-22
9. Eur Respir J 2001; 18: 623-29
10. Thorax 2004;59:367-71
11. Thorax 2004;59;361-63
12. Am J Respir Crit Care Med 2004; 169: 168-73

 

Folic Acid Fortification of Foods Coincides With Drop in Stroke Deaths

 

Stroke mortality dropped rapidly in the US and Canada after folic acid fortification of enriched grain products was fully implemented in 1998.

The main reason for folic acid fortification was to reduce the occurrence of neural tube defects. The present findings, however, suggest that there may have been an unintended benefit as well.

There is accumulating, controversial evidence that homocysteine is an independent risk factor for stroke and ischaemic heart disease. The increase in folate concentration in the population is inversely associated with homocysteine levels which may help explain the drop in stroke mortality.

The researchers compared stroke mortality trends between 1990 and 2002 in the US and Canada with those in England and Wales , where folate fortification is not required.

Stroke mortality was already falling in the US and Canada from 1990 to 1997, but in 1998 a precipitous drop began. In the US , the annual decrease in mortality during the earlier period was 0.3%, whereas starting in 1998, the reduction was 2.9% (p = 0.0005). Similar results were seen in Canada .

Sensitivity analysis suggested that these trends in the US and Canada were probably not due to changes in known stroke risk factors. By contrast, stroke mortality rates did not decline significantly in England and Wales between 1990 and 2002.

If folic acid fortification is responsible for even a fraction of the accelerated decrease in stroke mortality, this public health benefit is an important bonus to the reduction in neural tube defect rates previously demonstrated.

Circulation 2006;113:1335-43

Stroke Risk Doubled in Men with Metabolic Syndrome

 

Men with the metabolic syndrome but who do not have diabetes or cardiovascular disease are at increased risk of stroke.

In a population-based cohort study, a group of Finnish researchers examined the association between the metabolic syndrome, as defined by National Cholesterol Education Program (NCEP) and World Health Organization (WHO) criteria, and stroke risk.

A total of 1131 men with no history of stroke, cardiovascular disease, or diabetes at baseline were included in the study. The subjects were followed for an average of 14.3 years.

A total of 187 men (14.8%) had metabolic syndrome according to WHO criteria at the beginning of follow-up, whereas 114 men (9.0%) had metabolic syndrome based on NCEP criteria. Sixty-five strokes occurred during follow-up, 47 of which were ischemic strokes.

After adjustment for socioeconomic status, smoking, alcohol, and family history of coronary heart disease, men with NCEP-defined metabolic syndrome had a 2.05-fold risk for all strokes (p = 0.042) and a 2.41-fold risk for ischemic stroke (p = 0.025). The risk ratios among men with metabolic syndrome according to WHO criteria were 1.82 (p = 0.046) for all strokes and 2.16 (p = 0.022) for ischemic strokes.

Prevention of the metabolic syndrome presents a great challenge for clinicians with respect to stroke. With the increase in the age of population and lack of physical activity, this risk will increase further and put a greater burden on the health system.

The author noted that healthy eating and enough regular physical activity should be recommended, and physicians should take more interest in asking about lifestyle and physical activity.

Stroke 2006;37:806-11

New Approvals Internationally

 

The US Food and Drug Administration (FDA) has approved rasagiline (Azilect), the first once-daily oral treatment for Parkinson's disease (PD). Rasagiline is indicated for the treatment of the signs and symptoms of PD as initial and as adjunct therapy to levodopa in moderate-to-advanced disease. It is expected to become available later this year in two dosage strengths. Rasagiline was approved based on data from three multicenter, ultinational, double-blind, randomized, placebo-controlled, clinical studies, which showed positive effects on motor impairments and activities of daily living in early PD and in moderate-to-advanced stage patients with good tolerance. Contraindications for rasagiline include moderate to severe liver disease, tumor of the adrenal gland and co administration with certain drugs. Side effects seen with rasagiline monotherapy are joint pain and indigestion; and when taken with levodopa are dyskinesias, accidental injury, weight loss, low blood pressure when standing, vomiting, joint pain, nausea, constipation, dry mouth, rash, and sleepiness.

New Guidelines

 

The American Heart Association (AHA) and the American Stroke Association (ASA) have updated the guidelines for the primary prevention of ischemic stroke published previously in 2001. These guidelines focus on the various risk factors for stroke such as hypertension, diabetes, hyperlipidemia, atrial fibrillation and the management recommendations for the same. These guidelines are endorsed by the American Academy of Neurology and have been published in the June 2006 edition of Stroke.

Stroke 2006;37:1583-1633

The full text of these guidelines is also available at:

http://www.cipladoc.com/html/neurology_update/treatmentguide.htm

TICKLE YOUR BRAIN

Answers

1. OCCIPITAL
2. HUNTINGTONS
3. MYASTHENIA GRAVIS
4. TROCHLEAR
5. AREA POSTREMA
6. SUBSTANTIA
7. DIHYDROERGOTAMINE
8. MENINGIOMA
9. CHOROID PLEXUS
10. MILLARD-GUBLER

Final answer:

MULTIPLE SCLEROSIS