Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 28, 2008 — The International Diabetes Federation (IDF) has issued a consensus statement on type 2 diabetes and obstructive sleep apnea (OSA) to assist clinicians in diagnosis, treatment, and prevention. The statement was published in the July issue of Diabetes Research and Clinical Practice and online on the IDF Web site.

“Recent research demonstrates the likelihood of a relationship between sleep-disordered breathing (SDB) and type 2 diabetes,” write co-chair Paul Zimmet, AO, MD, PhD, from Melbourne, Australia, and colleagues from the IDF Task Force on Epidemiology and Prevention. “Whilst the exact nature of the relationship between the two conditions remains uncertain, the association between them has important implications for public health and for individuals. Additionally, both type 2 diabetes and SDB are strongly associated with cardiovascular disease (CVD).”

The IDF Task Force on Epidemiology and Prevention convened a working group on sleep-disordered breathing and type 2 diabetes in 2007. Their goal was to review and evaluate current evidence information on sleep-disordered breathing and type 2 diabetes to make recommendations both for management and for further research.

Both type 2 diabetes (as well as abnormal glucose metabolism) and OSA have a high prevalence and often coexist. Although OSA, hypertension, and cardiovascular disease are also interrelated, this association may go beyond shared risk factors such as obesity, based on accumulating evidence. The IDF has mandated heightened awareness, improved clinical practice, and further scientific investigation into the links between type 2 diabetes and OSA because both conditions increase the risk for cardiovascular morbidity and mortality as well as for other adverse sequelae.

The benefits of treating OSA include better quality of life and blood pressure control. Although treating OSA may also improve glycemic control, obesity, and other cardiovascular risk factors, evidence regarding these potential benefits has been inconsistent to date.

For the treatment of OSA, the IDF recommends weight reduction in overweight and obese patients, avoidance of alcohol and sedative drugs, and use of continuous positive airway pressure (CPAP) treatment or dental appliances.

CPAP treatment uses a mask that is worn over the nose or mouth during sleep and that is linked to a machine delivering a continuous stream of compressed air to create positive pressure that helps keep the airways open and facilitates breathing. Dental appliances, which can be specifically designed by dentists with special expertise in the treatment of sleep apnea, can also keep the airway open during sleep.

In some cases, surgery may be indicated for OSA, if patients have enlarged tonsils and adenoids, nasal polyps, or facial deformities including a small jaw or a deviated nasal septum.

Individuals diagnosed with either type 2 diabetes or OSA should be screened for the other condition, according to the IDF. Those with OSA should be routinely screened for metabolic syndrome and type 2 diabetes because these screening tests are inexpensive and are easily performed, including waist measurement, blood pressure measurement, and levels of fasting lipids and glucose.

When indicated on the basis of these tests, a glucose tolerance test should also be performed. All persons with OSA should undergo monitoring of metabolic parameters, and those diagnosed with type 2 diabetes or its forerunners should be treated to reduce the risk for microvascular and macrovascular diabetic complications.

Particularly in the presence of classic symptoms such as witnessed apneas, heavy snoring, or daytime sleepiness, individuals diagnosed with diabetes should be screened for OSA. Appropriate testing with sleep study in a laboratory is useful, but simpler home monitoring devices can facilitate the diagnosis of OSA where facilities are limited.

“To date, there is not enough evidence to support screening of OSA in all people with diabetes since there is no conclusive evidence that treatment of OSA will improve metabolic parameters,” the study authors write. “Until more research information is available, IDF recommends a practical approach which is to investigate those people with classical symptoms such as witnessed apnoeas, heavy snoring or daytime sleepiness, despite the fact that some people with OSA will not be identified this way. People with diabetes with refractory hypertension should also be considered for screening since treating OSA may improve blood pressure.”

Screening questionnaires for OSA are not suitably specific for individuals with diabetes, who often report fatigue and daytime sleepiness even in the absence of OSA. However, people with symptomatic daytime sleepiness are most likely to benefit from treatment of OSA and are most likely to be compliant with long-term treatment. Therefore, identifying these symptoms in patients with diabetes may be useful, even if not specific for OSA.

In-laboratory polysomnography to diagnose OSA is expensive and may not be available in all clinical settings. A 2-stage approach may be useful in which a structured questionnaire, such as the Berlin questionnaire, is administered first to determine the likelihood of sleep apnea. Those classified as high risk based on the questionnaire may undergo additional testing with an overnight evaluation at home with pulse oximetry or portable monitoring.

Polysomnography may be indicated in individuals with a high pretest probability of OSA but with negative results on portable monitoring. Those with evidence of some form of sleep apnea should ideally be referred to a sleep specialist. Alternatively, an empiric trial of CPAP therapy with an autotitrating device may be prescribed under the supervision of a primary care clinician and a trained respiratory therapist.

“IDF recommends that all healthcare professionals involved with diabetes or OSA should be educated about the links between the two conditions and trained in their care,” the statement authors conclude. “Further research is needed to better understand the links between the two conditions and improve treatment and care. Finally, health policy makers and the general public must also be made more aware of OSA and the significant financial and disability burden that it places on both individuals and societies.”

• Clinical Context

The exact nature of the association between sleep-disordered breathing and type 2 diabetes, though still unclear, has important implications for public health as well as for individual patients, in part because both conditions are linked to cardiovascular disease. Although type 2 diabetes is highly recognized among clinicians and the public, awareness of sleep-disordered breathing is not as great, despite the associated healthcare costs and reduction in quality of life.

In 2007, the IDF Task Force on Epidemiology and Prevention convened a working group on sleep-disordered breathing and type 2 diabetes to review current evidence concerning these conditions and to make recommendations for both treatment and research. The Task Force recommended a global, multidisciplinary approach and generated a statement intended to facilitate prevention, diagnosis, and treatment of OSA and diabetes by healthcare professionals.

• Study Highlights

  1. Individuals diagnosed with either type 2 diabetes or OSA should be screened for the other condition.

  2. Those with OSA should be routinely screened for metabolic syndrome and type 2 diabetes with inexpensive, easily performed screening tests: waist and blood pressure measurement and levels of fasting lipids and glucose.

  3. A glucose tolerance test should also be performed when these test results are positive.

  4. Persons diagnosed with type 2 diabetes or its forerunners should be treated to reduce the risk for microvascular and macrovascular diabetic complications.

  5. Individuals diagnosed with diabetes should be screened for OSA, particularly when witnessed apneas, heavy snoring, or daytime sleepiness is present.

  6. People with diabetes with refractory hypertension should also be considered for screening because treating OSA may improve blood pressure.

  7. Because people with diabetes often report fatigue and daytime sleepiness even in the absence of OSA, screening questionnaires for OSA are not very specific in these patients.

  8. However, identifying these symptoms in patients with diabetes may be useful because people with symptomatic daytime sleepiness are most likely to benefit from treatment of OSA and are most likely to be compliant with long-term treatment.

  9. A structured questionnaire (eg, the Berlin questionnaire) may be given first to determine the likelihood of sleep apnea.

  10. Patients classified as high risk on the questionnaire may undergo additional testing with overnight evaluation at home with pulse oximetry or portable monitoring.

  11. Polysomnography may be indicated in individuals with a high pretest probability of OSA but with negative results on portable monitoring.

  12. Patients with evidence of some form of sleep apnea should ideally be referred to a sleep specialist.

  13. A primary care clinician may also prescribe an empiric trial of CPAP therapy with an autotitrating device, with the assistance of a trained respiratory therapist.

  14. Treating OSA improves quality of life and blood pressure control.

  15. Treating OSA may also improve glycemic control, obesity, and other cardiovascular risk factors, but evidence is unclear to date.

  16. Treatment of OSA includes weight reduction in overweight and obese patients, avoidance of alcohol and sedatives, and use of CPAP or dental appliances to keep the airways open and facilitate breathing.

  17. Surgery may be indicated for patients with OSA who have enlarged tonsils and adenoids, nasal polyps, a small jaw, or a deviated nasal septum.

• Pearls for Practice

  1. Individuals diagnosed with either type 2 diabetes or OSA should be screened for the other condition. Those with OSA should be routinely screened for metabolic syndrome and type 2 diabetes with inexpensive, easily performed screening tests, followed by a glucose tolerance test when these test results are positive.

  2. Individuals diagnosed with diabetes should be screened for OSA, particularly when witnessed apneas, heavy snoring, or daytime sleepiness is present. A structured questionnaire may be given first to determine the likelihood of sleep apnea. Patients classified as high risk may undergo additional testing with overnight evaluation at home with pulse oximetry or portable monitoring.

References

1. Diabetes Res Clinical Pract. 2008;81:2-12.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 28, 2008 — A study using data from the Sleep Heart Health Study shows a significant reduction in heart-rate variability in the elderly during sleep compared with the general population.

“Heart rate and heart-rate variability reflecting autonomic changes during different sleep stages persist in the elderly but may not follow patterns previously reported in younger subjects,” the researchers, with lead author Phyllis K. Stein, PhD, research associate professor of medicine and director of the Heart Rate Variability Laboratory in the department of internal medicine, cardiovascular division, at Washington University School of Medicine, in St. Louis, Missouri, conclude. “These discrepancies could result from erratic rhythm,” they said.

Taken together with previous research showing different sleep stages correlate with sympathetic and parasympathetic activity, they note, “We are looking for normal heart-rate variability changes over the night, by sleep stage. We want to see how this identifies high risk in elderly people.”

Their findings were reported here at SLEEP 2008: the 22nd Annual Meeting of the Associated Professional Sleep Societies.

• What’s Normal?

Cardiac autonomic function during different sleep stages can be measured using heart-rate variability, the researchers write. The relationship between heart rate, heart-rate variability, and sleep stages in the elderly is unknown.

This study aimed to find how autonomic function changes over time. “We think that once we find out what normal is, we can begin to see [correlations],” said Dr. Stein. “My interest in it is as a marker of normal vs abnormal neurocognitive function, but nobody actually knows what ‘normal’ is.”

For this study, Dr. Stein and colleagues used polysomnogram electrocardiograms (ECGs) from 116 participants, age 77 ± 4 years, all enrolled in the Sleep Heart Health Study. “Just the ECG signal by itself is a source of amazing information: we can pick up sleep apnea, we can pick up naps and also wake-up time,” she said. The polysomnograms, containing usable heart-rate-variability data in every sleep stage, were analyzed on a MARS 8000 Holter scanner (GE Medical Systems, Milwaukee, Wisconsin).

The ratio of heart-rate-to-heart-rate variability (HR/HRV) was calculated for every 2 minutes scored in the same stage and then averaged by stage. Stage 4 of sleep had to be omitted from the analysis because of a limited number of patients having usable stage 4 data (n = 11). They compared HR/HRV by sleep stage, and heart-rate variability by sleep stage was compared between participants with and without severe sleep apnea.

The results show significant changes in HR/HRV, seen for every sleep stage relative to the others. The results disagreed with previous studies in that the heart rate during rapid-eye-movement (REM) sleep was lower than during awake periods, with mean values of 65 bpm compared with 69 bpm, Dr. Stein noted in her oral presentation. Heart rates were lowest in stage 2 (64 bpm).

Heart-rate variability extracted from 122 polysomnograms was generally lowest in stage 3, at 31 milliseconds, compared with 37 milliseconds awake, 35 milliseconds in stage 1, and 39 milliseconds in REM sleep, she pointed out.

“Also unlike prior reports, low-frequency vs high-frequency ratio, extracted from 106 polysomnograms, was not highest in REM but in stage 2 (39 vs 41, respectively),” Dr. Stein said during her talk. The low-frequency power is a measure of heart-rate variability reflecting sympathetic and parasympathetic nervous system control of heart rate, she explained, whereas the high-frequency power reflects normal respiratory sinus arrhythmia but can be exaggerated by erratic rhythm.

Only very-low-frequency (VLF) power, a variable that captures variations in heart rate at the same underlying frequency as respiratory events, was significantly higher with severe sleep apnea (P = .023 at stage 1, P < .001 at stage 2, and P = .02 at stage 3). VLF differences were close to significant for REM (P = .06) and were not significant during awake periods. No other differences were observed.

“Except for VLF power, the presence of severe sleep apnea does not affect these relationships or heart-rate variability and sleep stage in the elderly,” said Dr. Stein.

• Pathology or Normal Aging?

“This study found that there was less heart-rate variability in the elderly during sleep, and that really has not been looked at before,”said James P. Krainson, MD, a physician with the Pulmonary Physicians of South Florida, and a diplomate of the American Board of Internal Medicine and Pulmonary Diseases. “So, the question is, is there underlying heart disease in the elderly, or is this just a normal aging pattern?” added Dr. Krainson.

Some of the implications of this study are that “these patients are more vulnerable to sudden death, to cardiac morbidity and mortality, and the heart-rate variability is lost as a precursor of these changes,” said Sanjeev V. Kothare, MD, associate director at the Sleep Center for Children, in Boston, Massachusetts, who attended the session.

“The next study that needs to be done is to look at the healthy population with less heart-rate variability and see whether they have any detectable underlying heart disease, to see if this reflects a degeneration of the heart, degeneration of the electrical conduction system of the heart, or whether this reflects just a normal aging pattern,” Dr. Krainson suggested.

“We have a data set of younger people that needs to be analyzed,” Dr. Stein agreed, “but those [subjects] are all males, and it might be different in men and women.”

Funding for this study was provided by grants from the National Heart, Lung, and Blood Institute. Dr. Stein, Dr. Kothare, and Dr. Krainson have disclosed no relevant financial relationships.

• Pearls for Practice

  1. Data from the Sleep Heart Health Study show that compared with the general population, the elderly have a significant reduction in heart-rate variability during sleep. For every sleep stage relative to the others, there were significant changes in HR/HRV. Heart rate was lowest in stage 2 sleep, and heart-rate variability was generally lowest in stage 3.

  2. This analysis showed that low frequency vs high frequency ratio was highest in stage 2, not in REM. Whether less heart-rate variability in the elderly during sleep signifies cardiovascular pathology or normal aging is still unclear. However, the elderly are at greater risk for sudden death and for cardiac morbidity and mortality, suggesting that heart-rate variability may be clinically significant.

References

1. SLEEP 2008: Abstract #0297. Presented June 10, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 28, 2008 — Low IQ in childhood is a risk factor for later development of vascular dementia (VaD), but not Alzheimer’s disease (AD), according to the results of a new study. Preteens who scored low on a cognitive assessment test were about 40% more likely to develop VaD as seniors than their schoolmates with higher IQs.

The study reinforces the notion that the risk for vascular dementia is lifelong and that prevention strategies could be implemented early on, according to 1 of the study authors, John M. Starr, FRCP-Ed, professor of health and aging at the University of Edinburgh, in Scotland. “Diseases in old age like dementia may have their origins much earlier in life,” he said. “Attention to vascular risk factors in middle age may have important consequences for reducing dementia rates later in life.”

Their findings are published online June 25 in Neurology.

• Much Earlier Origins

Dr. Starr and his colleagues took people with late-onset dementia who, on June 1, 1932 at about age 11 years, completed the Scottish Mental Survey (SMS). Almost every student in Scotland who was born in 1921–a total of 87,498 children, or 95% of the relevant population–took this test, which was a version of the 71-item Moray House Test (MHT). The MHT includes categories on directions, same-opposites, analogies, reasoning, arithmetical, spatial concepts, mixed sentences, and proverbs. This test, said Dr. Starr, has been validated as a “gold-standard” IQ test for 11-year-olds.

The results of the Scottish test were recorded in handwritten ledgers based on geographical area that were then stored and later transcribed onto a computerized database.

A total of 297 cases of dementia were identified from registries in Edinburgh. The latest date for case identification was August 2003, when subjects were about 82 years old.

• Two Control Groups

Of the 297 cases, 173 could be matched to control subjects (control group 1) who also completed the 1932 mental ability test. The remainder could not be matched because of name change, migration to Scotland after age 11 years, adoption, or other factors. Controls were matched based on age, sex, and district of birth registration. These controls were also separately matched on the basis of the father’s occupation (control group 2).

Among the patients with dementia, 86 (49.7%) had AD, 32 (18.5%) had VaD, 8 (4.6%) had mixed AD/VaD, 44 (25.4%) had unspecified dementia, 2 (1.2%) had Parkinson’s disease dementia, and 1 (0.6%) had “other” neurodegenerative dementia.

The preteens who had scored about half a standard deviation lower than other youngsters on the cognitive test were more likely to develop VaD years later (odds ratio, 0.62; 95% CI, 0.41 – 0.94), said Dr. Starr, for every 10-point increase in MHT score (0.7 standard deviation) compared with control group 2.

No other independent variable — paternal age at subject’s birth, maternal age at subject’s birth, or age of subject at SMS — had any significant effect on the model.

The researchers did not find any sex differences, but that may have been because there were not enough people in the study, said Dr. Starr.

• Association Not Found for AD

The association between lower cognitive ability and later diagnosis of dementia did not hold true for AD. “We hypothesize that the pathway that links lower childhood IQ with late-onset dementia is mainly through vascular disease,” said Dr. Starr told .

IQ may be considered representative of cognitive reserve, explained Dr. Starr. “Higher IQ relates to more reserve, so when something happens you have more reserves to draw on.” It’s possible, he said, that people with lower cognitive ability have less reserve to resist the pathological changes that lead to dementia. However, if a lack of cognitive reserve explains the link between childhood cognition and later dementia, “we would expect a similar effect on Alzheimer’s and vascular dementia,” which wasn’t the case in this study, said Dr. Starr.

The more likely possibility is that people with lower cognitive ability are exposed to more vascular insults — for example, higher blood pressure, more smoking, and more exposure to smoke-filled environments — that lead to dementia.

“If this pathway is mainly responsible, we would expect a greater effect on vascular dementia than Alzheimer’s disease; our results are consistent with this pathway being mainly responsible,” said Dr. Starr. This link between early cognition and later dementia may have something to do with what Dr. Starr referred to as “brain integrity.”

“The brain determines IQ, but it also controls blood pressure,” he said. “A lower IQ may reflect some general state of the brain leading to poorer blood pressure control systems.”

• Antenatal Conditions

Another possible contributing factor is the effect of antenatal conditions, added Dr. Starr. “Smaller babies have lower age-11 IQ but are also prone to more heart disease, etc, later in life.”

Since people with lower IQs are at greater risk, health policy makers “should bear this in mind when designing health-promotion materials,” said Dr. Starr. “Policies to reduce vascular risk are important to prevent dementia later in life.”

He also stressed that interventions that reduce heart disease and stroke risk are also likely to reduce later risk of dementia, particularly vascular dementia.

References

1. Neurology. Published online June 25, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 28, 2008 — Patients with multiple sclerosis (MS) have more than 5 times the risk of having restless legs syndrome (RLS) compared with a healthy population, a new study shows.

In a population of 202 consecutive patients with MS, the prevalence of diagnosed RLS was 14.6%, according to a late-breaking poster presented here at the Movement Disorder Society’s 12th International Congress of Parkinson’s Disease and Movement Disorders.

Among 212 healthy control subjects who were matched for sex and age, the prevalence was 2.8%. The risk of RLS was significantly higher for patients with MS than for controls (odds ratio, 5.76; P = .00002), the authors reported.

The data confirm the results of previous studies that have reported an association between RLS and MS, the researchers conclude.

In a news release from the society, primary author Giovanni Cossu, MD, from the General Hospital S. Michele AOB G. Brotzu, in Cagliari, Italy, said, “RLS [is] a phenomenon frequently observed in MS. Future studies, already in progress and oriented to establish a more accurate correlation between RLS phenomena and neurophysiological and [magnetic resonance imaging] MRI data of MS patients, may allow [us] to definitively include RLS as an integral symptom of MS.”

• Methods

All patients (135 females and 67 males) completed a structured questionnaire according to criteria of the International Restless Legs Syndrome Study Group (IRLSSG) (Allen RP et al. Sleep Med. 2003;4:101-119). Of the patients, 91 (45%) responded that they had symptoms of the syndrome. Patients who fulfilled the 4 criteria by their self-reports were examined by a neurologist to verify the presence of RLS. Of these patients, 29 received a diagnosis of RLS. Only 6 of the 212 controls had RLS.

• The 4 IRLSSG diagnostic criteria are as follows:

  1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without the uncomfortable sensations. Sometimes the arms or other body parts are involved in addition to the legs.

  2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying down or sitting.

  3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.

  4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or occur only in the evening or night. When symptoms are very severe, the worsening at night may not be noticeable but must have been previously present.

• Confirmation Needed

The current findings are important, but the study’s use of a questionnaire to determine RLS symptoms creates a selection bias, said the chair of the Congress Scientific Program Committee, Serge Przedborski, MD, PhD, professor of neurology and pathology at Columbia University, in New York, in an interview.

“This is interesting, but the result needs to be confirmed before I say anything to my patients with MS,” said Dr. Przedborski.

References

1. 12th International Congress of Parkinson’s Disease and Movement Disorders: Abstract LB6. Presented June 25, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 28, 2008 — About 10% of apparently healthy middle-aged adults have experienced silent cerebral infarcts (SCI), according to the latest results from the Framingham Offspring Study.

Furthermore, the study found risk factors typically associated with clinical stroke, including hypertension, elevated serum homocysteine, and carotid artery disease, are also associated with midlife SCI.

The study’s findings are consistent with previous community-based studies, which have estimated the prevalence of SCI between 5.8% and 17.7%, depending on age, ethnicity, presence of comorbidities, and imaging techniques.

“Our study shows that, in a middle-aged population free of clinical disease, there is a distressingly high prevalence of subclinical disease, as evidenced by these silent infarcts, which we know increase the risk of clinical stroke and cognitive impairment,” said study investigator Sudha Seshadri, MD, from Boston University School of Medicine, in Massachusetts.

“These findings also reinforce the need for clinicians to aggressively detect and manage cardiovascular risk factors, perhaps even earlier than midlife,” she added.

The study is published online June 26 in Stroke.

• Atrial Fibrillation Link

In addition to the prevalence data, the investigators also found that stroke risk factors, including hypertension, elevated plasma homocysteine, carotid stenosis, and increased carotid artery intimal medial thickness, are also significantly associated with silent infarcts.

Another, somewhat surprising, finding, said Dr. Seshadri, was a significant link between atrial fibrillation (AF) and SCI, with the data revealing that AF increased the risk for prevalent SCI more than 2-fold.

According to Dr. Seshadri, this finding may be an indication that AF is a simultaneous outcome, rather than a cause of SCI.

“While it is possible that tiny emboli resulting from atrial fibrillation may be causing these silent infarcts, it is probable that some of the risk factors for AF are the same as those for SCI. Therefore, it may be that atrial fibrillation is a marker for silent infarcts, rather than a cause, and that the 2 conditions are occurring together,” she said.

An offshoot of the Framingham Heart Study, a longitudinal study that began in 1948 with the goal of identifying common risk factors for cardiovascular disease, the Framingham Offspring Study, which began in 1971, includes the children and children’s spouses of the original cohort.

With an average age of 62 years, the current sample included 2040 offspring who attended the sixth examination (1996–1998) and underwent volumetric brain magnetic resonance imaging (MRI) in 2001 and were free of clinical stroke.

In addition, subjects were assessed using the Framingham Stroke Risk Profile (FSRP), a validated instrument that predicts 10-year probability of incident stroke and includes age, systolic blood pressure, antihypertensive therapy, diabetes mellitus, cigarette smoking, cardiovascular disease, AF, and left ventricular hypertrophy.

Subjects also underwent carotid imaging and measurement of cholesterol concentrations as well as plasma homocysteine.

• Need to Follow Guidelines

Among the 10.7% of study subjects who had MRI evidence of silent infarcts, 84% had a single lesion, most commonly located in the basal ganglia (52%). One-third of the lesions were subcortical, and 10% were cortical lesions.

According to the study, the aggregate FSRP score was significantly associated with prevalent SCI. Of the FRSP variables, AF, hypertension, and systolic blood pressure were all associated with an increased risk for silent infarct.

Of the variables not included in the FRSP, plasma homocysteine, carotid stenosis of 25% or greater, and increased intimal medial thickness were also associated with a higher risk for prevalent SCI. Neither age nor sex modified the effect of any of the risk factors on SCI prevalence.

The finding that there is a link between elevated homocysteine may warrant consideration of including SCI as an outcome in future studies looking at the potential benefit of vitamin supplementation.

While the study’s findings are not necessarily surprising, said Dr. Seshadri, they do underscore the need to follow guidelines for the early diagnosis and prevention of hypertension and atherosclerosis and their risk factors.

Unfortunately, she said, such guidelines have not been optimally implemented for a variety of reasons. “For instance, we know that over a lifetime, 9 out of 10 people will develop hypertension. When a condition is that common it tends to be regarded as the ‘norm.’ But we also know that the 10% of people who do not develop high blood pressure are healthier and live longer, better-quality lives. I would argue that even though a condition is regarded as the norm it should still be treated aggressively,” she said.

The study was supported by the National Heart, Lung, and Blood Institute; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke.

References

1. Stroke. Published online June 26, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 17, 2008 —Smoking is linked to an increased risk for memory deficit and cognitive decline in middle age in an analysis based on data from Whitehall II, a large, prospective cohort study.

The findings by Séverine Sabia, MSc, at the Institut National de la Santé et de la Recherche Médicale, in Villejuif, France, and colleagues, are published in the June 9 issue of the Archives of Internal Medicine.

Compared with study participants who had never smoked, after adjustment for other confounding factors, smokers had a 37% increased risk of having scores in the lowest quintile on a memory test (they were more likely to recall less than 5 of 20 words), said Ms. Sabia.

• Cognitive Decline in Middle Age

“This risk is quite important considering that we are only in middle-age when cognitive decline is just starting,” she noted. Evidence of this association at this age could support the hypothesis that smoking is involved in the pathogenesis of preclinical cognitive deficit and decline, which is a risk factor for later dementia, she added.

With the aging population and the projected increases in older adults with dementia, it is important to identify modifiable risk factors, she noted. “Our results suggest that smoking had an adverse effect on cognitive function in midlife, [but] 10 years after smoking cessation, there was little adverse effect of smoking on cognition,” she added. “Thus, public health messages should target smokers at all ages.”

A recent meta-analysis concluded that smoking is a risk factor for dementia, the group writes, adding that it is problematic to study the link between smoking and cognition (thinking, learning, and memory) in older people because many study participants do not return for follow-up visits, or they die from smoking-related diseases.

At the same time, there is increasing evidence that midlife risk factors play a role in later dementia.

• Does Smoking Affect Memory?

The group aimed to investigate the association between smoking history and cognitive function in middle-aged individuals.

They analyzed data from the Whitehall II study, which was designed to examine the socioeconomic gradient in health and disease. Whitehall II enrolled 10,308 London-based civil servants (6895 men and 3413 women) aged 35 to 55 years at baseline (phase 1) from 1985 to 1988.

Cognition was assessed at phase 5, when participants were aged 45 to 68 years (mean age, 55.5 years) and 5 years later, at phase 7, when participants were aged 50 to 74 years (mean age, 61 years), said Ms. Sabia.

Cognitive data from tests of memory, reasoning, vocabulary, and semantic and phonetic fluency were available for 5388 participants at phase 5 and 4659 participants at phase 7.

Smoking was assessed at baseline and at phase 5. At baseline, the smokers smoked an average of 14 cigarettes a day; 25% were light smokers (= 5 cigarettes/day) and 25% were heavy smokers (1 – 2 packs/day), but only 27 participants smoked more than 2 packs/day, she noted.

• Four Key Findings

The study presented 4 key findings, the group writes.

First, smoking in middle age was associated with memory deficit and decline in reasoning abilities. At phase 5, after adjustment for sex, age, socioeconomic differences, health behaviors, and health measures, current smokers vs participants who had never smoked had a 37% greater risk of being in the lowest quintile of cognitive function (odds ratio, 1.37; 95% confidence interval [CI], 1.10 – 1.73).

Second, compared with smokers, long-term ex-smokers (those who had stopped smoking before the beginning of the study) had a 30% lower risk for poor vocabulary and low verbal fluency.

Third, giving up smoking in midlife was accompanied by improvement in health habits such as drinking less alcohol, being more active, and eating more fruits and vegetables.

Fourth, compared with nonsmokers, smokers were more likely to die by phase 7 (an average 17.1 years of follow-up) or not to participate in cognitive tests, suggesting that nonparticipants had cognitive deficits and that, thus, the association between smoking and cognition in late midlife could be underestimated.

These findings are important because other research suggests that individuals with mild cognitive impairment progress to clinically diagnosed dementia at an accelerated rate, the group writes.

• Not Too Late to Stop Smoking

“During the past 20 years, public health messages about smoking have led to changes in smoking behavior,” they note. Based on the current study, “public health messages on smoking should continue to target smokers at all ages,” they conclude.

This study was supported by the British Medical Research Council, the French Ministry of Research, and the European Science Foundation. The Whitehall II study was supported by the British Medical Research Council; the British Heart Foundation; the British Health and Safety Executive; the British Department of Health; the National Heart, Lung, and Blood Institute; the National Institute on Aging; the Agency for Health Care Policy and Research; and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. Two of the study authors have obtained funding. The other study authors have disclosed no relevant financial relationships.

• Clinical Context

A meta-analysis by Anstey and colleagues in the August 15, 2007, issue of the American Journal of Epidemiology found that smoking is a risk factor for dementia. However, as noted by Kukull in the February 1, 2001, issue of Biological Psychiatry, the effects of smoking might be difficult to determine because of attrition and smoking-related mortality before the diagnosis of dementia. However, the effects of smoking on cognitive ability before the onset of dementia could be examined.

In the Whitehall II study described by Marmot and colleagues in the June 8, 1991, issue of The Lancet, civil servants were recruited in 1985 to assess the link between socioeconomic factors and health. This study uses the Whitehall II database to examine whether smoking history is associated with cognitive function in middle-aged adults and to assess the risk for death and participation in cognitive tests in those who smoke.

• Study Highlights

  1. 10,308 civil servants aged 35 to 55 years enrolled in phase 1 from 1985 to 1988, which included clinical examination and survey regarding smoking habits.

  2. Of 7830 who participated in phase 5 from 1997 to 1999, complete data were available for 5388 subjects.

  3. 4659 participated in phase 7 from 2002 to 2004.

  4. Mean follow-up was 17.1 years.

  5. Smoking history categories were never-smoker, long-term ex-smoker who stopped before phase 1, recent ex-smoker who stopped between phases 1 and 5, and current smoker at phase 5.

  6. Cognitive function testing occurred at phases 5 and 7:

     • Short-term verbal memory assessment by 20-word free recall test

     • Reasoning assessment by the Alice Heim AH4 Group Test of General Intelligence with use of verbal and mathematical reasoning items

     • Vocabulary assessment by Mill Hill Vocabulary Test

     • Phonemic and semantic verbal fluency

     • Results were adjusted for covariates:

     • Sociodemographics: age, sex, marital status, education, socioeconomic position

     • Health behaviors: alcohol use, fruit and vegetable intake, physical activity

     • Health measures at phase 5: coronary heart disease, stroke, diabetes mellitus, systolic and diastolic blood pressure, and serum cholesterol level

  7. Increased smoking trend was linked to lower socioeconomic status, less education, greater alcohol use, less fruit and vegetable intake, and higher cholesterol level.

  8. Characteristics not linked to smoking status included marital status, physical activity, coronary heart disease, stroke, diabetes mellitus, and blood pressure.

  9. Phase 5 subject vs baseline group was younger (55.5 vs 56.1 years), had fewer women (27.6% vs 33.1%), and had fewer people of low socioeconomic status (14.6% vs 22.7%).

  10. Adjusted risk for death was higher for current smokers at phase 1 vs never-smokers for men (hazard ratio [HR], 2.00; 95%, CI, 1.58 – 2.52) and women (HR, 2.46; 95% CI, 1.80 – 3.37).

  11. Risk for death was not higher for ex-smokers at phase 1 vs never-smokers.

  12. Likelihood of not participating in cognitive tests was higher for current smokers at phase 1 vs never-smokers for men (OR, 1.32; 95% CI, 1.16 – 1.51) and women (OR, 1.69; 95% CI, 1.41 – 2.02).

  13. Adjusted results for cognitive deficits at phase 5:

      • Current smokers vs never-smokers had memory deficit (OR, 1.37; 95% CI, 1.10 – 1.73; P < .05).

      • Long-term ex-smokers vs never-smokers were less likely to have deficits in memory (OR, 0.79; 95% CI, 0.65 – 0.96; P < .05), vocabulary (OR, 0.73; 95% CI, 0.60 – 0.87; P < .05), phonemic fluency (OR, 0.73; 95% CI, 0.61 – 0.87; P < .05), and semantic fluency (OR, 0.75; 95% CI, 0.63 – 0.89; P < .05).

      • Recent ex-smokers vs never-smokers had less risk for deficits in vocabulary (OR, 0.65; 95% CI, 0.49 – 0.85; P < .05) and semantic fluency (OR, 0.72; 95% CI, 0.55 – 0.94; P < .05).

  14. The only cognitive decline between phase 5 and phase 7 was for reasoning in current smokers (OR, 1.40; 95% CI, 1.11 – 1.75; P < .05) and recent ex-smokers (OR, 1.38; 95% CI, 1.07 – 1.77; P < .05) vs never-smokers.

  15. Current smokers at phase 5 showed no dose-response association between pack-years of smoking and cognitive deficit or decline.

  16. Post hoc analysis showed that recent ex-smokers had the smallest increase in alcohol use between phase 1 and phase 7 vs other groups and a greater increase in fruit and vegetable intake vs never-smokers.

  17. Limitations of the study included specific subject population, self-reporting of smoking habits, written answers for testing verbal fluency, and only 2 time points to assess change.

• Pearls for Practice

  1. After adjustment for age, sex, sociodemographics, and health behaviors, middle-aged smokers vs never-smokers are more likely to have cognitive deficits in memory and decline in reasoning skills. Long-term ex-smokers vs never-smokers are less likely to have deficits in memory, vocabulary, and fluency.

  2. Middle-aged adults who smoke have a higher risk for death or nonparticipation in cognitive tests.

References

1. Arch Intern Med. 2008;168:1165-1173.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 17, 2008 — During the initial stages of interferon beta treatment in patients with relapsing-remitting MS, monitoring by means of MRI scans and anti-interferon beta neutralizing antibodies (NAb) can be useful in predicting clinical response, Italian researchers report in the June issue of the Journal of Neurology, Neurosurgery and Psychiatry.

“Either having an MRI scan with signs of disease activity or a positive NAb test will predict a bad clinical response over the next 2 years of interferon beta treatment,” lead investigator Dr. Luca Durelli told Reuters Health.

Dr. Durelli of Ospedale San Luigi Gonzaga, Turin and colleagues came to this conclusion after studying 147 patients who underwent repeated MRI scans and NAb assays during the first 6 months of interferon beta therapy.

The researchers found a positive scan had a predictive sensitivity of 52% and a specificity of 80% for clinical disease activity in the following 18 months. The negative predictive value was 73% and the positive predictive value was 62%.

For NAb positivity, the corresponding values were 71% and 66%, and 92% and 29%. The combination of an active scan and NAb positivity had a sensitivity of 71%, a specificity of 86%, a negative predictive value of 94% and a positive predictive value of 50%.

In other words, continued Dr. Durelli, “Patients developing both MRI activity as well as NAb positivity carry a 50% risk of developing clinical activity…. This could be an indication to switch them to a different immune-modulatory or immune-suppressive treatment.”

In an accompanying editorial, Drs. Hans-Peter Hartung of Heinrich-Heine-University Dusseldorf and Joep Killestein of VU University, Amsterdam, express reservations about the findings, but nevertheless conclude that “it is a useful prospective study providing evidence of the existence of biomarkers that aid in identifying suboptimal interferon beta responders at an early stage.”

References

1. J Neurol Neurosurg Psychiatry 2008;79:616-617.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 17, 2008 — High-dose cyclophosphamide (HiCy) reduces disease activity and disability in people with severe aggressive multiple sclerosis (MS) who have not undergone bone marrow transplantation.

In a 2-year open-label trial of 9 patients with aggressive relapsing remitting MS (RRMS), investigators at Johns Hopkins University in Baltimore, Maryland, found that administering a 1-time immunoablative regimen of 50 mg per kilogram of intravenous cyclophosphamide over 4 consecutive days resulted in a statistically significant reduction in disability that was durable at an average follow-up of 23 months, with no adjunctive immunomodulatory therapies.

“We did not expect this [reduction in disability]. We found that disability levels at the beginning of the study were much greater than at the end of the study. Patients had a return of function that, for some, translated into significant improvements, such as returning to work, dispensing with walkers or canes, and regaining bladder control,” said Douglas A. Kerr, MD, PhD..

Furthermore, the treatment appeared safe and well tolerated, with no deaths or unexpected serious adverse events.

The study was published online June 9 in the Archives of Neurology.

• Starting From Scratch

Cyclophosphamide, a chemotherapeutic agent, has been used for about half a century, primarily to treat cancer. When it was used to treat MS in the 1980s, its efficacy as a single-pulse therapy was, at best, modest and did not justify its routine use, said Dr. Kerr.

Currently, cyclophosphamide is often used as a component of a chemotherapeutic cocktail given as adjunctive therapy preceding bone marrow transplantation for the treatment of RRMS.

The HiCy 1-time regimen used in the current study has been shown to be safe and effective in other autoimmune diseases, including lupus erythematosus, autoimmune aplastic anemia, and myasthenia gravis.

The regimen, which was developed about 15 years ago by Robert Brodsky, MD, and Richard Jones, MD, hematologists at Johns Hopkins, works by eliminating the “misbehaving” immune system while preserving hematopoietic stem cells, allowing the immune system to “recreate itself from scratch.” Based on promising results and these other autoimmune conditions, the investigators decided to test it in MS.

• Worst of the Worst

Nine patients — 6 men and 3 women — with RRMS were selected for the study. The mean age of the participants was 29 years. Eight subjects had failed conventional therapy and 1 was treatment naive. All had ongoing active inflammatory disease and a high risk for continued progression and loss of function.

“These patients were the worst of the worst in terms of the severity of their disease,” said Dr. Kerr.

The primary end point was safety and tolerability of the treatment. Secondary outcome measures included a change in gadolinium-enhancing lesions on magnetic resonance imaging and a change in disability measures on the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC).

At a mean follow-up of 23 months, investigators found an average reduction of 39.4% in disability and an average improvement in MSFC scores of 87%. In addition, the average number of brain lesions decreased, from 6.5 at study outset to 1.2 at follow-up.

Of the 9 study subjects, 5 had no disease activity at follow-up. The other 4, said Dr. Kerr, “did well, but not perfectly, and had some evidence of disease activity, usually demonstrated by a brain lesion and not a clinical attack. Still, it wasn’t perfect.”

Nevertheless, he said, overall patients experienced a dramatic improvement with this 1-time high-dose therapy that appears to reverse MS-related disability and is unlike any previous MS treatment.

Currently, he said, MS drugs that are available, or even those that are on the horizon, are designed solely to hold the disease at bay and limit disease progression. However, once patients stop taking the medication, the disease continues to advance.

“This treatment is based on a completely different model — a 1-time therapy with a long-term benefit,” said Dr. Kerr.

• Less Toxicity, Lower Cost

HiCy also offers several advantages over bone marrow transplantation, which has been associated with a 5% to 7% mortality rate and toxicity to a number of organs, including the brain. To date, he said, there has been no mortality or organ toxicity associated with HiCy therapy in the more than 250 patients who have received the treatment for other types of autoimmune disease.

Furthermore, the cost of bone marrow transplantation runs about $300,000 in the first year alone; HiCy therapy costs approximately $25,000 to $30,000.

Although the mechanism is not entirely clear, Dr. Kerr said it was interesting to note that patients with a return of function tended to have a shorter disease duration (less than 10 years) and more active inflammatory disease.

This finding is important, he said, and suggests that inflammation itself plays a role in MS disability and that “once you get rid of that inflammatory cascade within the nervous system, patients start to improve.”

Dr. Kerr said his team is currently working on improving the HiCy regimen, possibly by adding drugs that will help “reeducate” the immune system. In addition, he said, the investigators are also planning a multicenter phase 3 trial that will have broader inclusion criteria, enrolling patients with less severe, less aggressive disease.

References

1. Arch Neuro. Published online before print June 9, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 12, 2008 — What is the role of anticholinergic bladder control medications in patients taking acetylcholinesterase inhibitors for dementia? Do they affect cognition?

The cognitive decline that is sometimes seen in older adults may be due, at least partially, to the use of anticholinergic medications (ie, muscarinic receptor antagonists). These include the Parkinson/tardive dyskinesia drugs trihexyphenidyl and benztropine, antihistamines (diphenhydramine, chlorpheniramine, meclizine, etc), tricyclic antidepressants, antipsychotics, antiarrhythmics, skeletal muscle relaxants, and paroxetine.

Other drugs that block acetylcholine receptors to a milder extent may also be important, particularly when effects are additive and/or blood-brain barrier penetration is enhanced. Many drugs block acetylcholine receptors to a minor extent, including commonly used agents, such as prednisone, warfarin, and digoxin. Additionally, the drug metabolites may have different receptor subtype affinities than the parent compounds.

In Alzheimer’s disease, the loss of synapses containing acetylcholine is one of the critical aspects producing dementia. Acetylcholinesterase inhibitors (donepezil and others) are used to treat this deficit. Unfortunately, these drugs produce only modest benefit. To maximize the benefit, we should try to avoid the use of medications that may produce a countereffect. Do the anticholinergic medications used for incontinence affect cognition? To understand this issue we need to look at the receptor subtypes.

Acetylcholine binds to 2 classes of receptors, nicotinic and muscarinic. Both have a role in learning and memory.[1,2] There are 5 known subtypes of muscarinic receptors (M1-M5). Different regions of the brain include all 5 receptor subtypes, including the hippocampus and cortex, the primary regions involved in memory and learning.[3-5] By studying knockout mice (ie, mice missing 1 type of receptor), researchers have found that mice lacking in any of the receptor subtypes (with the exception of M3) display various cognitive deficits. In one study, M3 knockout mice performed at normal levels of cognition and behavior.[6]

The detrusor muscle, which controls bladder contraction, contains all 5 subtypes, with a predominance of M2 and M3. In in vitro studies, the M3 subtype mediates detrusor contraction.[5] M2 receptors are also involved, although the role is not thought to be as central.[7]

Along with receptor specificity, whether or not the drug enters the central nervous system (CNS) is important. Agents used for peripheral effects, such as inhibiting bladder muscle contraction, should have low CNS penetration. This may be the case in most patients, yet in others the blood-brain barrier may not be as effective. This barrier can decrease with age, disease, extent of dementia, stress, and the use of medications.[1,5]

On the basis of current knowledge, the most important concern with the use of an incontinence drug would be specificity for the M3 receptor. This should result in the lowest incidence of cognitive effects. The adverse events of dry mouth and constipation (primarily) and dry, blurred vision would remain, because M3 receptors are present in the smooth muscle of the bowel, salivary glands, and eyes. Even so, these side effects are not consistent across the agents, eg, the oxybutynin patch causes less dry mouth but can cause pruritus, and darifenacin has a higher incidence of constipation, especially at a higher dose.

Focusing on M3 specificity and cognition, the M3-specific agents cause little or no cognitive decline.[7-11] In studies of darifenacin, an overactive bladder drug that is highly selective for M3, there was no significant difference seen in cognitive function between patients taking the drug and those on placebo.[8,10] Solifenacin, another highly selective agent, also does not appear to cause any significant cognitive decline.[9] Tolterodine and trospium, although not as M3-specific as darifenacin and solifenacin, have low CNS penetration and thus have a low incidence of cognitive effects; however, this should be viewed with caution because the subjects in clinical trials would have a tighter CNS barrier than patients with conditions that could cause the barrier to weaken.[1,11]

In contrast, a study of anticholinergic agents and effects on cognition found that the use of oxybutynin — which does not bind to M2 or M5 but does bind well to M1, M3, and M4 — resulted in a decrease in cognitive ability equal to 1 standard deviation below the norm for nonusers. The reduction in cognitive performance was considered mild compared with some of the other agents studied (eg, hydroxyzine and imipramine), but it was not insignificant.[12]

References

1. Chew ML. Anticholinergic Medications and Cognition in Older Adults [dissertation]. Pittsburgh: University of Pittsburgh; 2007.

2. Quirion R. Cholinergic markers in Alzheimer disease and the autoregulation of acetylcholine release. J Psychiatry Neurosci. 1993;18:226-234.

3. Levey AI. Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci U S A. 1996;93:13541-13546.

4. Abrams P, Andersson K-E, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. J Pharmacol. 2006;148:565-578.

5. Yamada M, Miyakawa T, Duttaroy A, et al. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature. 2001;410:207-212.

6. Sharath S. Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol. 2006;147:S80-S87.

7. Steers W, Corcos J, Foote J, et al. An investigation of dose titration with darifenacin, an M3 selective receptor antagonist. BJU Int. 2005;95:580-586. Erratum in: BJU Int. 2005;95:1385-1386.

8. Clemett D, Jarvis B. Tolterodine: a review of its use in the treatment of overactive bladder. Drugs Aging. 2001;18:277-304.

9. Solifenacin (Vesicare) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.

10. Darifenacin (Enablex) [package insert]. East Hanover, NJ: Novartis Pharma Stein Inc; 2007.

11. Halaska M, Ralph D, Widemann A, et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World J Urol. 2003;20:392-399.

12. Ancelin ML, Artero S, Portet F, et al. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ. 2006;332:455-459.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

June 9, 2008 — Stroke, the third leading cause of death in the United States, is a leading cause of adult neurological disability and accounts for the greatest number of hospitalizations for neurological disease. Although treatment of acute stroke has the potential of reducing death and disability, it is likely that prevention will more effectively reduce the ravages of stroke. The patient who is recovering from a mild stroke or who has had a recent transient ischemic attack (TIA) is at high risk of stroke recurrence, physical and intellectual disability, long-term institutionalization, and death.

There is substantial evidence from observational epidemiological studies and clinical trials that recurrent ischemic stroke can be prevented (Table 1). Control of risk factors is important for prevention of a first stroke and is practical after ischemic stroke and TIA have occurred. Identification of the specific ischemic stroke mechanism, eg, TIA or minor stroke ipsilateral to a moderate or severe internal carotid stenosis, guides decision making with regard to recurrent stroke prevention therapy (Table 2). A patient with symptomatic cerebrovascular disease is likely to have other cardiovascular diseases or is predisposed to develop them. Preventive measures should complement reduction in risk of atherothrombotic events in the coronary arteries and other arterial territories. Certain nonmodifiable characteristics identify persons at high risk of stroke and stroke recurrence. These include advancing age, male sex, and black and Hispanic race-ethnic backgrounds. Some risk factors, however, such as elevated blood pressure, cigarette smoking, obesity, impaired glucose tolerance, and physical inactivity, are modifiable. Other conditions, ie, prior cardiovascular diseases such as coronary heart disease with angina or prior myocardial infarction, valvular heart disease, congestive heart failure, atrial fibrillation, increased left ventricular mass, and certain other echocardiographic abnormalities, identify persons at increased risk who may be treated with antithrombotic therapy. More recently, other modifiable risk factors for stroke have been identified. These are elevated total and low-density lipoprotein (LDL) cholesterol in patients with prior coronary heart disease and elevated plasma homocysteine levels.

Table 1. Guide to Risk Reduction for Patients With Ischemic Cerebrovascular Disease (Patients Who Have Already Had Their First TIA or Stroke): General Risk-Factor–Specific Recommendations