Michele G. Sullivan

Perioperative β-Blockers may reduce the risk of myocardial infarction after noncardiac surgery, but they confer a doubling in the risk of disabling strokes, especially among lower-risk patients, according to a meta-analysis of 33 randomized controlled trials.

In light of these findings, the guideline committee of the American College of Cardiology, which recommends the drugs for patients undergoing noncardiac surgery, “should soften their stance on perioperative β-Blockade until definitive evidence shows clear benefit,” Dr. Sripal Bangalore wrote in an article published online in The Lancet (doi:10.1016/S0140–6736(08)61560–3). “β-Blockers should not be routinely used for perioperative treatment … unless patients are already taking them for clinically indicated reasons.”

The risks associated with β-Blockers were most apparent in trials that included low- to intermediate-risk patients, particularly the recent Perioperative Ischemic Evaluation (POISE) trial, which is considered a landmark study (Lancet 2008; 371:1839–47). POISE, which included more than 8,300 patients randomized to extended-release metoprolol succinate or placebo before surgery, found a doubling in the risk of stroke among those in the active group.

The drugs also were associated with significant increases in other cardiac problems, wrote Dr. Bangalore of Brigham and Women's Hospital, Boston, and his colleagues. “For the overall cohort, we estimate that treatment of 1,000 patients with β-Blockers results in 16 fewer nonfatal myocardial infarctions in survivors, but at the expense of three disabling strokes, 45 patients with clinically significant perioperative bradycardia, 59 with hypotension, and potentially increased mortality.”

The 33 trials included in the meta-analysis comprised 12,300 patients: 6,300 randomly assigned to β-Blockers and 6,000 given placebo. The trials varied with regard to the drug used, the dosage, and the timing and duration of administration.

Overall, β-Blockers did not result in any significant decrease in the risk of all-cause mortality, cardiovascular mortality, or heart failure. There was a 35% decreased risk of nonfatal heart attack (number needed to treat [NNT]: 63), and a 64% decreased risk of myocardial ischemia (NNT: 16). But the investigators also found a 116% increased risk of nonfatal stroke (number needed to harm [NNH]: 275), based on trials with low- or intermediate-risk patients.

β-Blockade also resulted in a tripling of the risk of perioperative bradycardia (NNH: 8), as well as a 70% increased risk of perioperative hypotension (NNH: 17).

When the investigators examined outcomes according to the risk level of patients included in each trial, trials including high-risk patients drove the beneficial effects of β-Blockers, while trials with low- or intermediate-risk patients drove the risks.

In high-risk trials, the investigators found no increased risk of all-cause mortality, an 81% decreased risk of nonfatal MI (NNT: 15), and a 69% decreased risk of MI (NNT: 9), although there were no significant benefits for cardiovascular mortality or heart failure.

Trials conducted using low- or intermediate-risk patients found a 28% increased risk of all-cause mortality (NNH: 164), and a 116% increased risk of nonfatal stroke (NNH: 275), with a 28% decreased risk of nonfatal MI (NNT: 80), a 59% decreased risk of myocardial ischemia (NNT: 23), and no reduction in rates of cardiovascular mortality or heart failure.

The POISE trial carried the most statistical weight among lower-risk trials, while a 1999 study by Dutch researcher Don Poldermans, Ph.D., drove the findings among high-risk trials. That study randomized 59 patients with high-risk echocardiographic findings to perioperative bisoprolol or standard care. Nine patients in the standard-care group and two in the bisoprolol group died of cardiac causes during the perioperative period (N. Eng. J. Med. 1999;341:1789–94).

In the Poldermans trial, Dr. Bangalore and his colleagues wrote, “52% of patients had had a previous myocardial infarction and all had a positive stress test. These patients might have needed to be on a β-Blocker for secondary prevention irrespective of the need to undergo surgery.”

There were no sponsors for the study, noted the authors, none of whom declared any financial conflicts of interest regarding the study.

Perioperative β-Blockers may reduce the risk of myocardial infarction after noncardiac surgery, but they confer a doubling in the risk of disabling strokes, especially among lower-risk patients, according to a meta-analysis of 33 randomized controlled trials.

In light of these findings, the guideline committee of the American College of Cardiology, which recommends the drugs for patients undergoing noncardiac surgery, “should soften their stance on perioperative β-Blockade until definitive evidence shows clear benefit,” Dr. Sripal Bangalore wrote in an article published online in The Lancet (doi:10.1016/S0140–6736(08)61560–3). “β-Blockers should not be routinely used for perioperative treatment … unless patients are already taking them for clinically indicated reasons.”

The risks associated with β-Blockers were most apparent in trials that included low- to intermediate-risk patients, particularly the recent Perioperative Ischemic Evaluation (POISE) trial, which is considered a landmark study (Lancet 2008; 371:1839–47). POISE, which included more than 8,300 patients randomized to extended-release metoprolol succinate or placebo before surgery, found a doubling in the risk of stroke among those in the active group.

The drugs also were associated with significant increases in other cardiac problems, wrote Dr. Bangalore of Brigham and Women's Hospital, Boston, and his colleagues. “For the overall cohort, we estimate that treatment of 1,000 patients with β-Blockers results in 16 fewer nonfatal myocardial infarctions in survivors, but at the expense of three disabling strokes, 45 patients with clinically significant perioperative bradycardia, 59 with hypotension, and potentially increased mortality.”

The 33 trials included in the meta-analysis comprised 12,300 patients: 6,300 randomly assigned to β-Blockers and 6,000 given placebo. The trials varied with regard to the drug used, the dosage, and the timing and duration of administration.

Overall, β-Blockers did not result in any significant decrease in the risk of all-cause mortality, cardiovascular mortality, or heart failure. There was a 35% decreased risk of nonfatal heart attack (number needed to treat [NNT]: 63), and a 64% decreased risk of myocardial ischemia (NNT: 16). But the investigators also found a 116% increased risk of nonfatal stroke (number needed to harm [NNH]: 275), based on trials with low- or intermediate-risk patients.

β-Blockade also resulted in a tripling of the risk of perioperative bradycardia (NNH: 8), as well as a 70% increased risk of perioperative hypotension (NNH: 17).

When the investigators examined outcomes according to the risk level of patients included in each trial, trials including high-risk patients drove the beneficial effects of β-Blockers, while trials with low- or intermediate-risk patients drove the risks.

In high-risk trials, the investigators found no increased risk of all-cause mortality, an 81% decreased risk of nonfatal MI (NNT: 15), and a 69% decreased risk of MI (NNT: 9), although there were no significant benefits for cardiovascular mortality or heart failure.

Trials conducted using low- or intermediate-risk patients found a 28% increased risk of all-cause mortality (NNH: 164), and a 116% increased risk of nonfatal stroke (NNH: 275), with a 28% decreased risk of nonfatal MI (NNT: 80), a 59% decreased risk of myocardial ischemia (NNT: 23), and no reduction in rates of cardiovascular mortality or heart failure.

The POISE trial carried the most statistical weight among lower-risk trials, while a 1999 study by Dutch researcher Don Poldermans, Ph.D., drove the findings among high-risk trials. That study randomized 59 patients with high-risk echocardiographic findings to perioperative bisoprolol or standard care. Nine patients in the standard-care group and two in the bisoprolol group died of cardiac causes during the perioperative period (N. Eng. J. Med. 1999;341:1789–94).

In the Poldermans trial, Dr. Bangalore and his colleagues wrote, “52% of patients had had a previous myocardial infarction and all had a positive stress test. These patients might have needed to be on a β-Blocker for secondary prevention irrespective of the need to undergo surgery.”

There were no sponsors for the study, noted the authors, none of whom declared any financial conflicts of interest regarding the study.

Perioperative β-Blockers may reduce the risk of myocardial infarction after noncardiac surgery, but they confer a doubling in the risk of disabling strokes, especially among lower-risk patients, according to a meta-analysis of 33 randomized controlled trials.

In light of these findings, the guideline committee of the American College of Cardiology, which recommends the drugs for patients undergoing noncardiac surgery, “should soften their stance on perioperative β-Blockade until definitive evidence shows clear benefit,” Dr. Sripal Bangalore wrote in an article published online in The Lancet (doi:10.1016/S0140–6736(08)61560–3). “β-Blockers should not be routinely used for perioperative treatment … unless patients are already taking them for clinically indicated reasons.”

The risks associated with β-Blockers were most apparent in trials that included low- to intermediate-risk patients, particularly the recent Perioperative Ischemic Evaluation (POISE) trial, which is considered a landmark study (Lancet 2008; 371:1839–47). POISE, which included more than 8,300 patients randomized to extended-release metoprolol succinate or placebo before surgery, found a doubling in the risk of stroke among those in the active group.

The drugs also were associated with significant increases in other cardiac problems, wrote Dr. Bangalore of Brigham and Women's Hospital, Boston, and his colleagues. “For the overall cohort, we estimate that treatment of 1,000 patients with β-Blockers results in 16 fewer nonfatal myocardial infarctions in survivors, but at the expense of three disabling strokes, 45 patients with clinically significant perioperative bradycardia, 59 with hypotension, and potentially increased mortality.”

The 33 trials included in the meta-analysis comprised 12,300 patients: 6,300 randomly assigned to β-Blockers and 6,000 given placebo. The trials varied with regard to the drug used, the dosage, and the timing and duration of administration.

Overall, β-Blockers did not result in any significant decrease in the risk of all-cause mortality, cardiovascular mortality, or heart failure. There was a 35% decreased risk of nonfatal heart attack (number needed to treat [NNT]: 63), and a 64% decreased risk of myocardial ischemia (NNT: 16). But the investigators also found a 116% increased risk of nonfatal stroke (number needed to harm [NNH]: 275), based on trials with low- or intermediate-risk patients.

β-Blockade also resulted in a tripling of the risk of perioperative bradycardia (NNH: 8), as well as a 70% increased risk of perioperative hypotension (NNH: 17).

When the investigators examined outcomes according to the risk level of patients included in each trial, trials including high-risk patients drove the beneficial effects of β-Blockers, while trials with low- or intermediate-risk patients drove the risks.

In high-risk trials, the investigators found no increased risk of all-cause mortality, an 81% decreased risk of nonfatal MI (NNT: 15), and a 69% decreased risk of MI (NNT: 9), although there were no significant benefits for cardiovascular mortality or heart failure.

Trials conducted using low- or intermediate-risk patients found a 28% increased risk of all-cause mortality (NNH: 164), and a 116% increased risk of nonfatal stroke (NNH: 275), with a 28% decreased risk of nonfatal MI (NNT: 80), a 59% decreased risk of myocardial ischemia (NNT: 23), and no reduction in rates of cardiovascular mortality or heart failure.

The POISE trial carried the most statistical weight among lower-risk trials, while a 1999 study by Dutch researcher Don Poldermans, Ph.D., drove the findings among high-risk trials. That study randomized 59 patients with high-risk echocardiographic findings to perioperative bisoprolol or standard care. Nine patients in the standard-care group and two in the bisoprolol group died of cardiac causes during the perioperative period (N. Eng. J. Med. 1999;341:1789–94).

In the Poldermans trial, Dr. Bangalore and his colleagues wrote, “52% of patients had had a previous myocardial infarction and all had a positive stress test. These patients might have needed to be on a β-Blocker for secondary prevention irrespective of the need to undergo surgery.”

There were no sponsors for the study, noted the authors, none of whom declared any financial conflicts of interest regarding the study.

BARCELONA — When given within a month of the precipitating event, cognitive therapy and prolonged exposure therapy are equally effective at decreasing the incidence of posttraumatic stress disorder—and both strategies are significantly more effective than treatment with escitalopram, study results showed.

The drug was no better than placebo or no treatment at all, a finding that disappointed Dr. Arieh Y. Shalev. “I'm saddened by it,” he said at the annual congress of the European College of Neuropsychopharmacology. “We wanted this to have a positive effect, because we thought, in the case of mass trauma, it would be very good to have a compound that could be distributed soon after the event.”

Dr. Shalev, director and founder of the Center for Traumatic Stress at Hadassah University Hospital, Jerusalem, presented the results of a randomized controlled trial of early intervention for posttraumatic stress disorder (PTSD). The potential study group consisted of 5,285 survivors of a traumatic event, who were all identified by emergency room records. All the subjects were contacted by telephone within a few days of discharge.

Most of the traumatic events (75%) involved a motor vehicle accident, 14% were work related, and 4% were terrorist events.

Researchers invited 1,470 survivors who expressed some PTSD symptoms to a clinical assessment. Almost half (49%) declined this invitation right away, Dr. Shalev said, indicating an enormous cultural barrier to seeking PTSD treatment.

Of those who were assessed, 398 had qualifying symptoms; 298 of those subjects were randomized into the trial, with treatment beginning within 20 days of the traumatic event. Treatment arms included 12 weekly sessions of cognitive therapy, 12 weekly sessions of prolonged exposure, 12 weeks of blinded treatment with placebo or 20 mg of the SSRI escitalopram (Lexapro), or 12 weeks on a waiting list. The group on the waiting list received only weekly telephone calls to check on their well-being and respond to emergencies.

All groups showed significantly reduced rates of PTSD. Cognitive therapy and prolonged exposure had the lowest incidence of PTSD (18% and 21%, respectively). Although escitalopram reduced the incidence of PTSD to 61%, it was not any more effective than placebo or being placed on the waiting list; the incidence of PTSD was reduced to 59% with placebo and to 57% for those on the waiting list.

BARCELONA — When given within a month of the precipitating event, cognitive therapy and prolonged exposure therapy are equally effective at decreasing the incidence of posttraumatic stress disorder—and both strategies are significantly more effective than treatment with escitalopram, study results showed.

The drug was no better than placebo or no treatment at all, a finding that disappointed Dr. Arieh Y. Shalev. “I'm saddened by it,” he said at the annual congress of the European College of Neuropsychopharmacology. “We wanted this to have a positive effect, because we thought, in the case of mass trauma, it would be very good to have a compound that could be distributed soon after the event.”

Dr. Shalev, director and founder of the Center for Traumatic Stress at Hadassah University Hospital, Jerusalem, presented the results of a randomized controlled trial of early intervention for posttraumatic stress disorder (PTSD). The potential study group consisted of 5,285 survivors of a traumatic event, who were all identified by emergency room records. All the subjects were contacted by telephone within a few days of discharge.

Most of the traumatic events (75%) involved a motor vehicle accident, 14% were work related, and 4% were terrorist events.

Researchers invited 1,470 survivors who expressed some PTSD symptoms to a clinical assessment. Almost half (49%) declined this invitation right away, Dr. Shalev said, indicating an enormous cultural barrier to seeking PTSD treatment.

Of those who were assessed, 398 had qualifying symptoms; 298 of those subjects were randomized into the trial, with treatment beginning within 20 days of the traumatic event. Treatment arms included 12 weekly sessions of cognitive therapy, 12 weekly sessions of prolonged exposure, 12 weeks of blinded treatment with placebo or 20 mg of the SSRI escitalopram (Lexapro), or 12 weeks on a waiting list. The group on the waiting list received only weekly telephone calls to check on their well-being and respond to emergencies.

All groups showed significantly reduced rates of PTSD. Cognitive therapy and prolonged exposure had the lowest incidence of PTSD (18% and 21%, respectively). Although escitalopram reduced the incidence of PTSD to 61%, it was not any more effective than placebo or being placed on the waiting list; the incidence of PTSD was reduced to 59% with placebo and to 57% for those on the waiting list.

BARCELONA — When given within a month of the precipitating event, cognitive therapy and prolonged exposure therapy are equally effective at decreasing the incidence of posttraumatic stress disorder—and both strategies are significantly more effective than treatment with escitalopram, study results showed.

The drug was no better than placebo or no treatment at all, a finding that disappointed Dr. Arieh Y. Shalev. “I'm saddened by it,” he said at the annual congress of the European College of Neuropsychopharmacology. “We wanted this to have a positive effect, because we thought, in the case of mass trauma, it would be very good to have a compound that could be distributed soon after the event.”

Dr. Shalev, director and founder of the Center for Traumatic Stress at Hadassah University Hospital, Jerusalem, presented the results of a randomized controlled trial of early intervention for posttraumatic stress disorder (PTSD). The potential study group consisted of 5,285 survivors of a traumatic event, who were all identified by emergency room records. All the subjects were contacted by telephone within a few days of discharge.

Most of the traumatic events (75%) involved a motor vehicle accident, 14% were work related, and 4% were terrorist events.

Researchers invited 1,470 survivors who expressed some PTSD symptoms to a clinical assessment. Almost half (49%) declined this invitation right away, Dr. Shalev said, indicating an enormous cultural barrier to seeking PTSD treatment.

Of those who were assessed, 398 had qualifying symptoms; 298 of those subjects were randomized into the trial, with treatment beginning within 20 days of the traumatic event. Treatment arms included 12 weekly sessions of cognitive therapy, 12 weekly sessions of prolonged exposure, 12 weeks of blinded treatment with placebo or 20 mg of the SSRI escitalopram (Lexapro), or 12 weeks on a waiting list. The group on the waiting list received only weekly telephone calls to check on their well-being and respond to emergencies.

All groups showed significantly reduced rates of PTSD. Cognitive therapy and prolonged exposure had the lowest incidence of PTSD (18% and 21%, respectively). Although escitalopram reduced the incidence of PTSD to 61%, it was not any more effective than placebo or being placed on the waiting list; the incidence of PTSD was reduced to 59% with placebo and to 57% for those on the waiting list.

BOSTON — Rapid in-office testing for infectious diseases can help physicians get the right drug on board as quickly as possible, and cut down on unnecessary testing and inappropriate antibiotics.

“Having the diagnosis in real time can affect clinical decision making,” Dr. Leonard Krilov said at the annual meeting of the American Academy of Pediatrics. “For instance, with rapid influenza testing, it's been shown that doctors who have a confirmed diagnosis from a rapid flu test order fewer unnecessary tests, fewer radiographs, and give out fewer antibiotics and more antiviral drugs.”

The only diagnostic tests approved for use in the office setting are those that have been waived by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) law. Waived tests are defined as simple laboratory examinations and procedures that are cleared by the Food and Drug Administration for home use; employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible; and pose no reasonable risk of harm to the patient if it's performed incorrectly.

The most common in-office tests for infectious diseases include those for group A streptococcus (GAS), influenza, respiratory syncytial virus (RSV), mononucleosis, and human immunodeficiency virus (HIV), said Dr. Krilov, chief of pediatric infectious diseases at Winthrop University Hospital, Mineola, N.Y.

There are 35 CLIA-waived tests for GAS, with varying ranges of sensitivity and specificity. “Overall, the tests are very specific, ranging from 85% to 100%, but the concern is that the sensitivity is quite variable and can be as low as 62%,” Dr. Krilov said.

Because of this, a negative test always requires a backup throat culture for confirmation. On the other hand, “If you get a positive test, you can believe it. There's no need for a culture,” he said.

However, even a positive test doesn't mean that the presenting symptoms are because of GAS pharyngitis. “Recovery of group A strep from the pharynx doesn't necessarily distinguish true infection from carriers who might happen to have a coincidental viral pharyngitis. You can't completely rely on the test—you have to be able to interpret the clinical picture as well.”

Of the 15 rapid influenza tests available, 3 are waived for office use; they all give results in about 30 minutes. While they are highly specific (90%–95%), the sensitivity isn't great (70%–75%), Dr. Krilov said.

Because of this, “successfully using these is somewhat dependent on the time of year and the likelihood of influenza infection in your community. False positives and true negatives are more likely if prevalence is low, but false negatives and true positives are more likely in the midst of an epidemic. But in the right time of winter, with the right clinical picture, a positive test is both believable and important.”

Accuracy also depends on when during the course of illness testing occurs. In children, most of the viral shedding occurs in the first 48 hours. The quality of the specimen is very important as well, Dr. Krilov noted. “The more secretions you get, the more cell material you get, so a nasal wash or aspirate is probably better than a nasopharyngeal swab.”

In light of the continued emergence of antibiotic-resistant bacteria, an early, certain diagnosis of viral illness can significantly decrease inappropriate antibiotic prescribing, Dr. Krilov said.

A 2003 study enrolled 391 patients with symptoms of influenza; all had a rapid flu test done in the hospital. Half of the referring physicians were given the results; these doctors ordered significantly fewer lab tests and x-rays and prescribed significantly fewer antibiotics than physicians who didn't know the diagnosis. In addition, Dr. Krilov said, treatment costs and hospital length of stay were significantly lower for patients whose diagnosis was known; the rate of antiviral prescriptions given to these patients also was significantly higher than for those whose diagnosis was not known (Pediatrics 2003;112:363–7).

Most testing for RSV is done in the hospital, but one test is available for office use. It detects RSV fusion protein, and results are available in 15 minutes. The kit has a sensitivity of up to 88% and specificity of up to 100%. “Again, if it's winter and RSV is in the community, you can believe a positive result,” he said. “It might be useful in how you monitor the patient, and it's very helpful in preventing unnecessary antibiotic use.”

Monospot is the only CLIA-waived test for mononucleosis. Again, accuracy depends on timing, Dr. Krilov said. “A negative test in the first week of illness doesn't mean they don't have the disease. Typically, it isn't until the second week of illness that the heterophile antibodies are made, and they can persist for 6 months or more. So using this test to follow the course of disease, or as a way of determining when kids can go back to school, is not worthwhile.”

Children younger than 6 years may not even make the heterophile antibodies, so a negative test on a young child shouldn't affect clinical decision-making, Dr. Krilov said. “The antibodies are detected in up to 85% of older kids and adolescents, but [in] 40% or less of those younger than 4 years. If you have a patient of the appropriate age and symptoms, and the test is negative, treat it as early disease and test again in 1–2 weeks. Or you have the option of sending to the lab for specific serology.”

Dr. Krilov also spoke about in-office HIV testing. Two CLIA-waived kits are available and give results in 20 minutes. “It's useful in some clinical settings, since it allows more people to be tested … but they don't give a complete diagnostics, so a positive test must always be confirmed by the Western blot analysis. The other part of HIV testing is, if you do the test, it needs to be done in conjunction with counseling and hooking patients into appropriate follow-up.”

BOSTON — Rapid in-office testing for infectious diseases can help physicians get the right drug on board as quickly as possible, and cut down on unnecessary testing and inappropriate antibiotics.

“Having the diagnosis in real time can affect clinical decision making,” Dr. Leonard Krilov said at the annual meeting of the American Academy of Pediatrics. “For instance, with rapid influenza testing, it's been shown that doctors who have a confirmed diagnosis from a rapid flu test order fewer unnecessary tests, fewer radiographs, and give out fewer antibiotics and more antiviral drugs.”

The only diagnostic tests approved for use in the office setting are those that have been waived by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) law. Waived tests are defined as simple laboratory examinations and procedures that are cleared by the Food and Drug Administration for home use; employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible; and pose no reasonable risk of harm to the patient if it's performed incorrectly.

The most common in-office tests for infectious diseases include those for group A streptococcus (GAS), influenza, respiratory syncytial virus (RSV), mononucleosis, and human immunodeficiency virus (HIV), said Dr. Krilov, chief of pediatric infectious diseases at Winthrop University Hospital, Mineola, N.Y.

There are 35 CLIA-waived tests for GAS, with varying ranges of sensitivity and specificity. “Overall, the tests are very specific, ranging from 85% to 100%, but the concern is that the sensitivity is quite variable and can be as low as 62%,” Dr. Krilov said.

Because of this, a negative test always requires a backup throat culture for confirmation. On the other hand, “If you get a positive test, you can believe it. There's no need for a culture,” he said.

However, even a positive test doesn't mean that the presenting symptoms are because of GAS pharyngitis. “Recovery of group A strep from the pharynx doesn't necessarily distinguish true infection from carriers who might happen to have a coincidental viral pharyngitis. You can't completely rely on the test—you have to be able to interpret the clinical picture as well.”

Of the 15 rapid influenza tests available, 3 are waived for office use; they all give results in about 30 minutes. While they are highly specific (90%–95%), the sensitivity isn't great (70%–75%), Dr. Krilov said.

Because of this, “successfully using these is somewhat dependent on the time of year and the likelihood of influenza infection in your community. False positives and true negatives are more likely if prevalence is low, but false negatives and true positives are more likely in the midst of an epidemic. But in the right time of winter, with the right clinical picture, a positive test is both believable and important.”

Accuracy also depends on when during the course of illness testing occurs. In children, most of the viral shedding occurs in the first 48 hours. The quality of the specimen is very important as well, Dr. Krilov noted. “The more secretions you get, the more cell material you get, so a nasal wash or aspirate is probably better than a nasopharyngeal swab.”

In light of the continued emergence of antibiotic-resistant bacteria, an early, certain diagnosis of viral illness can significantly decrease inappropriate antibiotic prescribing, Dr. Krilov said.

A 2003 study enrolled 391 patients with symptoms of influenza; all had a rapid flu test done in the hospital. Half of the referring physicians were given the results; these doctors ordered significantly fewer lab tests and x-rays and prescribed significantly fewer antibiotics than physicians who didn't know the diagnosis. In addition, Dr. Krilov said, treatment costs and hospital length of stay were significantly lower for patients whose diagnosis was known; the rate of antiviral prescriptions given to these patients also was significantly higher than for those whose diagnosis was not known (Pediatrics 2003;112:363–7).

Most testing for RSV is done in the hospital, but one test is available for office use. It detects RSV fusion protein, and results are available in 15 minutes. The kit has a sensitivity of up to 88% and specificity of up to 100%. “Again, if it's winter and RSV is in the community, you can believe a positive result,” he said. “It might be useful in how you monitor the patient, and it's very helpful in preventing unnecessary antibiotic use.”

Monospot is the only CLIA-waived test for mononucleosis. Again, accuracy depends on timing, Dr. Krilov said. “A negative test in the first week of illness doesn't mean they don't have the disease. Typically, it isn't until the second week of illness that the heterophile antibodies are made, and they can persist for 6 months or more. So using this test to follow the course of disease, or as a way of determining when kids can go back to school, is not worthwhile.”

Children younger than 6 years may not even make the heterophile antibodies, so a negative test on a young child shouldn't affect clinical decision-making, Dr. Krilov said. “The antibodies are detected in up to 85% of older kids and adolescents, but [in] 40% or less of those younger than 4 years. If you have a patient of the appropriate age and symptoms, and the test is negative, treat it as early disease and test again in 1–2 weeks. Or you have the option of sending to the lab for specific serology.”

Dr. Krilov also spoke about in-office HIV testing. Two CLIA-waived kits are available and give results in 20 minutes. “It's useful in some clinical settings, since it allows more people to be tested … but they don't give a complete diagnostics, so a positive test must always be confirmed by the Western blot analysis. The other part of HIV testing is, if you do the test, it needs to be done in conjunction with counseling and hooking patients into appropriate follow-up.”

BOSTON — Rapid in-office testing for infectious diseases can help physicians get the right drug on board as quickly as possible, and cut down on unnecessary testing and inappropriate antibiotics.

“Having the diagnosis in real time can affect clinical decision making,” Dr. Leonard Krilov said at the annual meeting of the American Academy of Pediatrics. “For instance, with rapid influenza testing, it's been shown that doctors who have a confirmed diagnosis from a rapid flu test order fewer unnecessary tests, fewer radiographs, and give out fewer antibiotics and more antiviral drugs.”

The only diagnostic tests approved for use in the office setting are those that have been waived by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) law. Waived tests are defined as simple laboratory examinations and procedures that are cleared by the Food and Drug Administration for home use; employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible; and pose no reasonable risk of harm to the patient if it's performed incorrectly.

The most common in-office tests for infectious diseases include those for group A streptococcus (GAS), influenza, respiratory syncytial virus (RSV), mononucleosis, and human immunodeficiency virus (HIV), said Dr. Krilov, chief of pediatric infectious diseases at Winthrop University Hospital, Mineola, N.Y.

There are 35 CLIA-waived tests for GAS, with varying ranges of sensitivity and specificity. “Overall, the tests are very specific, ranging from 85% to 100%, but the concern is that the sensitivity is quite variable and can be as low as 62%,” Dr. Krilov said.

Because of this, a negative test always requires a backup throat culture for confirmation. On the other hand, “If you get a positive test, you can believe it. There's no need for a culture,” he said.

However, even a positive test doesn't mean that the presenting symptoms are because of GAS pharyngitis. “Recovery of group A strep from the pharynx doesn't necessarily distinguish true infection from carriers who might happen to have a coincidental viral pharyngitis. You can't completely rely on the test—you have to be able to interpret the clinical picture as well.”

Of the 15 rapid influenza tests available, 3 are waived for office use; they all give results in about 30 minutes. While they are highly specific (90%–95%), the sensitivity isn't great (70%–75%), Dr. Krilov said.

Because of this, “successfully using these is somewhat dependent on the time of year and the likelihood of influenza infection in your community. False positives and true negatives are more likely if prevalence is low, but false negatives and true positives are more likely in the midst of an epidemic. But in the right time of winter, with the right clinical picture, a positive test is both believable and important.”

Accuracy also depends on when during the course of illness testing occurs. In children, most of the viral shedding occurs in the first 48 hours. The quality of the specimen is very important as well, Dr. Krilov noted. “The more secretions you get, the more cell material you get, so a nasal wash or aspirate is probably better than a nasopharyngeal swab.”

In light of the continued emergence of antibiotic-resistant bacteria, an early, certain diagnosis of viral illness can significantly decrease inappropriate antibiotic prescribing, Dr. Krilov said.

A 2003 study enrolled 391 patients with symptoms of influenza; all had a rapid flu test done in the hospital. Half of the referring physicians were given the results; these doctors ordered significantly fewer lab tests and x-rays and prescribed significantly fewer antibiotics than physicians who didn't know the diagnosis. In addition, Dr. Krilov said, treatment costs and hospital length of stay were significantly lower for patients whose diagnosis was known; the rate of antiviral prescriptions given to these patients also was significantly higher than for those whose diagnosis was not known (Pediatrics 2003;112:363–7).

Most testing for RSV is done in the hospital, but one test is available for office use. It detects RSV fusion protein, and results are available in 15 minutes. The kit has a sensitivity of up to 88% and specificity of up to 100%. “Again, if it's winter and RSV is in the community, you can believe a positive result,” he said. “It might be useful in how you monitor the patient, and it's very helpful in preventing unnecessary antibiotic use.”

Monospot is the only CLIA-waived test for mononucleosis. Again, accuracy depends on timing, Dr. Krilov said. “A negative test in the first week of illness doesn't mean they don't have the disease. Typically, it isn't until the second week of illness that the heterophile antibodies are made, and they can persist for 6 months or more. So using this test to follow the course of disease, or as a way of determining when kids can go back to school, is not worthwhile.”

Children younger than 6 years may not even make the heterophile antibodies, so a negative test on a young child shouldn't affect clinical decision-making, Dr. Krilov said. “The antibodies are detected in up to 85% of older kids and adolescents, but [in] 40% or less of those younger than 4 years. If you have a patient of the appropriate age and symptoms, and the test is negative, treat it as early disease and test again in 1–2 weeks. Or you have the option of sending to the lab for specific serology.”

Dr. Krilov also spoke about in-office HIV testing. Two CLIA-waived kits are available and give results in 20 minutes. “It's useful in some clinical settings, since it allows more people to be tested … but they don't give a complete diagnostics, so a positive test must always be confirmed by the Western blot analysis. The other part of HIV testing is, if you do the test, it needs to be done in conjunction with counseling and hooking patients into appropriate follow-up.”

CHICAGO – Continuous intravenous infusions of immunoglobulin for 9 months stabilized cognition and function for Alzheimer's patients enrolled in a small placebo-controlled trial.

The 18-month-long phase II study included 24 patients with mild to moderate Alzheimer's. For the first 6 months, they were randomized either to placebo or to one of four intravenous immunoglobulin (IVIG) doses.

For the remaining 12 months, all the participants were switched to IVIG, but raters were still blinded to the dosing, said Dr. Norman Relkin, who presented the study's 9-month results at the International Conference on Alzheimer's Disease.

Patients who had received IVIG continuously for 9 months showed significantly better scores on measures of cognition and activities of daily living than did those taking placebo.

When the IVIG arms were analyzed by dose, 0.4 g/kg of body weight every 2 weeks provided the best results in global functioning, cognition, and activities of daily living, Dr. Relkin said at the meeting, which was sponsored by the Alzheimer's Association.

Planning for a larger, phase III trial is underway; it is to be conducted at 35 academic centers in the United States.

Dr. Relkin of Cornell University, New York, coauthored another IVIG study published earlier this year that found that improvements in Alzheimer's patients treated with IVIG lasted only as long as the treatment continued.

The trial of continuous IVIG treatment was cosponsored by the National Institutes of Health and Baxter International Inc.

Dr. Relkin said he received grants and research support from Baxter.

CHICAGO – Continuous intravenous infusions of immunoglobulin for 9 months stabilized cognition and function for Alzheimer's patients enrolled in a small placebo-controlled trial.

The 18-month-long phase II study included 24 patients with mild to moderate Alzheimer's. For the first 6 months, they were randomized either to placebo or to one of four intravenous immunoglobulin (IVIG) doses.

For the remaining 12 months, all the participants were switched to IVIG, but raters were still blinded to the dosing, said Dr. Norman Relkin, who presented the study's 9-month results at the International Conference on Alzheimer's Disease.

Patients who had received IVIG continuously for 9 months showed significantly better scores on measures of cognition and activities of daily living than did those taking placebo.

When the IVIG arms were analyzed by dose, 0.4 g/kg of body weight every 2 weeks provided the best results in global functioning, cognition, and activities of daily living, Dr. Relkin said at the meeting, which was sponsored by the Alzheimer's Association.

Planning for a larger, phase III trial is underway; it is to be conducted at 35 academic centers in the United States.

Dr. Relkin of Cornell University, New York, coauthored another IVIG study published earlier this year that found that improvements in Alzheimer's patients treated with IVIG lasted only as long as the treatment continued.

The trial of continuous IVIG treatment was cosponsored by the National Institutes of Health and Baxter International Inc.

Dr. Relkin said he received grants and research support from Baxter.

CHICAGO – Continuous intravenous infusions of immunoglobulin for 9 months stabilized cognition and function for Alzheimer's patients enrolled in a small placebo-controlled trial.

The 18-month-long phase II study included 24 patients with mild to moderate Alzheimer's. For the first 6 months, they were randomized either to placebo or to one of four intravenous immunoglobulin (IVIG) doses.

For the remaining 12 months, all the participants were switched to IVIG, but raters were still blinded to the dosing, said Dr. Norman Relkin, who presented the study's 9-month results at the International Conference on Alzheimer's Disease.

Patients who had received IVIG continuously for 9 months showed significantly better scores on measures of cognition and activities of daily living than did those taking placebo.

When the IVIG arms were analyzed by dose, 0.4 g/kg of body weight every 2 weeks provided the best results in global functioning, cognition, and activities of daily living, Dr. Relkin said at the meeting, which was sponsored by the Alzheimer's Association.

Planning for a larger, phase III trial is underway; it is to be conducted at 35 academic centers in the United States.

Dr. Relkin of Cornell University, New York, coauthored another IVIG study published earlier this year that found that improvements in Alzheimer's patients treated with IVIG lasted only as long as the treatment continued.

The trial of continuous IVIG treatment was cosponsored by the National Institutes of Health and Baxter International Inc.

Dr. Relkin said he received grants and research support from Baxter.

MADRID — Patients with a cardiovascular abnormality who also take an ergotamine-derived dopamine agonist are at an increased risk for a worsening of their heart problems.

But “most patients who stop ergotamine-derived treatment seem to remain stable or improve their cardiovascular abnormality over 1 year,” Dr. Videke G. Rasmussen wrote in a poster presented at the annual congress of the European Federation of Neurological Societies.

Dr. Rasmussen's prospective observational study included 144 patients with Parkinson's disease, of whom 40 had a diagnosis of cardiac valve disease or pulmonary hypertension confirmed by echo-cardiogram at the beginning of the study.

Aortic regurgitation was present in 32 patients (mild, 16; moderate, 14; severe, 2). One patient had moderate mitral regurgitation. Two had moderate tricuspid regurgitation; one of these also had moderate mitral regurgitation, and the other also had mild aortic regurgitation. Two patients had mitral and tricuspid regurgitation plus pulmonary hypertension, and two had isolated pulmonary hypertension.

At baseline, 35 patients were taking ergo- tamine-derived dopamine agonists (EDDA) and 8 were taking non-ergotamine-derived drugs (non-EDDA). After the initial echo-cardiogram, 5 patients taking EDDAs continued that treatment, and 27 switched to a non-EDDA. The eight who were originally taking a non-EDDA continued to do so.

After a mean of 15 months, patients had repeat echocardiograms that were compared with baseline. Of the five who continued on an EDDA, one showed improvement in the cardiovascular condition, one showed no change, and three showed worsening of their condition. Of the 27 who switched from an EDDA to a non-EDDA, 7 (26%) showed improvement, 15 (56%) had no change, and 5 (18%) showed worsening.

None of the eight who took a non-EDDA for the entire study period showed a worsening in their cardiac condition during the follow-up visit. One patient showed improvement; seven showed no change.

Dr. Rasmussen, a cardiologist at Aarhus (Denmark) University Hospital, had no conflicts of interest with regard to the study.

MADRID — Patients with a cardiovascular abnormality who also take an ergotamine-derived dopamine agonist are at an increased risk for a worsening of their heart problems.

But “most patients who stop ergotamine-derived treatment seem to remain stable or improve their cardiovascular abnormality over 1 year,” Dr. Videke G. Rasmussen wrote in a poster presented at the annual congress of the European Federation of Neurological Societies.

Dr. Rasmussen's prospective observational study included 144 patients with Parkinson's disease, of whom 40 had a diagnosis of cardiac valve disease or pulmonary hypertension confirmed by echo-cardiogram at the beginning of the study.

Aortic regurgitation was present in 32 patients (mild, 16; moderate, 14; severe, 2). One patient had moderate mitral regurgitation. Two had moderate tricuspid regurgitation; one of these also had moderate mitral regurgitation, and the other also had mild aortic regurgitation. Two patients had mitral and tricuspid regurgitation plus pulmonary hypertension, and two had isolated pulmonary hypertension.

At baseline, 35 patients were taking ergo- tamine-derived dopamine agonists (EDDA) and 8 were taking non-ergotamine-derived drugs (non-EDDA). After the initial echo-cardiogram, 5 patients taking EDDAs continued that treatment, and 27 switched to a non-EDDA. The eight who were originally taking a non-EDDA continued to do so.

After a mean of 15 months, patients had repeat echocardiograms that were compared with baseline. Of the five who continued on an EDDA, one showed improvement in the cardiovascular condition, one showed no change, and three showed worsening of their condition. Of the 27 who switched from an EDDA to a non-EDDA, 7 (26%) showed improvement, 15 (56%) had no change, and 5 (18%) showed worsening.

None of the eight who took a non-EDDA for the entire study period showed a worsening in their cardiac condition during the follow-up visit. One patient showed improvement; seven showed no change.

Dr. Rasmussen, a cardiologist at Aarhus (Denmark) University Hospital, had no conflicts of interest with regard to the study.

MADRID — Patients with a cardiovascular abnormality who also take an ergotamine-derived dopamine agonist are at an increased risk for a worsening of their heart problems.

But “most patients who stop ergotamine-derived treatment seem to remain stable or improve their cardiovascular abnormality over 1 year,” Dr. Videke G. Rasmussen wrote in a poster presented at the annual congress of the European Federation of Neurological Societies.

Dr. Rasmussen's prospective observational study included 144 patients with Parkinson's disease, of whom 40 had a diagnosis of cardiac valve disease or pulmonary hypertension confirmed by echo-cardiogram at the beginning of the study.

Aortic regurgitation was present in 32 patients (mild, 16; moderate, 14; severe, 2). One patient had moderate mitral regurgitation. Two had moderate tricuspid regurgitation; one of these also had moderate mitral regurgitation, and the other also had mild aortic regurgitation. Two patients had mitral and tricuspid regurgitation plus pulmonary hypertension, and two had isolated pulmonary hypertension.

At baseline, 35 patients were taking ergo- tamine-derived dopamine agonists (EDDA) and 8 were taking non-ergotamine-derived drugs (non-EDDA). After the initial echo-cardiogram, 5 patients taking EDDAs continued that treatment, and 27 switched to a non-EDDA. The eight who were originally taking a non-EDDA continued to do so.

After a mean of 15 months, patients had repeat echocardiograms that were compared with baseline. Of the five who continued on an EDDA, one showed improvement in the cardiovascular condition, one showed no change, and three showed worsening of their condition. Of the 27 who switched from an EDDA to a non-EDDA, 7 (26%) showed improvement, 15 (56%) had no change, and 5 (18%) showed worsening.

None of the eight who took a non-EDDA for the entire study period showed a worsening in their cardiac condition during the follow-up visit. One patient showed improvement; seven showed no change.

Dr. Rasmussen, a cardiologist at Aarhus (Denmark) University Hospital, had no conflicts of interest with regard to the study.

MADRID — Patients with microcephaly, hemimegalencephaly, tuberous sclerosis, and polymicrogyria have an earlier onset of epilepsy and are more likely to experience comorbid neurologic and cognitive deficits than are patients with other malformations, according to an observational study performed in Austria.

“In comparison, patients with focal cortical dysplasia very rarely had cognitive impairment or neurologic deficits,” Dr. Giorgi Kuchukhidze said at the annual congress of the European Federation of Neurological Societies.

Dr. Kuchukhidze, a neurologist at the Medical University of Innsbruck, Austria, discussed the results of his prospective study of 237 epilepsy patients, all of whom were seen at the university's tertiary epilepsy referral center. All of the patients had a cortical malformation as the root cause of their seizure disorder.

“Certain EEG patterns and clinical pictures create a strong suspicion of malformations of cortical development,” he said. However, the prognosis for such patients is not always grim. “Up to 70% of patients with these malformations can become seizure-free after antiepileptic surgery.”

The most commonly observed malformations in the cohort were focal cortical dysplasia (62; 26%) and polymicrogyria (49; 21%). There were also 30 patients with periventricular nodular heterotopia, 27 with ganglioglioma, 26 with tuberous sclerosis, 14 with microcephaly, 13 with hemimegalencephaly, 8 with dysembryo-plastic neuroepithelial tumor, 6 with subcortical laminar heterotopia, and 2 with lissencephaly/pachygyria.

The mean age of seizure onset was 12 years, but this varied with the type of malformation. “The majority of patients with microcephaly, hemimegalencephaly, and tuberous sclerosis had seizure onset during the first year of life, whereas in most of the patients with focal cortical dysplasia, ganglioglioma, and periventricular heterotopia, the seizures manifested during the second decade of life,” Dr. Kuchukhidze said.

Delayed developmental milestones were seen in 39% of the patients, and various levels of cognitive impairment were present in 43%. “These were apparent in the majority of patients with microcephaly, tuberous sclerosis, hemimegalencephaly, and polymicrogyria,” he said.

Generalized seizures—either West's or Lennox-Gastaut syndrome—were significantly associated with microcephaly, tuberous sclerosis, and diffuse focal lesions. Temporal lobe epilepsy was significantly associated with single focal lesions and focal cortical dysplasia. Medically refractory epilepsy was present in 150 patients (63%). Forty-three patients underwent epilepsy surgery, and 26 of them (60%) have been seizure-free for at least 1 year after the procedure.

MADRID — Patients with microcephaly, hemimegalencephaly, tuberous sclerosis, and polymicrogyria have an earlier onset of epilepsy and are more likely to experience comorbid neurologic and cognitive deficits than are patients with other malformations, according to an observational study performed in Austria.

“In comparison, patients with focal cortical dysplasia very rarely had cognitive impairment or neurologic deficits,” Dr. Giorgi Kuchukhidze said at the annual congress of the European Federation of Neurological Societies.

Dr. Kuchukhidze, a neurologist at the Medical University of Innsbruck, Austria, discussed the results of his prospective study of 237 epilepsy patients, all of whom were seen at the university's tertiary epilepsy referral center. All of the patients had a cortical malformation as the root cause of their seizure disorder.

“Certain EEG patterns and clinical pictures create a strong suspicion of malformations of cortical development,” he said. However, the prognosis for such patients is not always grim. “Up to 70% of patients with these malformations can become seizure-free after antiepileptic surgery.”

The most commonly observed malformations in the cohort were focal cortical dysplasia (62; 26%) and polymicrogyria (49; 21%). There were also 30 patients with periventricular nodular heterotopia, 27 with ganglioglioma, 26 with tuberous sclerosis, 14 with microcephaly, 13 with hemimegalencephaly, 8 with dysembryo-plastic neuroepithelial tumor, 6 with subcortical laminar heterotopia, and 2 with lissencephaly/pachygyria.

The mean age of seizure onset was 12 years, but this varied with the type of malformation. “The majority of patients with microcephaly, hemimegalencephaly, and tuberous sclerosis had seizure onset during the first year of life, whereas in most of the patients with focal cortical dysplasia, ganglioglioma, and periventricular heterotopia, the seizures manifested during the second decade of life,” Dr. Kuchukhidze said.

Delayed developmental milestones were seen in 39% of the patients, and various levels of cognitive impairment were present in 43%. “These were apparent in the majority of patients with microcephaly, tuberous sclerosis, hemimegalencephaly, and polymicrogyria,” he said.

Generalized seizures—either West's or Lennox-Gastaut syndrome—were significantly associated with microcephaly, tuberous sclerosis, and diffuse focal lesions. Temporal lobe epilepsy was significantly associated with single focal lesions and focal cortical dysplasia. Medically refractory epilepsy was present in 150 patients (63%). Forty-three patients underwent epilepsy surgery, and 26 of them (60%) have been seizure-free for at least 1 year after the procedure.

MADRID — Patients with microcephaly, hemimegalencephaly, tuberous sclerosis, and polymicrogyria have an earlier onset of epilepsy and are more likely to experience comorbid neurologic and cognitive deficits than are patients with other malformations, according to an observational study performed in Austria.

“In comparison, patients with focal cortical dysplasia very rarely had cognitive impairment or neurologic deficits,” Dr. Giorgi Kuchukhidze said at the annual congress of the European Federation of Neurological Societies.

Dr. Kuchukhidze, a neurologist at the Medical University of Innsbruck, Austria, discussed the results of his prospective study of 237 epilepsy patients, all of whom were seen at the university's tertiary epilepsy referral center. All of the patients had a cortical malformation as the root cause of their seizure disorder.

“Certain EEG patterns and clinical pictures create a strong suspicion of malformations of cortical development,” he said. However, the prognosis for such patients is not always grim. “Up to 70% of patients with these malformations can become seizure-free after antiepileptic surgery.”

The most commonly observed malformations in the cohort were focal cortical dysplasia (62; 26%) and polymicrogyria (49; 21%). There were also 30 patients with periventricular nodular heterotopia, 27 with ganglioglioma, 26 with tuberous sclerosis, 14 with microcephaly, 13 with hemimegalencephaly, 8 with dysembryo-plastic neuroepithelial tumor, 6 with subcortical laminar heterotopia, and 2 with lissencephaly/pachygyria.

The mean age of seizure onset was 12 years, but this varied with the type of malformation. “The majority of patients with microcephaly, hemimegalencephaly, and tuberous sclerosis had seizure onset during the first year of life, whereas in most of the patients with focal cortical dysplasia, ganglioglioma, and periventricular heterotopia, the seizures manifested during the second decade of life,” Dr. Kuchukhidze said.

Delayed developmental milestones were seen in 39% of the patients, and various levels of cognitive impairment were present in 43%. “These were apparent in the majority of patients with microcephaly, tuberous sclerosis, hemimegalencephaly, and polymicrogyria,” he said.

Generalized seizures—either West's or Lennox-Gastaut syndrome—were significantly associated with microcephaly, tuberous sclerosis, and diffuse focal lesions. Temporal lobe epilepsy was significantly associated with single focal lesions and focal cortical dysplasia. Medically refractory epilepsy was present in 150 patients (63%). Forty-three patients underwent epilepsy surgery, and 26 of them (60%) have been seizure-free for at least 1 year after the procedure.

MADRID — Deep brain stimulation shows considerable promise for reducing intractable seizures in patients who are not candidates for epilepsy surgery, even though there have been few large-scale controlled trials to back up the practice.

“We have no idea what the best stimulation parameters are, we don't know whether to stimulate in response to epileptiform activity or continuously, and, of course, the search for the optimal target is ongoing,” Dr. Paul Boon said at the annual congress of the European Federation of Neurological Societies. “Most of our information has come from uncontrolled studies and case reports, which included about 115 people worldwide.”

Now, data from three new or upcoming studies might help shed light on some of these questions, said Dr. Boon of University Hospital Ghent (Belgium), where he and his colleagues are leaders in researching an epilepsy application for DBS.

Some of the earliest studies, in the 1980s and early 1990s, used the electrodes in the brain's cerebellar regions, but with very little effect, so the cerebellum is no longer considered a target. The caudate nucleus and centromedial nucleus of the thalamus have also been examined as possible targets, but in very small numbers of patients and with varying results, said Dr. Boon.

The most promising approach to date is bilateral stimulation of the anterior thalamic nucleus, he said. Early uncontrolled studies of this application had small patient numbers, but their success led to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial of 110 patients with medically refractory partial-onset seizures.

All of the patients received the implants; for the first 3 months, only half of the patient had their stimulators turned on. After this blinded treatment phase, all of the patients received neurostimulation. The results are due to be presented at the American Epilepsy Society meeting in Seattle in December. By way of detailing his financial conflicts of interest, Dr. Boon said in an interview that Medtronic Inc., the company that makes DBS hardware, has been and is providing devices and electrodes in support of the pilot trial, and has provided an educational grant.

The medial temporal lobe and the hippocampus are other potential targets. Last year, Dr. Boon and his colleagues published a study of 12 patients with refractory temporal lobe epilepsy, who were also candidates for surgery. Instead of implanting recording electrodes during the presurgical period, they implanted DBS electrodes in the medial temporal lobe.

“We aimed to adjust the simulation parameters to get a 50% reduction in spikes for 7 consecutive days,” he said. “If the patient achieved that, then we went to chronic stimulation, and if they did not achieve that, then we adjusted the parameters until we met those criteria. If the patient still didn't achieve the reduction, then we removed the electrodes and proceeded to surgery.”

Of the 12 patients, 10 underwent long-term DBS, and 2 had the resection. After a mean follow-up of 31 months, both of the surgical patients were seizure free. One of the DBS patients had a seizure reduction of more than 90%; five had a reduction of at least 50%, and two had a reduction of 30%-40% (Epilepsia 2007;48:1551–60).

“We got a 70% response rate, with no significant adverse events or changes in memory,” he said. “This shows that DBS of the medial temporal lobe is safe, feasible, and effective.”

Dr. Boon and his group are also seeking to recruit 45 patients for an upcoming study in which they will compare DBS of the hippocampus with medial temporal lobe resection or with hippocampal DBS delayed for 6 months after implantation. The 1-year CoRaStiR (Controlled Randomized Stimulation Versus Resection) trial will also be sponsored by Medtronic.

Researchers believe that DBS controls seizures by desynchronizing synchronized high-voltage cortical discharges. During chronic DBS, the stimulation is applied constantly to the epileptogenic focus, regardless of the area's own discharge.

However, there is some evidence that stimulation only in response to epileptiform activity might be more effective. This “closed-loop” stimulation would require a device that could read and analyze brain waves and then “decide” what type of stimulation to deliver—a process that clearly presents a technological challenge.

Early external devices were tested in small numbers of patients in the late 1990s and early 2000s. More recently, a California-based company, NeuroPace Inc., has developed the RNS System, which includes fully implantable intracranial components as well as external products, he said.

The device consists of an implanted neurostimulator with one or two strip leads that can be placed in different areas of the brain to allow activity to be monitored and controlled. An external programming device allows the stimulator to detect predetermined electrographic patterns; the physician can also program the type of response that the device delivers.

A treatment can consist of up to five different stimulation parameters delivered sequentially. After each stimulation, the device tries to detect further epileptiform activity; it will deliver the next stimulation if such activity is present, or cease stimulation if there is no epileptiform discharge.

In a feasibility study of 65 patients, the system was deemed safe. In a preliminary analysis of 24 patients, the response rate (defined as a seizure reduction of at least 50%) was 43% for complex partial seizures and 35% for total disabling seizures, which included simple partial motor, complex partial, and secondarily generalized tonic-clonic seizures (Neurotherapeutics 2008;5:68–74).

NeuroPace is recruiting up to 240 patients with refractory partial-onset seizures for a randomized, sham-controlled trial of the system, with 2–3 years of follow-up. During the initial 4-month double-blinded phase, half of the patients will have the system turned on and half of them will have it remain off, after which all of the patients will receive stimulation.

MADRID — Deep brain stimulation shows considerable promise for reducing intractable seizures in patients who are not candidates for epilepsy surgery, even though there have been few large-scale controlled trials to back up the practice.

“We have no idea what the best stimulation parameters are, we don't know whether to stimulate in response to epileptiform activity or continuously, and, of course, the search for the optimal target is ongoing,” Dr. Paul Boon said at the annual congress of the European Federation of Neurological Societies. “Most of our information has come from uncontrolled studies and case reports, which included about 115 people worldwide.”

Now, data from three new or upcoming studies might help shed light on some of these questions, said Dr. Boon of University Hospital Ghent (Belgium), where he and his colleagues are leaders in researching an epilepsy application for DBS.

Some of the earliest studies, in the 1980s and early 1990s, used the electrodes in the brain's cerebellar regions, but with very little effect, so the cerebellum is no longer considered a target. The caudate nucleus and centromedial nucleus of the thalamus have also been examined as possible targets, but in very small numbers of patients and with varying results, said Dr. Boon.

The most promising approach to date is bilateral stimulation of the anterior thalamic nucleus, he said. Early uncontrolled studies of this application had small patient numbers, but their success led to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial of 110 patients with medically refractory partial-onset seizures.

All of the patients received the implants; for the first 3 months, only half of the patient had their stimulators turned on. After this blinded treatment phase, all of the patients received neurostimulation. The results are due to be presented at the American Epilepsy Society meeting in Seattle in December. By way of detailing his financial conflicts of interest, Dr. Boon said in an interview that Medtronic Inc., the company that makes DBS hardware, has been and is providing devices and electrodes in support of the pilot trial, and has provided an educational grant.

The medial temporal lobe and the hippocampus are other potential targets. Last year, Dr. Boon and his colleagues published a study of 12 patients with refractory temporal lobe epilepsy, who were also candidates for surgery. Instead of implanting recording electrodes during the presurgical period, they implanted DBS electrodes in the medial temporal lobe.

“We aimed to adjust the simulation parameters to get a 50% reduction in spikes for 7 consecutive days,” he said. “If the patient achieved that, then we went to chronic stimulation, and if they did not achieve that, then we adjusted the parameters until we met those criteria. If the patient still didn't achieve the reduction, then we removed the electrodes and proceeded to surgery.”

Of the 12 patients, 10 underwent long-term DBS, and 2 had the resection. After a mean follow-up of 31 months, both of the surgical patients were seizure free. One of the DBS patients had a seizure reduction of more than 90%; five had a reduction of at least 50%, and two had a reduction of 30%-40% (Epilepsia 2007;48:1551–60).

“We got a 70% response rate, with no significant adverse events or changes in memory,” he said. “This shows that DBS of the medial temporal lobe is safe, feasible, and effective.”

Dr. Boon and his group are also seeking to recruit 45 patients for an upcoming study in which they will compare DBS of the hippocampus with medial temporal lobe resection or with hippocampal DBS delayed for 6 months after implantation. The 1-year CoRaStiR (Controlled Randomized Stimulation Versus Resection) trial will also be sponsored by Medtronic.

Researchers believe that DBS controls seizures by desynchronizing synchronized high-voltage cortical discharges. During chronic DBS, the stimulation is applied constantly to the epileptogenic focus, regardless of the area's own discharge.

However, there is some evidence that stimulation only in response to epileptiform activity might be more effective. This “closed-loop” stimulation would require a device that could read and analyze brain waves and then “decide” what type of stimulation to deliver—a process that clearly presents a technological challenge.

Early external devices were tested in small numbers of patients in the late 1990s and early 2000s. More recently, a California-based company, NeuroPace Inc., has developed the RNS System, which includes fully implantable intracranial components as well as external products, he said.

The device consists of an implanted neurostimulator with one or two strip leads that can be placed in different areas of the brain to allow activity to be monitored and controlled. An external programming device allows the stimulator to detect predetermined electrographic patterns; the physician can also program the type of response that the device delivers.

A treatment can consist of up to five different stimulation parameters delivered sequentially. After each stimulation, the device tries to detect further epileptiform activity; it will deliver the next stimulation if such activity is present, or cease stimulation if there is no epileptiform discharge.

In a feasibility study of 65 patients, the system was deemed safe. In a preliminary analysis of 24 patients, the response rate (defined as a seizure reduction of at least 50%) was 43% for complex partial seizures and 35% for total disabling seizures, which included simple partial motor, complex partial, and secondarily generalized tonic-clonic seizures (Neurotherapeutics 2008;5:68–74).

NeuroPace is recruiting up to 240 patients with refractory partial-onset seizures for a randomized, sham-controlled trial of the system, with 2–3 years of follow-up. During the initial 4-month double-blinded phase, half of the patients will have the system turned on and half of them will have it remain off, after which all of the patients will receive stimulation.

MADRID — Deep brain stimulation shows considerable promise for reducing intractable seizures in patients who are not candidates for epilepsy surgery, even though there have been few large-scale controlled trials to back up the practice.

“We have no idea what the best stimulation parameters are, we don't know whether to stimulate in response to epileptiform activity or continuously, and, of course, the search for the optimal target is ongoing,” Dr. Paul Boon said at the annual congress of the European Federation of Neurological Societies. “Most of our information has come from uncontrolled studies and case reports, which included about 115 people worldwide.”

Now, data from three new or upcoming studies might help shed light on some of these questions, said Dr. Boon of University Hospital Ghent (Belgium), where he and his colleagues are leaders in researching an epilepsy application for DBS.

Some of the earliest studies, in the 1980s and early 1990s, used the electrodes in the brain's cerebellar regions, but with very little effect, so the cerebellum is no longer considered a target. The caudate nucleus and centromedial nucleus of the thalamus have also been examined as possible targets, but in very small numbers of patients and with varying results, said Dr. Boon.

The most promising approach to date is bilateral stimulation of the anterior thalamic nucleus, he said. Early uncontrolled studies of this application had small patient numbers, but their success led to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial of 110 patients with medically refractory partial-onset seizures.

All of the patients received the implants; for the first 3 months, only half of the patient had their stimulators turned on. After this blinded treatment phase, all of the patients received neurostimulation. The results are due to be presented at the American Epilepsy Society meeting in Seattle in December. By way of detailing his financial conflicts of interest, Dr. Boon said in an interview that Medtronic Inc., the company that makes DBS hardware, has been and is providing devices and electrodes in support of the pilot trial, and has provided an educational grant.

The medial temporal lobe and the hippocampus are other potential targets. Last year, Dr. Boon and his colleagues published a study of 12 patients with refractory temporal lobe epilepsy, who were also candidates for surgery. Instead of implanting recording electrodes during the presurgical period, they implanted DBS electrodes in the medial temporal lobe.

“We aimed to adjust the simulation parameters to get a 50% reduction in spikes for 7 consecutive days,” he said. “If the patient achieved that, then we went to chronic stimulation, and if they did not achieve that, then we adjusted the parameters until we met those criteria. If the patient still didn't achieve the reduction, then we removed the electrodes and proceeded to surgery.”

Of the 12 patients, 10 underwent long-term DBS, and 2 had the resection. After a mean follow-up of 31 months, both of the surgical patients were seizure free. One of the DBS patients had a seizure reduction of more than 90%; five had a reduction of at least 50%, and two had a reduction of 30%-40% (Epilepsia 2007;48:1551–60).

“We got a 70% response rate, with no significant adverse events or changes in memory,” he said. “This shows that DBS of the medial temporal lobe is safe, feasible, and effective.”

Dr. Boon and his group are also seeking to recruit 45 patients for an upcoming study in which they will compare DBS of the hippocampus with medial temporal lobe resection or with hippocampal DBS delayed for 6 months after implantation. The 1-year CoRaStiR (Controlled Randomized Stimulation Versus Resection) trial will also be sponsored by Medtronic.

Researchers believe that DBS controls seizures by desynchronizing synchronized high-voltage cortical discharges. During chronic DBS, the stimulation is applied constantly to the epileptogenic focus, regardless of the area's own discharge.

However, there is some evidence that stimulation only in response to epileptiform activity might be more effective. This “closed-loop” stimulation would require a device that could read and analyze brain waves and then “decide” what type of stimulation to deliver—a process that clearly presents a technological challenge.

Early external devices were tested in small numbers of patients in the late 1990s and early 2000s. More recently, a California-based company, NeuroPace Inc., has developed the RNS System, which includes fully implantable intracranial components as well as external products, he said.

The device consists of an implanted neurostimulator with one or two strip leads that can be placed in different areas of the brain to allow activity to be monitored and controlled. An external programming device allows the stimulator to detect predetermined electrographic patterns; the physician can also program the type of response that the device delivers.

A treatment can consist of up to five different stimulation parameters delivered sequentially. After each stimulation, the device tries to detect further epileptiform activity; it will deliver the next stimulation if such activity is present, or cease stimulation if there is no epileptiform discharge.

In a feasibility study of 65 patients, the system was deemed safe. In a preliminary analysis of 24 patients, the response rate (defined as a seizure reduction of at least 50%) was 43% for complex partial seizures and 35% for total disabling seizures, which included simple partial motor, complex partial, and secondarily generalized tonic-clonic seizures (Neurotherapeutics 2008;5:68–74).

NeuroPace is recruiting up to 240 patients with refractory partial-onset seizures for a randomized, sham-controlled trial of the system, with 2–3 years of follow-up. During the initial 4-month double-blinded phase, half of the patients will have the system turned on and half of them will have it remain off, after which all of the patients will receive stimulation.

MADRID — High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplant may be a promising new treatment option for multiple sclerosis, based on results that were obtained in a series of 56 Russian patients.

The treatment combination improved or stabilized the condition in 92% of the patients and resulted in long-term, progression-free survival in 83%, lead investigator Dr. Yury Shevchenko reported at the annual congress of the European Federation of Neurological Societies.

He presented full data for 48 patients, all of whom had 6–30 months of follow-up (mean of 19 months).

The patients' mean age was 32 years and their mean disease duration was 7 years. Of the 56 patients, 27 had secondary progressive disease, 10 had primary progressive, 18 had relapsing-remitting disease, and 1 had progressive-relapsing disease. Their mean EDSS (Expanded Disability Status Scale) score was 6.

All patients underwent the BEAM conditioning regimen before surgery. This regimen consisted of high-dose BCNU (carmustine) at 300 mg/m2 on day 6 before the stem cell transplant; etoposide at 200 mg/m2, cytarabine at 200 mg/m2 from day 5 to day 2 before transplant, and melphalan 140 mg/m2 on the day before transplant (Exp. Hematol. 2008;36:922–8).

Patients tolerated the conditioning and transplant very well, said Dr. Shevchenko of the Pirogov National Medical Surgical Center, Moscow.

Neutropenic fever occurred in 52%; thrombocytopenia in 50%; transient increases in liver enzymes in 46%; and enteritis in 18%. There were no transplant-related deaths.

Clinical improvement (defined as a decrease on the EDSS score of at least 0.5 points) occurred in 27 patients, and stabilization occurred in 17 patients, Dr. Shevchenko said. The published study noted that nine patients had “dramatic improvement.”

One patient with secondary progressive disease and another patient with relapsing-remitting disease worsened within 6 months of the transplant but then stabilized during follow-up.

MR imaging results were available for 37 patients. Of these, 16 had active lesions at baseline, and all of these became inactive during follow-up. Of the 21 patients without active lesions at baseline, 20 remained inactive and one developed an active lesion.

There was one death, the paper noted. This patient, with secondary progressive disease, deteriorated 12 months after transplantation. About 4 years after the procedure, she developed acute promyelocytic leukemia and died of a cerebral hemorrhage.

MADRID — High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplant may be a promising new treatment option for multiple sclerosis, based on results that were obtained in a series of 56 Russian patients.

The treatment combination improved or stabilized the condition in 92% of the patients and resulted in long-term, progression-free survival in 83%, lead investigator Dr. Yury Shevchenko reported at the annual congress of the European Federation of Neurological Societies.

He presented full data for 48 patients, all of whom had 6–30 months of follow-up (mean of 19 months).

The patients' mean age was 32 years and their mean disease duration was 7 years. Of the 56 patients, 27 had secondary progressive disease, 10 had primary progressive, 18 had relapsing-remitting disease, and 1 had progressive-relapsing disease. Their mean EDSS (Expanded Disability Status Scale) score was 6.

All patients underwent the BEAM conditioning regimen before surgery. This regimen consisted of high-dose BCNU (carmustine) at 300 mg/m2 on day 6 before the stem cell transplant; etoposide at 200 mg/m2, cytarabine at 200 mg/m2 from day 5 to day 2 before transplant, and melphalan 140 mg/m2 on the day before transplant (Exp. Hematol. 2008;36:922–8).

Patients tolerated the conditioning and transplant very well, said Dr. Shevchenko of the Pirogov National Medical Surgical Center, Moscow.

Neutropenic fever occurred in 52%; thrombocytopenia in 50%; transient increases in liver enzymes in 46%; and enteritis in 18%. There were no transplant-related deaths.

Clinical improvement (defined as a decrease on the EDSS score of at least 0.5 points) occurred in 27 patients, and stabilization occurred in 17 patients, Dr. Shevchenko said. The published study noted that nine patients had “dramatic improvement.”

One patient with secondary progressive disease and another patient with relapsing-remitting disease worsened within 6 months of the transplant but then stabilized during follow-up.

MR imaging results were available for 37 patients. Of these, 16 had active lesions at baseline, and all of these became inactive during follow-up. Of the 21 patients without active lesions at baseline, 20 remained inactive and one developed an active lesion.

There was one death, the paper noted. This patient, with secondary progressive disease, deteriorated 12 months after transplantation. About 4 years after the procedure, she developed acute promyelocytic leukemia and died of a cerebral hemorrhage.

MADRID — High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplant may be a promising new treatment option for multiple sclerosis, based on results that were obtained in a series of 56 Russian patients.

The treatment combination improved or stabilized the condition in 92% of the patients and resulted in long-term, progression-free survival in 83%, lead investigator Dr. Yury Shevchenko reported at the annual congress of the European Federation of Neurological Societies.

He presented full data for 48 patients, all of whom had 6–30 months of follow-up (mean of 19 months).

The patients' mean age was 32 years and their mean disease duration was 7 years. Of the 56 patients, 27 had secondary progressive disease, 10 had primary progressive, 18 had relapsing-remitting disease, and 1 had progressive-relapsing disease. Their mean EDSS (Expanded Disability Status Scale) score was 6.

All patients underwent the BEAM conditioning regimen before surgery. This regimen consisted of high-dose BCNU (carmustine) at 300 mg/m2 on day 6 before the stem cell transplant; etoposide at 200 mg/m2, cytarabine at 200 mg/m2 from day 5 to day 2 before transplant, and melphalan 140 mg/m2 on the day before transplant (Exp. Hematol. 2008;36:922–8).

Patients tolerated the conditioning and transplant very well, said Dr. Shevchenko of the Pirogov National Medical Surgical Center, Moscow.

Neutropenic fever occurred in 52%; thrombocytopenia in 50%; transient increases in liver enzymes in 46%; and enteritis in 18%. There were no transplant-related deaths.

Clinical improvement (defined as a decrease on the EDSS score of at least 0.5 points) occurred in 27 patients, and stabilization occurred in 17 patients, Dr. Shevchenko said. The published study noted that nine patients had “dramatic improvement.”

One patient with secondary progressive disease and another patient with relapsing-remitting disease worsened within 6 months of the transplant but then stabilized during follow-up.

MR imaging results were available for 37 patients. Of these, 16 had active lesions at baseline, and all of these became inactive during follow-up. Of the 21 patients without active lesions at baseline, 20 remained inactive and one developed an active lesion.

There was one death, the paper noted. This patient, with secondary progressive disease, deteriorated 12 months after transplantation. About 4 years after the procedure, she developed acute promyelocytic leukemia and died of a cerebral hemorrhage.

The first family-based genome-wide association study for Alzheimer's disease has identified four new genes that may significantly affect the risk of developing the disease.

The gene with the strongest association lies on chromosome 14, not far from the early-onset familial Alzheimer's gene presenilin-1, Dr. Rudolph Tanzi said in an interview. “What we don't know yet, is whether this is a coincidence or whether there is some interaction going on with that gene.”

Dr. Tanzi, director of the Massachusetts General Hospital's genetics and aging research unit in Boston, and his coinvestigators published the results of their study in the November issue of the American Journal of Human Genetics (doi:10.1016/j.ajhg.2008.10.008

The initial portion of the study included a genome-wide screen of more than 1,400 DNA samples taken from 410 families with at least three Alzheimer's-affected members. This analysis revealed five candidate genes: one closely linked to the apolipoprotein E gene, variations of which are associated with late-onset Alzheimer's, and four previously unknown single nucleotide polymorphisms (SNPs), said Dr. Tanzi. “We took these top hits and screened another 900 families for them, and after correcting for all the possible variables, we still had overall genome-wide significance with all of them, with the best hit in the novel chromosome 14 gene.”

The second-best associated gene is involved in innate immune response. “This was quite a surprise, to see a gene involved with response to bacterial and viral infection implicated in Alzheimer's,” Dr. Tanzi said. “This now has us thinking more about the possible role of infection in Alzheimer's etiology.”

The third novel SNP resides in the gene that causes spinocerebellar ataxia, a neurodegenerative movement disorder. “Although none of our Alzheimer's samples had spinocerebellar ataxia, the location of this gene near the cause of another neurodegenerative disease is interesting. Perhaps a different mutation in this gene might cause Alzheimer's,” Dr. Tanzi said.

The final SNP is located in a gene for a synaptic protein—a logical association given the role of synaptic dysfunction in AD.

At this point, it's impossible to predict the extent of influence these genetic variants may confer on Alzheimer's risk, he said. “We refrain from making a big deal about odds ratios in family studies, because those numbers are only specific to those families—the odds ratio in the population at large could be less impressive. But if I had to guess, for our best hit I'd say it might end up to be a doubling of risk in the general population.”

The next step will be replication studies from other researchers, he said. He doesn't expect anyone to come up with a complete match for his team's conclusions. “In Alzheimer's, there's so much heterogeneity that when you test in case-control studies, you might not see an association even if it's there. It will probably be a mixed bag.”

The study opens a new door in genetic research for Alzheimer's, Dr. Tanzi said. New genome chips capable of scanning almost the entire code at once are taking some of the guesswork out of genetic studies. “Much of what we have done in the past is look for variants in a gene that we picked based on a favorite hypothesis. This adds an element of bias to your results. The beauty of this is that these results are totally unbiased. With the gene chip, you just see what falls out as significant and wait to be surprised.”

Dr. Tanzi's lab has been involved in genetic analysis of Alzheimer's disease since the 1980s, codiscovering all three early-onset genes out of the four total genes that are known for the disease. “We also learned that the four genes only account for 30% of the genetics of Alzheimer's disease,” while twin studies suggest that at least 80% of cases involve some inherited factor. “Look at how much we've learned with only 30% of the genetics solved and imagine what we could learn if we knew the other 70%.”

The first family-based genome-wide association study for Alzheimer's disease has identified four new genes that may significantly affect the risk of developing the disease.

The gene with the strongest association lies on chromosome 14, not far from the early-onset familial Alzheimer's gene presenilin-1, Dr. Rudolph Tanzi said in an interview. “What we don't know yet, is whether this is a coincidence or whether there is some interaction going on with that gene.”

Dr. Tanzi, director of the Massachusetts General Hospital's genetics and aging research unit in Boston, and his coinvestigators published the results of their study in the November issue of the American Journal of Human Genetics (doi:10.1016/j.ajhg.2008.10.008

The initial portion of the study included a genome-wide screen of more than 1,400 DNA samples taken from 410 families with at least three Alzheimer's-affected members. This analysis revealed five candidate genes: one closely linked to the apolipoprotein E gene, variations of which are associated with late-onset Alzheimer's, and four previously unknown single nucleotide polymorphisms (SNPs), said Dr. Tanzi. “We took these top hits and screened another 900 families for them, and after correcting for all the possible variables, we still had overall genome-wide significance with all of them, with the best hit in the novel chromosome 14 gene.”

The second-best associated gene is involved in innate immune response. “This was quite a surprise, to see a gene involved with response to bacterial and viral infection implicated in Alzheimer's,” Dr. Tanzi said. “This now has us thinking more about the possible role of infection in Alzheimer's etiology.”

The third novel SNP resides in the gene that causes spinocerebellar ataxia, a neurodegenerative movement disorder. “Although none of our Alzheimer's samples had spinocerebellar ataxia, the location of this gene near the cause of another neurodegenerative disease is interesting. Perhaps a different mutation in this gene might cause Alzheimer's,” Dr. Tanzi said.

The final SNP is located in a gene for a synaptic protein—a logical association given the role of synaptic dysfunction in AD.

At this point, it's impossible to predict the extent of influence these genetic variants may confer on Alzheimer's risk, he said. “We refrain from making a big deal about odds ratios in family studies, because those numbers are only specific to those families—the odds ratio in the population at large could be less impressive. But if I had to guess, for our best hit I'd say it might end up to be a doubling of risk in the general population.”

The next step will be replication studies from other researchers, he said. He doesn't expect anyone to come up with a complete match for his team's conclusions. “In Alzheimer's, there's so much heterogeneity that when you test in case-control studies, you might not see an association even if it's there. It will probably be a mixed bag.”

The study opens a new door in genetic research for Alzheimer's, Dr. Tanzi said. New genome chips capable of scanning almost the entire code at once are taking some of the guesswork out of genetic studies. “Much of what we have done in the past is look for variants in a gene that we picked based on a favorite hypothesis. This adds an element of bias to your results. The beauty of this is that these results are totally unbiased. With the gene chip, you just see what falls out as significant and wait to be surprised.”

Dr. Tanzi's lab has been involved in genetic analysis of Alzheimer's disease since the 1980s, codiscovering all three early-onset genes out of the four total genes that are known for the disease. “We also learned that the four genes only account for 30% of the genetics of Alzheimer's disease,” while twin studies suggest that at least 80% of cases involve some inherited factor. “Look at how much we've learned with only 30% of the genetics solved and imagine what we could learn if we knew the other 70%.”

The first family-based genome-wide association study for Alzheimer's disease has identified four new genes that may significantly affect the risk of developing the disease.

The gene with the strongest association lies on chromosome 14, not far from the early-onset familial Alzheimer's gene presenilin-1, Dr. Rudolph Tanzi said in an interview. “What we don't know yet, is whether this is a coincidence or whether there is some interaction going on with that gene.”

Dr. Tanzi, director of the Massachusetts General Hospital's genetics and aging research unit in Boston, and his coinvestigators published the results of their study in the November issue of the American Journal of Human Genetics (doi:10.1016/j.ajhg.2008.10.008

The initial portion of the study included a genome-wide screen of more than 1,400 DNA samples taken from 410 families with at least three Alzheimer's-affected members. This analysis revealed five candidate genes: one closely linked to the apolipoprotein E gene, variations of which are associated with late-onset Alzheimer's, and four previously unknown single nucleotide polymorphisms (SNPs), said Dr. Tanzi. “We took these top hits and screened another 900 families for them, and after correcting for all the possible variables, we still had overall genome-wide significance with all of them, with the best hit in the novel chromosome 14 gene.”

The second-best associated gene is involved in innate immune response. “This was quite a surprise, to see a gene involved with response to bacterial and viral infection implicated in Alzheimer's,” Dr. Tanzi said. “This now has us thinking more about the possible role of infection in Alzheimer's etiology.”

The third novel SNP resides in the gene that causes spinocerebellar ataxia, a neurodegenerative movement disorder. “Although none of our Alzheimer's samples had spinocerebellar ataxia, the location of this gene near the cause of another neurodegenerative disease is interesting. Perhaps a different mutation in this gene might cause Alzheimer's,” Dr. Tanzi said.

The final SNP is located in a gene for a synaptic protein—a logical association given the role of synaptic dysfunction in AD.

At this point, it's impossible to predict the extent of influence these genetic variants may confer on Alzheimer's risk, he said. “We refrain from making a big deal about odds ratios in family studies, because those numbers are only specific to those families—the odds ratio in the population at large could be less impressive. But if I had to guess, for our best hit I'd say it might end up to be a doubling of risk in the general population.”

The next step will be replication studies from other researchers, he said. He doesn't expect anyone to come up with a complete match for his team's conclusions. “In Alzheimer's, there's so much heterogeneity that when you test in case-control studies, you might not see an association even if it's there. It will probably be a mixed bag.”

The study opens a new door in genetic research for Alzheimer's, Dr. Tanzi said. New genome chips capable of scanning almost the entire code at once are taking some of the guesswork out of genetic studies. “Much of what we have done in the past is look for variants in a gene that we picked based on a favorite hypothesis. This adds an element of bias to your results. The beauty of this is that these results are totally unbiased. With the gene chip, you just see what falls out as significant and wait to be surprised.”

Dr. Tanzi's lab has been involved in genetic analysis of Alzheimer's disease since the 1980s, codiscovering all three early-onset genes out of the four total genes that are known for the disease. “We also learned that the four genes only account for 30% of the genetics of Alzheimer's disease,” while twin studies suggest that at least 80% of cases involve some inherited factor. “Look at how much we've learned with only 30% of the genetics solved and imagine what we could learn if we knew the other 70%.”

BOSTON — Rapid in-office testing for infectious diseases can help physicians get the right drug on board as quickly as possible, and cut down on unnecessary testing and inappropriate antibiotics.

“I really do believe that having the diagnosis in real time can affect clinical decision making,” Dr. Leonard Krilov said at the annual meeting of the American Academy of Pediatrics. “For instance, with rapid influenza testing, it's been shown that doctors who have a confirmed diagnosis from a rapid flu test order less unnecessary tests, fewer radiographs, and give out less antibiotics and more antiviral drugs.”

The only diagnostic tests approved for use in the office setting are those that have been waived by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) law.

Waived tests are defined as simple laboratory examinations and procedures that are cleared by the Food and Drug Administration for home use; employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible; and pose no reasonable risk of harm to the patient if it's performed incorrectly.

The most common in-office tests for infectious diseases include those for group A streptococcus (GAS), influenza, respiratory syncytial virus (RSV), mononucleosis, and human immunodeficiency virus (HIV), said Dr. Krilov, chief of pediatric infectious diseases at Winthrop University Hospital, Mineola, N.Y.

There are 35 CLIA-waived tests for GAS, with varying ranges of sensitivity and specificity.

“Overall, the tests are very specific, ranging from 85% to 100%, but the concern is that the sensitivity is quite variable and can be as low as 62%,” Dr. Krilov reported.

Because of this, a negative test always requires a backup throat culture for confirmation. On the other hand, “If you get a positive test, you can believe it. There's no need for a culture,” he said.

However, even a positive test doesn't mean that the presenting symptoms are because of GAS pharyngitis.

“Recovery of group A strep from the pharynx doesn't necessarily distinguish true infection from carriers who might happen to have a coincidental viral pharyngitis. You can't completely rely on the test—you have to be able to interpret the clinical picture as well,” Dr. Krilov explained.

Of the 15 rapid influenza tests available, 3 are waived for office use; they all yield results in about 30 minutes. Although they are highly specific (90%–95%), the sensitivity isn't great (70%–75%), Dr. Krilov said.

Because of this, he continued, “successfully using these is somewhat dependent on the time of year and the likelihood of influenza infection in your community. False positives and true negatives are more likely if prevalence is low, but false negatives and true positives are more likely in the midst of an epidemic. But in the right time of winter, with the right clinical picture, a positive test is both believable and important.”

Accuracy also depends on when during the course of illness testing occurs. In children, most of the viral shedding occurs in the first 48 hours.

The quality of the specimen is very important as well, Dr. Krilov noted. “The more secretions you get, the more cell material you get, so a nasal wash or aspirate is probably better than a nasopharyngeal swab.”

Especially in light of the continued emergence of antibiotic-resistant bacteria, an early, certain diagnosis of viral illness can significantly decrease inappropriate antibiotic prescribing, Dr. Krilov said. A 2003 study enrolled 391 patients with symptoms of influenza; all had a rapid flu test done in the hospital. Half of the referring physicians were given the results; these doctors ordered significantly fewer lab tests and x-rays and prescribed significantly fewer antibiotics than physicians who didn't know the diagnosis.

Additionally, Dr. Krilov reported, treatment costs and hospital length of stay were significantly lower for patients whose diagnosis was known; the rate of antiviral prescriptions given to these patients also was significantly higher than for those whose diagnosis was not known (Pediatrics 2003;112:363–7).

Most testing for RSV is done in the hospital, but one test is available for office use. It detects RSV fusion protein, and results are available in 15 minutes. The kit has a sensitivity of up to 88% and specificity of up to 100%.

“Again, if it's winter and RSV is in the community, you can believe a positive result,” he said. “It might be useful in how you monitor the patient, and it's very helpful in preventing unnecessary antibiotic use. But I'm not sure it helps much with family education or helps you make any decision about admission.”

Monospot is the only CLIA-waived test for mononucleosis. Again, accuracy depends on timing, Dr. Krilov said. “A negative test in the first week of illness does not mean they don't have the disease. Typically it isn't until the second week of illness that the heterophile antibodies are made, and they can persist for 6 months or more. So using this test to follow the course of disease, or as a way of determining when the kids can go back to school and sports, is not worthwhile.”

Children younger than 6 years may not even make the heterophile antibodies, so a negative test on a young child shouldn't affect clinical decision-making, Dr. Krilov said. “The antibodies are detected in up to 85% of older kids and adolescents, but [in] 40% or less of those younger than 4 years. If you have a patient of the appropriate age and the appropriate symptoms, and the test is negative, you can treat it as early disease and test again in 1–2 weeks. Or you have the option of sending to the lab for specific serology.”

Dr. Krilov also touched on the issue of in-office HIV testing. Two CLIA-waived kits are available and give results in 20 minutes. “I think it's useful in some clinical settings, since it allows more people to be tested. At present, we estimate that up to 280,000 people in the U.S. are unaware that they have an HIV infection. The bad news is they don't give a complete diagnostics, so a positive test always has to be confirmed by the Western blot analysis, and a false positive can create a lot of anxiety. The other part of HIV testing is, if you do the test, it needs to be done in conjunction with counseling and hooking patients into appropriate follow-up.”

BOSTON — Rapid in-office testing for infectious diseases can help physicians get the right drug on board as quickly as possible, and cut down on unnecessary testing and inappropriate antibiotics.

“I really do believe that having the diagnosis in real time can affect clinical decision making,” Dr. Leonard Krilov said at the annual meeting of the American Academy of Pediatrics. “For instance, with rapid influenza testing, it's been shown that doctors who have a confirmed diagnosis from a rapid flu test order less unnecessary tests, fewer radiographs, and give out less antibiotics and more antiviral drugs.”

The only diagnostic tests approved for use in the office setting are those that have been waived by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) law.

Waived tests are defined as simple laboratory examinations and procedures that are cleared by the Food and Drug Administration for home use; employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible; and pose no reasonable risk of harm to the patient if it's performed incorrectly.

The most common in-office tests for infectious diseases include those for group A streptococcus (GAS), influenza, respiratory syncytial virus (RSV), mononucleosis, and human immunodeficiency virus (HIV), said Dr. Krilov, chief of pediatric infectious diseases at Winthrop University Hospital, Mineola, N.Y.

There are 35 CLIA-waived tests for GAS, with varying ranges of sensitivity and specificity.

“Overall, the tests are very specific, ranging from 85% to 100%, but the concern is that the sensitivity is quite variable and can be as low as 62%,” Dr. Krilov reported.

Because of this, a negative test always requires a backup throat culture for confirmation. On the other hand, “If you get a positive test, you can believe it. There's no need for a culture,” he said.

However, even a positive test doesn't mean that the presenting symptoms are because of GAS pharyngitis.

“Recovery of group A strep from the pharynx doesn't necessarily distinguish true infection from carriers who might happen to have a coincidental viral pharyngitis. You can't completely rely on the test—you have to be able to interpret the clinical picture as well,” Dr. Krilov explained.

Of the 15 rapid influenza tests available, 3 are waived for office use; they all yield results in about 30 minutes. Although they are highly specific (90%–95%), the sensitivity isn't great (70%–75%), Dr. Krilov said.

Because of this, he continued, “successfully using these is somewhat dependent on the time of year and the likelihood of influenza infection in your community. False positives and true negatives are more likely if prevalence is low, but false negatives and true positives are more likely in the midst of an epidemic. But in the right time of winter, with the right clinical picture, a positive test is both believable and important.”

Accuracy also depends on when during the course of illness testing occurs. In children, most of the viral shedding occurs in the first 48 hours.

The quality of the specimen is very important as well, Dr. Krilov noted. “The more secretions you get, the more cell material you get, so a nasal wash or aspirate is probably better than a nasopharyngeal swab.”

Especially in light of the continued emergence of antibiotic-resistant bacteria, an early, certain diagnosis of viral illness can significantly decrease inappropriate antibiotic prescribing, Dr. Krilov said. A 2003 study enrolled 391 patients with symptoms of influenza; all had a rapid flu test done in the hospital. Half of the referring physicians were given the results; these doctors ordered significantly fewer lab tests and x-rays and prescribed significantly fewer antibiotics than physicians who didn't know the diagnosis.

Additionally, Dr. Krilov reported, treatment costs and hospital length of stay were significantly lower for patients whose diagnosis was known; the rate of antiviral prescriptions given to these patients also was significantly higher than for those whose diagnosis was not known (Pediatrics 2003;112:363–7).

Most testing for RSV is done in the hospital, but one test is available for office use. It detects RSV fusion protein, and results are available in 15 minutes. The kit has a sensitivity of up to 88% and specificity of up to 100%.

“Again, if it's winter and RSV is in the community, you can believe a positive result,” he said. “It might be useful in how you monitor the patient, and it's very helpful in preventing unnecessary antibiotic use. But I'm not sure it helps much with family education or helps you make any decision about admission.”

Monospot is the only CLIA-waived test for mononucleosis. Again, accuracy depends on timing, Dr. Krilov said. “A negative test in the first week of illness does not mean they don't have the disease. Typically it isn't until the second week of illness that the heterophile antibodies are made, and they can persist for 6 months or more. So using this test to follow the course of disease, or as a way of determining when the kids can go back to school and sports, is not worthwhile.”

Children younger than 6 years may not even make the heterophile antibodies, so a negative test on a young child shouldn't affect clinical decision-making, Dr. Krilov said. “The antibodies are detected in up to 85% of older kids and adolescents, but [in] 40% or less of those younger than 4 years. If you have a patient of the appropriate age and the appropriate symptoms, and the test is negative, you can treat it as early disease and test again in 1–2 weeks. Or you have the option of sending to the lab for specific serology.”

Dr. Krilov also touched on the issue of in-office HIV testing. Two CLIA-waived kits are available and give results in 20 minutes. “I think it's useful in some clinical settings, since it allows more people to be tested. At present, we estimate that up to 280,000 people in the U.S. are unaware that they have an HIV infection. The bad news is they don't give a complete diagnostics, so a positive test always has to be confirmed by the Western blot analysis, and a false positive can create a lot of anxiety. The other part of HIV testing is, if you do the test, it needs to be done in conjunction with counseling and hooking patients into appropriate follow-up.”

BOSTON — Rapid in-office testing for infectious diseases can help physicians get the right drug on board as quickly as possible, and cut down on unnecessary testing and inappropriate antibiotics.

“I really do believe that having the diagnosis in real time can affect clinical decision making,” Dr. Leonard Krilov said at the annual meeting of the American Academy of Pediatrics. “For instance, with rapid influenza testing, it's been shown that doctors who have a confirmed diagnosis from a rapid flu test order less unnecessary tests, fewer radiographs, and give out less antibiotics and more antiviral drugs.”

The only diagnostic tests approved for use in the office setting are those that have been waived by the Clinical Laboratory Improvement Amendments of 1988 (CLIA) law.

Waived tests are defined as simple laboratory examinations and procedures that are cleared by the Food and Drug Administration for home use; employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible; and pose no reasonable risk of harm to the patient if it's performed incorrectly.

The most common in-office tests for infectious diseases include those for group A streptococcus (GAS), influenza, respiratory syncytial virus (RSV), mononucleosis, and human immunodeficiency virus (HIV), said Dr. Krilov, chief of pediatric infectious diseases at Winthrop University Hospital, Mineola, N.Y.

There are 35 CLIA-waived tests for GAS, with varying ranges of sensitivity and specificity.

“Overall, the tests are very specific, ranging from 85% to 100%, but the concern is that the sensitivity is quite variable and can be as low as 62%,” Dr. Krilov reported.

Because of this, a negative test always requires a backup throat culture for confirmation. On the other hand, “If you get a positive test, you can believe it. There's no need for a culture,” he said.

However, even a positive test doesn't mean that the presenting symptoms are because of GAS pharyngitis.

“Recovery of group A strep from the pharynx doesn't necessarily distinguish true infection from carriers who might happen to have a coincidental viral pharyngitis. You can't completely rely on the test—you have to be able to interpret the clinical picture as well,” Dr. Krilov explained.

Of the 15 rapid influenza tests available, 3 are waived for office use; they all yield results in about 30 minutes. Although they are highly specific (90%–95%), the sensitivity isn't great (70%–75%), Dr. Krilov said.

Because of this, he continued, “successfully using these is somewhat dependent on the time of year and the likelihood of influenza infection in your community. False positives and true negatives are more likely if prevalence is low, but false negatives and true positives are more likely in the midst of an epidemic. But in the right time of winter, with the right clinical picture, a positive test is both believable and important.”

Accuracy also depends on when during the course of illness testing occurs. In children, most of the viral shedding occurs in the first 48 hours.

The quality of the specimen is very important as well, Dr. Krilov noted. “The more secretions you get, the more cell material you get, so a nasal wash or aspirate is probably better than a nasopharyngeal swab.”

Especially in light of the continued emergence of antibiotic-resistant bacteria, an early, certain diagnosis of viral illness can significantly decrease inappropriate antibiotic prescribing, Dr. Krilov said. A 2003 study enrolled 391 patients with symptoms of influenza; all had a rapid flu test done in the hospital. Half of the referring physicians were given the results; these doctors ordered significantly fewer lab tests and x-rays and prescribed significantly fewer antibiotics than physicians who didn't know the diagnosis.

Additionally, Dr. Krilov reported, treatment costs and hospital length of stay were significantly lower for patients whose diagnosis was known; the rate of antiviral prescriptions given to these patients also was significantly higher than for those whose diagnosis was not known (Pediatrics 2003;112:363–7).

Most testing for RSV is done in the hospital, but one test is available for office use. It detects RSV fusion protein, and results are available in 15 minutes. The kit has a sensitivity of up to 88% and specificity of up to 100%.

“Again, if it's winter and RSV is in the community, you can believe a positive result,” he said. “It might be useful in how you monitor the patient, and it's very helpful in preventing unnecessary antibiotic use. But I'm not sure it helps much with family education or helps you make any decision about admission.”

Monospot is the only CLIA-waived test for mononucleosis. Again, accuracy depends on timing, Dr. Krilov said. “A negative test in the first week of illness does not mean they don't have the disease. Typically it isn't until the second week of illness that the heterophile antibodies are made, and they can persist for 6 months or more. So using this test to follow the course of disease, or as a way of determining when the kids can go back to school and sports, is not worthwhile.”

Children younger than 6 years may not even make the heterophile antibodies, so a negative test on a young child shouldn't affect clinical decision-making, Dr. Krilov said. “The antibodies are detected in up to 85% of older kids and adolescents, but [in] 40% or less of those younger than 4 years. If you have a patient of the appropriate age and the appropriate symptoms, and the test is negative, you can treat it as early disease and test again in 1–2 weeks. Or you have the option of sending to the lab for specific serology.”

Dr. Krilov also touched on the issue of in-office HIV testing. Two CLIA-waived kits are available and give results in 20 minutes. “I think it's useful in some clinical settings, since it allows more people to be tested. At present, we estimate that up to 280,000 people in the U.S. are unaware that they have an HIV infection. The bad news is they don't give a complete diagnostics, so a positive test always has to be confirmed by the Western blot analysis, and a false positive can create a lot of anxiety. The other part of HIV testing is, if you do the test, it needs to be done in conjunction with counseling and hooking patients into appropriate follow-up.”