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Acetyl-l-Carnitine Yields Mixed Results for Chemo-Induced Neuropathy
CHICAGO – The impact of acetyl-l-carnitine on chemotherapy-induced peripheral neuropathy may depend largely on the clinical context and patient population, a pair of phase III trials suggests.
Acetyl-l-carnitine (ALC), a natural substance marketed over the counter as a dietary supplement, is popular among cancer patients as a result of preclinical and early-phase data in chemotherapy-related neuropathy and also a study in patients with diabetes-related peripheral neuropathy.
But in a trial among 409 U.S. women receiving adjuvant chemotherapy for breast cancer, those who took ALC not only had no decrease in the development of peripheral neuropathy symptoms relative to peers who were given a placebo, but actually had an increase. And they had a higher rate of serious neuropathy, too.
In contrast, in a trial among more than 200 Chinese patients with various cancers who had peripheral neuropathy from previous chemotherapy, those who took ALC were more likely than those who took a placebo to have an improvement of at least one grade in their neuropathy. They also were more likely to have improvements in fatigue and strength.
Taken together, the two trials, which were reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology, provide yet another cautionary lesson on the complexity of combining conventional and complementary therapies.
"The use of ALC for prevention is not recommended, and I would say, based on [these results], should be cautioned against. It will be interesting to see the carnitine data and to understand, as much as possible, why the trial was negative," commented Debra L. Barton, Ph.D., of the Mayo Clinic in Rochester, Minn., who was invited to discuss the research. "Further studies are needed to really understand if ALC should be used to treat peripheral neuropathy."
ALC for Prevention of Peripheral Neuropathy
In the first trial, Southwest Oncology Group (SWOG) protocol S0715, investigators led by Dr. Dawn L. Hershman randomized women receiving adjuvant taxane chemotherapy for early breast cancer evenly to either oral ALC 1,000 mg three times daily or matching placebo, for 24 weeks.
Compared with their counterparts in the placebo group, women in the ALC group were more likely to have a greater than 5-point adjusted decrease on the neurotoxicity subscale of the Functional Assessment of Cancer Therapy–Taxane (FACT-NTX) instrument at 12 weeks (odds ratio, 1.48; P = .08) and also at 24 weeks (38% vs. 28%; OR, 1.57; P = .05).
This magnitude of worsening is clinically meaningful, maintained Dr. Hershman of Columbia University in New York, "so this is not like a lot of studies where you find a statistically significant difference that’s not clinically meaningful."
In addition, the incidence of grade 3/4 neurotoxicity was 3.8% with ALC, much higher than the 0.5% seen with placebo.
Patients in the ALC group also had scores on the FACT trial outcome index subscale (FACT-TOI), an overall measure of function, that were on average 3.5 points lower (worse) than those among their placebo counterparts (P = .03). There were no significant differences between groups in terms of fatigue and other toxicities.
The investigators have collected biosamples and will be assessing potential biological correlates with peripheral neuropathy outcomes, according to Dr. Hershman.
"We are looking at DNA, oxidative stress, and carnitine levels to better understand the mechanisms of chemotherapy-induced peripheral neuropathy to begin with, because there is not a whole lot known in terms of mechanism," she said. "If we can figure out what makes people worse, then we will maybe be able to figure out how to make people better from a more mechanistic standpoint, because there are very few drugs to treat chemotherapy-induced peripheral neuropathy."
An obvious concern from the trial’s findings is that ALC may somehow potentiate the neurotoxic effects of taxanes. "Based on these data, physicians should be telling patients not to take ALC during adjuvant chemotherapy," Dr. Hershman concluded. "You need to talk to patients. We know from the literature that overwhelmingly large number of patients take supplements during chemotherapy and afterward, many of which have not been tested. It’s important to get that history from patients."
Dr. Barton, the discussant, praised the trial’s rigorous methodology and proposed that there may have been several reasons for the lack of ALC benefit in preventing neuropathy, despite compelling earlier data.
Previous prevention research was done in animals and thus may not translate to humans, she said. And a positive trial for treatment in humans used intravenous administration, which may result in different bioavailability. Finally, "ALC capsules needed to be taken three times a day, and they are rather large, and these patients were, after all, on chemotherapy. They were likely nauseated [and] dyspeptic, and taking what some might call a horse pill three times a day could not have been an easy task. The study did use pill diaries, but we know those aren’t a perfect tool for adherence."
"The great thing is that the study collected blood and they are able to look at carnitine levels," Dr. Barton said. "So if carnitine is up in the group that got acetyl-carnitine and not in the group that got placebo, well, I think that pretty much confirms that this just didn’t work."
ALC for Treatment of Peripheral Neuropathy
In the second trial, protocol ZHAOKE-2007L03540, investigators led by Dr. Yuanjue Sun of the Sixth Affiliated Hospital of Shanghai (China) Jiao Tong University, enrolled 239 patients who had cancer of various types and stages, had completed chemotherapy, and had had at least grade 2 peripheral neuropathy for up to 6 months.
They were randomly assigned to receive either oral ALC at a dose of 3 g/day or matching placebo, for 8 weeks, with outcomes assessed at clinic visits or by telephone.
Analyses showed that compared with their counterparts in the placebo group, patients in the ALC group were more likely to have had an improvement of at least one grade in their neuropathy, both at 8 weeks (51% vs. 24%; P less than .001) and at 12 weeks (58% vs. 40%; P less than .001).
In terms of secondary outcomes, the ALC group was also more likely to have had an improvement in cancer-related fatigue (31% vs. 20%; P = .048), physical strength (29% vs. 13%; P = .02), and electrophysiology in peripheral nerves (75% vs. 58%; P = .02).
The two groups had statistically indistinguishable rates of adverse events (20% vs. 15%) and adverse reactions (6% vs. 5%). The most common events were gastrointestinal ones and skin allergies.
"This is the first time to confirm that ALC has a positive effect to cure chemotherapy-induced peripheral neuropathy in the Chinese population," Dr. Sun commented through a translator.
"I think the very important thing for this trial is, it is a different kind of patient population. Before this, most clinical trials were performed in [whites] or maybe Americans. This is an only-Asian [population]," he noted, and it is possible that there are genetic differences in how ALC is metabolized.
Dr. Barton, the discussant, took a cautionary view, saying that "there are some things to consider before going out and telling patients to consider acetyl-carnitine for their peripheral neuropathy."
It was unclear from the results reported whether the two treatment groups were well balanced and what criteria were used to define improvement for the secondary outcomes, she noted. Additionally, "outcome measures were all provider graded, [and there were] no self-report measures, so it is difficult to understand the impact of treatment on symptoms, particularly from the patient perspective," she noted.
Dr. Hershman, Dr. Sun, and Dr. Barton disclosed no relevant conflicts of interest; the ZHAOKE-2007L03540 trial was sponsored by Lee’s Pharmaceutical Limited.
CHICAGO – The impact of acetyl-l-carnitine on chemotherapy-induced peripheral neuropathy may depend largely on the clinical context and patient population, a pair of phase III trials suggests.
Acetyl-l-carnitine (ALC), a natural substance marketed over the counter as a dietary supplement, is popular among cancer patients as a result of preclinical and early-phase data in chemotherapy-related neuropathy and also a study in patients with diabetes-related peripheral neuropathy.
But in a trial among 409 U.S. women receiving adjuvant chemotherapy for breast cancer, those who took ALC not only had no decrease in the development of peripheral neuropathy symptoms relative to peers who were given a placebo, but actually had an increase. And they had a higher rate of serious neuropathy, too.
In contrast, in a trial among more than 200 Chinese patients with various cancers who had peripheral neuropathy from previous chemotherapy, those who took ALC were more likely than those who took a placebo to have an improvement of at least one grade in their neuropathy. They also were more likely to have improvements in fatigue and strength.
Taken together, the two trials, which were reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology, provide yet another cautionary lesson on the complexity of combining conventional and complementary therapies.
"The use of ALC for prevention is not recommended, and I would say, based on [these results], should be cautioned against. It will be interesting to see the carnitine data and to understand, as much as possible, why the trial was negative," commented Debra L. Barton, Ph.D., of the Mayo Clinic in Rochester, Minn., who was invited to discuss the research. "Further studies are needed to really understand if ALC should be used to treat peripheral neuropathy."
ALC for Prevention of Peripheral Neuropathy
In the first trial, Southwest Oncology Group (SWOG) protocol S0715, investigators led by Dr. Dawn L. Hershman randomized women receiving adjuvant taxane chemotherapy for early breast cancer evenly to either oral ALC 1,000 mg three times daily or matching placebo, for 24 weeks.
Compared with their counterparts in the placebo group, women in the ALC group were more likely to have a greater than 5-point adjusted decrease on the neurotoxicity subscale of the Functional Assessment of Cancer Therapy–Taxane (FACT-NTX) instrument at 12 weeks (odds ratio, 1.48; P = .08) and also at 24 weeks (38% vs. 28%; OR, 1.57; P = .05).
This magnitude of worsening is clinically meaningful, maintained Dr. Hershman of Columbia University in New York, "so this is not like a lot of studies where you find a statistically significant difference that’s not clinically meaningful."
In addition, the incidence of grade 3/4 neurotoxicity was 3.8% with ALC, much higher than the 0.5% seen with placebo.
Patients in the ALC group also had scores on the FACT trial outcome index subscale (FACT-TOI), an overall measure of function, that were on average 3.5 points lower (worse) than those among their placebo counterparts (P = .03). There were no significant differences between groups in terms of fatigue and other toxicities.
The investigators have collected biosamples and will be assessing potential biological correlates with peripheral neuropathy outcomes, according to Dr. Hershman.
"We are looking at DNA, oxidative stress, and carnitine levels to better understand the mechanisms of chemotherapy-induced peripheral neuropathy to begin with, because there is not a whole lot known in terms of mechanism," she said. "If we can figure out what makes people worse, then we will maybe be able to figure out how to make people better from a more mechanistic standpoint, because there are very few drugs to treat chemotherapy-induced peripheral neuropathy."
An obvious concern from the trial’s findings is that ALC may somehow potentiate the neurotoxic effects of taxanes. "Based on these data, physicians should be telling patients not to take ALC during adjuvant chemotherapy," Dr. Hershman concluded. "You need to talk to patients. We know from the literature that overwhelmingly large number of patients take supplements during chemotherapy and afterward, many of which have not been tested. It’s important to get that history from patients."
Dr. Barton, the discussant, praised the trial’s rigorous methodology and proposed that there may have been several reasons for the lack of ALC benefit in preventing neuropathy, despite compelling earlier data.
Previous prevention research was done in animals and thus may not translate to humans, she said. And a positive trial for treatment in humans used intravenous administration, which may result in different bioavailability. Finally, "ALC capsules needed to be taken three times a day, and they are rather large, and these patients were, after all, on chemotherapy. They were likely nauseated [and] dyspeptic, and taking what some might call a horse pill three times a day could not have been an easy task. The study did use pill diaries, but we know those aren’t a perfect tool for adherence."
"The great thing is that the study collected blood and they are able to look at carnitine levels," Dr. Barton said. "So if carnitine is up in the group that got acetyl-carnitine and not in the group that got placebo, well, I think that pretty much confirms that this just didn’t work."
ALC for Treatment of Peripheral Neuropathy
In the second trial, protocol ZHAOKE-2007L03540, investigators led by Dr. Yuanjue Sun of the Sixth Affiliated Hospital of Shanghai (China) Jiao Tong University, enrolled 239 patients who had cancer of various types and stages, had completed chemotherapy, and had had at least grade 2 peripheral neuropathy for up to 6 months.
They were randomly assigned to receive either oral ALC at a dose of 3 g/day or matching placebo, for 8 weeks, with outcomes assessed at clinic visits or by telephone.
Analyses showed that compared with their counterparts in the placebo group, patients in the ALC group were more likely to have had an improvement of at least one grade in their neuropathy, both at 8 weeks (51% vs. 24%; P less than .001) and at 12 weeks (58% vs. 40%; P less than .001).
In terms of secondary outcomes, the ALC group was also more likely to have had an improvement in cancer-related fatigue (31% vs. 20%; P = .048), physical strength (29% vs. 13%; P = .02), and electrophysiology in peripheral nerves (75% vs. 58%; P = .02).
The two groups had statistically indistinguishable rates of adverse events (20% vs. 15%) and adverse reactions (6% vs. 5%). The most common events were gastrointestinal ones and skin allergies.
"This is the first time to confirm that ALC has a positive effect to cure chemotherapy-induced peripheral neuropathy in the Chinese population," Dr. Sun commented through a translator.
"I think the very important thing for this trial is, it is a different kind of patient population. Before this, most clinical trials were performed in [whites] or maybe Americans. This is an only-Asian [population]," he noted, and it is possible that there are genetic differences in how ALC is metabolized.
Dr. Barton, the discussant, took a cautionary view, saying that "there are some things to consider before going out and telling patients to consider acetyl-carnitine for their peripheral neuropathy."
It was unclear from the results reported whether the two treatment groups were well balanced and what criteria were used to define improvement for the secondary outcomes, she noted. Additionally, "outcome measures were all provider graded, [and there were] no self-report measures, so it is difficult to understand the impact of treatment on symptoms, particularly from the patient perspective," she noted.
Dr. Hershman, Dr. Sun, and Dr. Barton disclosed no relevant conflicts of interest; the ZHAOKE-2007L03540 trial was sponsored by Lee’s Pharmaceutical Limited.
CHICAGO – The impact of acetyl-l-carnitine on chemotherapy-induced peripheral neuropathy may depend largely on the clinical context and patient population, a pair of phase III trials suggests.
Acetyl-l-carnitine (ALC), a natural substance marketed over the counter as a dietary supplement, is popular among cancer patients as a result of preclinical and early-phase data in chemotherapy-related neuropathy and also a study in patients with diabetes-related peripheral neuropathy.
But in a trial among 409 U.S. women receiving adjuvant chemotherapy for breast cancer, those who took ALC not only had no decrease in the development of peripheral neuropathy symptoms relative to peers who were given a placebo, but actually had an increase. And they had a higher rate of serious neuropathy, too.
In contrast, in a trial among more than 200 Chinese patients with various cancers who had peripheral neuropathy from previous chemotherapy, those who took ALC were more likely than those who took a placebo to have an improvement of at least one grade in their neuropathy. They also were more likely to have improvements in fatigue and strength.
Taken together, the two trials, which were reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology, provide yet another cautionary lesson on the complexity of combining conventional and complementary therapies.
"The use of ALC for prevention is not recommended, and I would say, based on [these results], should be cautioned against. It will be interesting to see the carnitine data and to understand, as much as possible, why the trial was negative," commented Debra L. Barton, Ph.D., of the Mayo Clinic in Rochester, Minn., who was invited to discuss the research. "Further studies are needed to really understand if ALC should be used to treat peripheral neuropathy."
ALC for Prevention of Peripheral Neuropathy
In the first trial, Southwest Oncology Group (SWOG) protocol S0715, investigators led by Dr. Dawn L. Hershman randomized women receiving adjuvant taxane chemotherapy for early breast cancer evenly to either oral ALC 1,000 mg three times daily or matching placebo, for 24 weeks.
Compared with their counterparts in the placebo group, women in the ALC group were more likely to have a greater than 5-point adjusted decrease on the neurotoxicity subscale of the Functional Assessment of Cancer Therapy–Taxane (FACT-NTX) instrument at 12 weeks (odds ratio, 1.48; P = .08) and also at 24 weeks (38% vs. 28%; OR, 1.57; P = .05).
This magnitude of worsening is clinically meaningful, maintained Dr. Hershman of Columbia University in New York, "so this is not like a lot of studies where you find a statistically significant difference that’s not clinically meaningful."
In addition, the incidence of grade 3/4 neurotoxicity was 3.8% with ALC, much higher than the 0.5% seen with placebo.
Patients in the ALC group also had scores on the FACT trial outcome index subscale (FACT-TOI), an overall measure of function, that were on average 3.5 points lower (worse) than those among their placebo counterparts (P = .03). There were no significant differences between groups in terms of fatigue and other toxicities.
The investigators have collected biosamples and will be assessing potential biological correlates with peripheral neuropathy outcomes, according to Dr. Hershman.
"We are looking at DNA, oxidative stress, and carnitine levels to better understand the mechanisms of chemotherapy-induced peripheral neuropathy to begin with, because there is not a whole lot known in terms of mechanism," she said. "If we can figure out what makes people worse, then we will maybe be able to figure out how to make people better from a more mechanistic standpoint, because there are very few drugs to treat chemotherapy-induced peripheral neuropathy."
An obvious concern from the trial’s findings is that ALC may somehow potentiate the neurotoxic effects of taxanes. "Based on these data, physicians should be telling patients not to take ALC during adjuvant chemotherapy," Dr. Hershman concluded. "You need to talk to patients. We know from the literature that overwhelmingly large number of patients take supplements during chemotherapy and afterward, many of which have not been tested. It’s important to get that history from patients."
Dr. Barton, the discussant, praised the trial’s rigorous methodology and proposed that there may have been several reasons for the lack of ALC benefit in preventing neuropathy, despite compelling earlier data.
Previous prevention research was done in animals and thus may not translate to humans, she said. And a positive trial for treatment in humans used intravenous administration, which may result in different bioavailability. Finally, "ALC capsules needed to be taken three times a day, and they are rather large, and these patients were, after all, on chemotherapy. They were likely nauseated [and] dyspeptic, and taking what some might call a horse pill three times a day could not have been an easy task. The study did use pill diaries, but we know those aren’t a perfect tool for adherence."
"The great thing is that the study collected blood and they are able to look at carnitine levels," Dr. Barton said. "So if carnitine is up in the group that got acetyl-carnitine and not in the group that got placebo, well, I think that pretty much confirms that this just didn’t work."
ALC for Treatment of Peripheral Neuropathy
In the second trial, protocol ZHAOKE-2007L03540, investigators led by Dr. Yuanjue Sun of the Sixth Affiliated Hospital of Shanghai (China) Jiao Tong University, enrolled 239 patients who had cancer of various types and stages, had completed chemotherapy, and had had at least grade 2 peripheral neuropathy for up to 6 months.
They were randomly assigned to receive either oral ALC at a dose of 3 g/day or matching placebo, for 8 weeks, with outcomes assessed at clinic visits or by telephone.
Analyses showed that compared with their counterparts in the placebo group, patients in the ALC group were more likely to have had an improvement of at least one grade in their neuropathy, both at 8 weeks (51% vs. 24%; P less than .001) and at 12 weeks (58% vs. 40%; P less than .001).
In terms of secondary outcomes, the ALC group was also more likely to have had an improvement in cancer-related fatigue (31% vs. 20%; P = .048), physical strength (29% vs. 13%; P = .02), and electrophysiology in peripheral nerves (75% vs. 58%; P = .02).
The two groups had statistically indistinguishable rates of adverse events (20% vs. 15%) and adverse reactions (6% vs. 5%). The most common events were gastrointestinal ones and skin allergies.
"This is the first time to confirm that ALC has a positive effect to cure chemotherapy-induced peripheral neuropathy in the Chinese population," Dr. Sun commented through a translator.
"I think the very important thing for this trial is, it is a different kind of patient population. Before this, most clinical trials were performed in [whites] or maybe Americans. This is an only-Asian [population]," he noted, and it is possible that there are genetic differences in how ALC is metabolized.
Dr. Barton, the discussant, took a cautionary view, saying that "there are some things to consider before going out and telling patients to consider acetyl-carnitine for their peripheral neuropathy."
It was unclear from the results reported whether the two treatment groups were well balanced and what criteria were used to define improvement for the secondary outcomes, she noted. Additionally, "outcome measures were all provider graded, [and there were] no self-report measures, so it is difficult to understand the impact of treatment on symptoms, particularly from the patient perspective," she noted.
Dr. Hershman, Dr. Sun, and Dr. Barton disclosed no relevant conflicts of interest; the ZHAOKE-2007L03540 trial was sponsored by Lee’s Pharmaceutical Limited.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: Patients taking ALC for prevention were more likely to have a greater than 5-point worsening of FACT-NTX score (38% vs. 28%), whereas patients taking ALC for treatment were more likely to have an improvement of at least one grade in neuropathy (51% vs. 24%).
Data Source: Investigators presented separate, randomized, placebo-controlled phase III trials among 410 women receiving adjuvant taxane chemotherapy for breast cancer and 239 patients with cancer and chemotherapy-induced peripheral neuropathy.
Disclosures: Dr. Hershman, Dr. Sun, and Dr. Barton disclosed no relevant conflicts of interest; the ZHAOKE-2007L03540 trial was sponsored by Lee’s Pharmaceutical Limited.
Drinking Patterns Linked to Cognitive Impairment in Older Adults
VANCOUVER, B.C. – Certain patterns of alcohol consumption appear detrimental to older adults’ cognitive health, according to a pair of longitudinal cohort studies.
In a study of older women, moderate drinking at a mean age of 81 years and initiation of drinking after a mean age of 68 years increased the odds of cognitive impairment. In a study of older men and women, those consuming large amounts of alcohol in a single sitting, so-called binge drinking, were more likely to be in the top decile of cognitive decline over time.
These new findings call into question what constitutes risky drinking in older adults and conventional practices of risk assessment, investigators reported at the Alzheimer’s Association International Conference 2012.
Drinking Patterns in Older Women
A team led by Tina D. Hoang, M.S.P.H., of the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, analyzed data from 1,306 community-dwelling, dementia-free women aged 65 years or older from the Study of Osteoporotic Fractures.
Research has suggested a J-shaped association between alcohol intake and dementia risk, whereby moderate alcohol intake is protective, she noted. However, "in most of the studies for dementia that are prospective, the follow-up time is between 5 and 6 years, and in terms of assessment of alcohol use, it’s primarily at baseline, focusing on midlife and early late-life stages of alcohol use. Few studies have really looked at patterns of use or changes in use over time."
The women studied had serial assessments of drinking over time and a cognitive evaluation at year 20, when they were, on average, 88 years old. At that time, 41% had cognitive impairment.
Adjusted analyses showed that women who, at baseline, reported drinking more in the past had 1.3-fold higher odds of developing cognitive impairment relative to their counterparts who had not changed their drinking habits up to that point.
With regard to current drinking, light and moderate drinkers had nonsignificantly reduced odds of cognitive impairment relative to nondrinkers at mean ages of 68 and 75 years. But moderate drinkers at a mean age of 81 years had 1.6-fold higher odds of cognitive impairment as same-aged nondrinkers.
Finally, with respect to patterns of use over the first 16 years of follow-up, women who started drinking during this time had threefold higher odds of cognitive impairment than did their counterparts who were consistently nondrinkers.
"It may be that alcohol use has different effects throughout the life course," Ms. Hoang commented. "As adults age, they may be taking more medications, and it may be ... there are interactions of alcohol with those medications."
Alternately, there may be interactions with apolipoprotein e (APOE) genotype, not assessed in the study, or the brains of the oldest old adults may be more vulnerable to the effects of alcohol. Finally, changing patterns of use over time may just be indicators of events such as illness, which themselves might increase risk of cognitive impairment.
"The American Geriatric Society recommends screening older adults for at-risk drinking, defined as drinking greater than one drink per day for older adults," Ms. Hoang noted. "We think that our findings suggest that it may be important to not just screen older adults for at-risk drinking or alcohol abuse, but also to look at history of past use and changes in use that may be associated with cognitive impairment.
"We think our findings also indicate that moderate use may not be protective in the oldest old, and it just shows the need for more life-course research so we can understand the effects of moderate alcohol use at different stages of life," she concluded.
Binge Drinking in Older Men and Women
A team led by Iain A. Lang, Ph.D., of Peninsula College of Medicine and Dentistry in Exeter, Devon, England, studied binge drinking among 5,075 U.S. community-dwelling men and women aged 65 years or older from the Health and Retirement Study.
Research on alcohol consumption and cognitive decline has generally not included many heavy drinkers, he pointed out. "I think this is because of what may be a recurring problem in studies of this type, that people who are heavy drinkers either don’t participate in cohort studies or else misrepresent their drinking levels."
Cognitive well-being was assessed in the older adults over an 8-year period with the Telephone Interview for Cognitive Status (TICS) total score and memory component.
Results showed that at baseline, 4.3% of the participants binge drank (consumed at least four drinks on a single occasion) at least once monthly, and 2% did so at least twice monthly.
In multivariate analyses, the older adults binge drinking at least once monthly had 1.62-fold higher odds of being in the top 10% of cognitive decline, and those binge drinking at least twice monthly had 2.47-fold higher odds. Additionally, the latter had 2.49-fold higher odds of being in the top 10% of memory decline.
"The findings are fairly robust, and I think that the main implication is that older adults should be aware that heavy episodic drinking is associated with an increased risk of cognitive decline," Dr. Lang said. The J-shaped risk curve whereby moderate drinking is protective may well exist, but previous studies have overlooked the pattern of drinking that people engage in, he said.
He proposed that there may well be a big difference between consuming seven drinks on one occasion, versus a single drink a day for seven days – even though people are often simply asked how much they drink in a week.
"Older adults and their care providers and others should be aware that these drinking patterns are important," he said, adding that physicians who are concerned about their patients’ alcohol drinking "ought to be aware that it’s the pattern of drinking and not just the total amount that’s of consequence here."
Additionally, "I think it’s quite important that we don’t consider binge drinking simply to be a problem of younger adults, which is often what we see," maintained Dr. Lang. "A lot of the media attention and research attention is focused on adolescents, college students, and younger adults in whom binge drinking is more common. We need to be aware that binge drinking goes on and is a health problem in older adults as well."
Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.
VANCOUVER, B.C. – Certain patterns of alcohol consumption appear detrimental to older adults’ cognitive health, according to a pair of longitudinal cohort studies.
In a study of older women, moderate drinking at a mean age of 81 years and initiation of drinking after a mean age of 68 years increased the odds of cognitive impairment. In a study of older men and women, those consuming large amounts of alcohol in a single sitting, so-called binge drinking, were more likely to be in the top decile of cognitive decline over time.
These new findings call into question what constitutes risky drinking in older adults and conventional practices of risk assessment, investigators reported at the Alzheimer’s Association International Conference 2012.
Drinking Patterns in Older Women
A team led by Tina D. Hoang, M.S.P.H., of the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, analyzed data from 1,306 community-dwelling, dementia-free women aged 65 years or older from the Study of Osteoporotic Fractures.
Research has suggested a J-shaped association between alcohol intake and dementia risk, whereby moderate alcohol intake is protective, she noted. However, "in most of the studies for dementia that are prospective, the follow-up time is between 5 and 6 years, and in terms of assessment of alcohol use, it’s primarily at baseline, focusing on midlife and early late-life stages of alcohol use. Few studies have really looked at patterns of use or changes in use over time."
The women studied had serial assessments of drinking over time and a cognitive evaluation at year 20, when they were, on average, 88 years old. At that time, 41% had cognitive impairment.
Adjusted analyses showed that women who, at baseline, reported drinking more in the past had 1.3-fold higher odds of developing cognitive impairment relative to their counterparts who had not changed their drinking habits up to that point.
With regard to current drinking, light and moderate drinkers had nonsignificantly reduced odds of cognitive impairment relative to nondrinkers at mean ages of 68 and 75 years. But moderate drinkers at a mean age of 81 years had 1.6-fold higher odds of cognitive impairment as same-aged nondrinkers.
Finally, with respect to patterns of use over the first 16 years of follow-up, women who started drinking during this time had threefold higher odds of cognitive impairment than did their counterparts who were consistently nondrinkers.
"It may be that alcohol use has different effects throughout the life course," Ms. Hoang commented. "As adults age, they may be taking more medications, and it may be ... there are interactions of alcohol with those medications."
Alternately, there may be interactions with apolipoprotein e (APOE) genotype, not assessed in the study, or the brains of the oldest old adults may be more vulnerable to the effects of alcohol. Finally, changing patterns of use over time may just be indicators of events such as illness, which themselves might increase risk of cognitive impairment.
"The American Geriatric Society recommends screening older adults for at-risk drinking, defined as drinking greater than one drink per day for older adults," Ms. Hoang noted. "We think that our findings suggest that it may be important to not just screen older adults for at-risk drinking or alcohol abuse, but also to look at history of past use and changes in use that may be associated with cognitive impairment.
"We think our findings also indicate that moderate use may not be protective in the oldest old, and it just shows the need for more life-course research so we can understand the effects of moderate alcohol use at different stages of life," she concluded.
Binge Drinking in Older Men and Women
A team led by Iain A. Lang, Ph.D., of Peninsula College of Medicine and Dentistry in Exeter, Devon, England, studied binge drinking among 5,075 U.S. community-dwelling men and women aged 65 years or older from the Health and Retirement Study.
Research on alcohol consumption and cognitive decline has generally not included many heavy drinkers, he pointed out. "I think this is because of what may be a recurring problem in studies of this type, that people who are heavy drinkers either don’t participate in cohort studies or else misrepresent their drinking levels."
Cognitive well-being was assessed in the older adults over an 8-year period with the Telephone Interview for Cognitive Status (TICS) total score and memory component.
Results showed that at baseline, 4.3% of the participants binge drank (consumed at least four drinks on a single occasion) at least once monthly, and 2% did so at least twice monthly.
In multivariate analyses, the older adults binge drinking at least once monthly had 1.62-fold higher odds of being in the top 10% of cognitive decline, and those binge drinking at least twice monthly had 2.47-fold higher odds. Additionally, the latter had 2.49-fold higher odds of being in the top 10% of memory decline.
"The findings are fairly robust, and I think that the main implication is that older adults should be aware that heavy episodic drinking is associated with an increased risk of cognitive decline," Dr. Lang said. The J-shaped risk curve whereby moderate drinking is protective may well exist, but previous studies have overlooked the pattern of drinking that people engage in, he said.
He proposed that there may well be a big difference between consuming seven drinks on one occasion, versus a single drink a day for seven days – even though people are often simply asked how much they drink in a week.
"Older adults and their care providers and others should be aware that these drinking patterns are important," he said, adding that physicians who are concerned about their patients’ alcohol drinking "ought to be aware that it’s the pattern of drinking and not just the total amount that’s of consequence here."
Additionally, "I think it’s quite important that we don’t consider binge drinking simply to be a problem of younger adults, which is often what we see," maintained Dr. Lang. "A lot of the media attention and research attention is focused on adolescents, college students, and younger adults in whom binge drinking is more common. We need to be aware that binge drinking goes on and is a health problem in older adults as well."
Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.
VANCOUVER, B.C. – Certain patterns of alcohol consumption appear detrimental to older adults’ cognitive health, according to a pair of longitudinal cohort studies.
In a study of older women, moderate drinking at a mean age of 81 years and initiation of drinking after a mean age of 68 years increased the odds of cognitive impairment. In a study of older men and women, those consuming large amounts of alcohol in a single sitting, so-called binge drinking, were more likely to be in the top decile of cognitive decline over time.
These new findings call into question what constitutes risky drinking in older adults and conventional practices of risk assessment, investigators reported at the Alzheimer’s Association International Conference 2012.
Drinking Patterns in Older Women
A team led by Tina D. Hoang, M.S.P.H., of the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, analyzed data from 1,306 community-dwelling, dementia-free women aged 65 years or older from the Study of Osteoporotic Fractures.
Research has suggested a J-shaped association between alcohol intake and dementia risk, whereby moderate alcohol intake is protective, she noted. However, "in most of the studies for dementia that are prospective, the follow-up time is between 5 and 6 years, and in terms of assessment of alcohol use, it’s primarily at baseline, focusing on midlife and early late-life stages of alcohol use. Few studies have really looked at patterns of use or changes in use over time."
The women studied had serial assessments of drinking over time and a cognitive evaluation at year 20, when they were, on average, 88 years old. At that time, 41% had cognitive impairment.
Adjusted analyses showed that women who, at baseline, reported drinking more in the past had 1.3-fold higher odds of developing cognitive impairment relative to their counterparts who had not changed their drinking habits up to that point.
With regard to current drinking, light and moderate drinkers had nonsignificantly reduced odds of cognitive impairment relative to nondrinkers at mean ages of 68 and 75 years. But moderate drinkers at a mean age of 81 years had 1.6-fold higher odds of cognitive impairment as same-aged nondrinkers.
Finally, with respect to patterns of use over the first 16 years of follow-up, women who started drinking during this time had threefold higher odds of cognitive impairment than did their counterparts who were consistently nondrinkers.
"It may be that alcohol use has different effects throughout the life course," Ms. Hoang commented. "As adults age, they may be taking more medications, and it may be ... there are interactions of alcohol with those medications."
Alternately, there may be interactions with apolipoprotein e (APOE) genotype, not assessed in the study, or the brains of the oldest old adults may be more vulnerable to the effects of alcohol. Finally, changing patterns of use over time may just be indicators of events such as illness, which themselves might increase risk of cognitive impairment.
"The American Geriatric Society recommends screening older adults for at-risk drinking, defined as drinking greater than one drink per day for older adults," Ms. Hoang noted. "We think that our findings suggest that it may be important to not just screen older adults for at-risk drinking or alcohol abuse, but also to look at history of past use and changes in use that may be associated with cognitive impairment.
"We think our findings also indicate that moderate use may not be protective in the oldest old, and it just shows the need for more life-course research so we can understand the effects of moderate alcohol use at different stages of life," she concluded.
Binge Drinking in Older Men and Women
A team led by Iain A. Lang, Ph.D., of Peninsula College of Medicine and Dentistry in Exeter, Devon, England, studied binge drinking among 5,075 U.S. community-dwelling men and women aged 65 years or older from the Health and Retirement Study.
Research on alcohol consumption and cognitive decline has generally not included many heavy drinkers, he pointed out. "I think this is because of what may be a recurring problem in studies of this type, that people who are heavy drinkers either don’t participate in cohort studies or else misrepresent their drinking levels."
Cognitive well-being was assessed in the older adults over an 8-year period with the Telephone Interview for Cognitive Status (TICS) total score and memory component.
Results showed that at baseline, 4.3% of the participants binge drank (consumed at least four drinks on a single occasion) at least once monthly, and 2% did so at least twice monthly.
In multivariate analyses, the older adults binge drinking at least once monthly had 1.62-fold higher odds of being in the top 10% of cognitive decline, and those binge drinking at least twice monthly had 2.47-fold higher odds. Additionally, the latter had 2.49-fold higher odds of being in the top 10% of memory decline.
"The findings are fairly robust, and I think that the main implication is that older adults should be aware that heavy episodic drinking is associated with an increased risk of cognitive decline," Dr. Lang said. The J-shaped risk curve whereby moderate drinking is protective may well exist, but previous studies have overlooked the pattern of drinking that people engage in, he said.
He proposed that there may well be a big difference between consuming seven drinks on one occasion, versus a single drink a day for seven days – even though people are often simply asked how much they drink in a week.
"Older adults and their care providers and others should be aware that these drinking patterns are important," he said, adding that physicians who are concerned about their patients’ alcohol drinking "ought to be aware that it’s the pattern of drinking and not just the total amount that’s of consequence here."
Additionally, "I think it’s quite important that we don’t consider binge drinking simply to be a problem of younger adults, which is often what we see," maintained Dr. Lang. "A lot of the media attention and research attention is focused on adolescents, college students, and younger adults in whom binge drinking is more common. We need to be aware that binge drinking goes on and is a health problem in older adults as well."
Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.
AT THE ALZHEIMER’S ASSOCIATION INTERNATIONAL CONFERENCE 2012
Major Finding: Elderly women who drank moderately and women who started drinking late in life had 1.6- and 3-fold higher odds, respectively, of cognitive impairment. Older adults who binge drank once and twice monthly had 1.62- and 2.47-fold higher odds, respectively, of being in the top decile of cognitive decline.
Data Source: Data are from a pair of longitudinal cohort studies: 1,306 women aged 65 years or older (Study of Osteoporotic Fractures) and 5,075 men and women aged 65 years or older (Health and Retirement Study).
Disclosures: Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.
Doubt Cast on Discrete-Phase Nature of Migraine With Aura
LOS ANGELES – Contrasting with current classification criteria and the usual wisdom that attacks of migraine with aura have discrete phases, new data suggest that headache is more often than not already present during the aura phase.
In a prospective, diary-based study of 201 adults experiencing 861 attacks of migraine with aura, headache was reported within 15 minutes of the onset of aura in 61% of attacks, researchers reported at the annual meeting of the American Headache Society.
Additionally, more than half of the attacks met formal diagnostic criteria for migraine or pragmatic criteria for probable migraine within this time frame.
"These results do not seem to be consistent with the current ICHD-2 [International Classification of Headache Disorders, second edition] classification that states that migraine headache usually follows the aura symptoms; that’s not the case here," commented lead researcher Dr. Jakob M. Hansen of the headache research and treatment program at the University of California, Los Angeles and the Danish Headache Center at the University of Copenhagen.
"Furthermore, we have already headache at the onset of aura, and that does seem to conflict with the idea that you have to have a [cortical] spreading depression to activate the trigeminovascular system to cause headache."
"These data suggest that the phases of migraine attack may not be as discrete as originally believed. This is food for thought," he added.
Session attendee Dr. Jes Olesen, also of the University of Copenhagen, was skeptical of the findings, however, noting that they contrast with those of large studies in which careful histories were taken. "Always when you find something that is clearly in contrast to what is sort of conventional wisdom, we have to think about possible sources of error. ... My idea is it could be because people are mixing up a little bit attacks with and without aura ... because patients tend to mix these things up if you don’t instruct them very, very carefully," he said.
"The good thing is, for [patients] to report anything during the study, they should have an aura that they were familiar with to include an attack. I think it’s highly unlikely that people were having a migraine attack without aura. They were asked in the electronic diary, ‘Do you have an aura right now?’ " Dr. Hansen explained. "Of course it’s possible that they answered, ‘Yes, I do,’ because we reminded them. But I think it’s unlikely that so many patients would respond wrongly to a very simple question like that."
Dr. Werner Becker of the University of Calgary (Alta.), who also attended the session, commented that "migraine patients who have premonitory symptoms will often report nausea or photophobia or phonophobia even during their premonitory phase, so I’m not all that surprised that maybe symptoms are occurring during the aura as well.
"Having said that, your findings of so much headache during the aura are very interesting. But I suppose your results are consistent with the idea that the hypothalamus activation is perhaps the first part of the migraine attack," he added.
Dr. Hansen and his coinvestigators studied patients who were enrolled in a randomized therapeutic trial and had migraine with aura.
In the first phase of the study (456 attacks), patients reported the time elapsed since aura onset in quarter hours, as well as pain intensity and associated symptoms. In the second phase (405 attacks), they reported baseline pain and associated symptoms within 1 hour of aura onset, immediately before treatment.
Results showed that for 61% of attacks in the study’s first phase, headache was already present at 0-15 minutes after aura onset, Dr. Hansen reported. Patients also commonly had nausea (40%), photophobia (84%), and phonophobia (67%) at this very early phase.
Additionally, a large proportion of attacks met criteria for migraine with aura within 15 minutes of the onset of aura: 22% with use of the stricter ICHD-2 criteria for migraine with aura, and 54% with use of less strict, pragmatic criteria for probable migraine with aura (defined as migraine aura plus any-intensity headache plus at least one associated symptom among nausea/vomiting, photophobia, and phonophobia).
"These results were, of course, somewhat surprising to us because of the conflict with many of the firmly held beliefs" on migraine with aura, Dr. Hansen commented. Nonetheless, "it seems that headache and migraine symptoms are present during the aura phase."
(For all attacks studied, headache occurred within an hour of aura onset in 73%; some 31% met the ICHD-2 criteria for migraine with aura, whereas 65% met the pragmatic criteria for probable migraine with aura.)
Dr. Hansen disclosed no relevant financial conflicts of interest.
LOS ANGELES – Contrasting with current classification criteria and the usual wisdom that attacks of migraine with aura have discrete phases, new data suggest that headache is more often than not already present during the aura phase.
In a prospective, diary-based study of 201 adults experiencing 861 attacks of migraine with aura, headache was reported within 15 minutes of the onset of aura in 61% of attacks, researchers reported at the annual meeting of the American Headache Society.
Additionally, more than half of the attacks met formal diagnostic criteria for migraine or pragmatic criteria for probable migraine within this time frame.
"These results do not seem to be consistent with the current ICHD-2 [International Classification of Headache Disorders, second edition] classification that states that migraine headache usually follows the aura symptoms; that’s not the case here," commented lead researcher Dr. Jakob M. Hansen of the headache research and treatment program at the University of California, Los Angeles and the Danish Headache Center at the University of Copenhagen.
"Furthermore, we have already headache at the onset of aura, and that does seem to conflict with the idea that you have to have a [cortical] spreading depression to activate the trigeminovascular system to cause headache."
"These data suggest that the phases of migraine attack may not be as discrete as originally believed. This is food for thought," he added.
Session attendee Dr. Jes Olesen, also of the University of Copenhagen, was skeptical of the findings, however, noting that they contrast with those of large studies in which careful histories were taken. "Always when you find something that is clearly in contrast to what is sort of conventional wisdom, we have to think about possible sources of error. ... My idea is it could be because people are mixing up a little bit attacks with and without aura ... because patients tend to mix these things up if you don’t instruct them very, very carefully," he said.
"The good thing is, for [patients] to report anything during the study, they should have an aura that they were familiar with to include an attack. I think it’s highly unlikely that people were having a migraine attack without aura. They were asked in the electronic diary, ‘Do you have an aura right now?’ " Dr. Hansen explained. "Of course it’s possible that they answered, ‘Yes, I do,’ because we reminded them. But I think it’s unlikely that so many patients would respond wrongly to a very simple question like that."
Dr. Werner Becker of the University of Calgary (Alta.), who also attended the session, commented that "migraine patients who have premonitory symptoms will often report nausea or photophobia or phonophobia even during their premonitory phase, so I’m not all that surprised that maybe symptoms are occurring during the aura as well.
"Having said that, your findings of so much headache during the aura are very interesting. But I suppose your results are consistent with the idea that the hypothalamus activation is perhaps the first part of the migraine attack," he added.
Dr. Hansen and his coinvestigators studied patients who were enrolled in a randomized therapeutic trial and had migraine with aura.
In the first phase of the study (456 attacks), patients reported the time elapsed since aura onset in quarter hours, as well as pain intensity and associated symptoms. In the second phase (405 attacks), they reported baseline pain and associated symptoms within 1 hour of aura onset, immediately before treatment.
Results showed that for 61% of attacks in the study’s first phase, headache was already present at 0-15 minutes after aura onset, Dr. Hansen reported. Patients also commonly had nausea (40%), photophobia (84%), and phonophobia (67%) at this very early phase.
Additionally, a large proportion of attacks met criteria for migraine with aura within 15 minutes of the onset of aura: 22% with use of the stricter ICHD-2 criteria for migraine with aura, and 54% with use of less strict, pragmatic criteria for probable migraine with aura (defined as migraine aura plus any-intensity headache plus at least one associated symptom among nausea/vomiting, photophobia, and phonophobia).
"These results were, of course, somewhat surprising to us because of the conflict with many of the firmly held beliefs" on migraine with aura, Dr. Hansen commented. Nonetheless, "it seems that headache and migraine symptoms are present during the aura phase."
(For all attacks studied, headache occurred within an hour of aura onset in 73%; some 31% met the ICHD-2 criteria for migraine with aura, whereas 65% met the pragmatic criteria for probable migraine with aura.)
Dr. Hansen disclosed no relevant financial conflicts of interest.
LOS ANGELES – Contrasting with current classification criteria and the usual wisdom that attacks of migraine with aura have discrete phases, new data suggest that headache is more often than not already present during the aura phase.
In a prospective, diary-based study of 201 adults experiencing 861 attacks of migraine with aura, headache was reported within 15 minutes of the onset of aura in 61% of attacks, researchers reported at the annual meeting of the American Headache Society.
Additionally, more than half of the attacks met formal diagnostic criteria for migraine or pragmatic criteria for probable migraine within this time frame.
"These results do not seem to be consistent with the current ICHD-2 [International Classification of Headache Disorders, second edition] classification that states that migraine headache usually follows the aura symptoms; that’s not the case here," commented lead researcher Dr. Jakob M. Hansen of the headache research and treatment program at the University of California, Los Angeles and the Danish Headache Center at the University of Copenhagen.
"Furthermore, we have already headache at the onset of aura, and that does seem to conflict with the idea that you have to have a [cortical] spreading depression to activate the trigeminovascular system to cause headache."
"These data suggest that the phases of migraine attack may not be as discrete as originally believed. This is food for thought," he added.
Session attendee Dr. Jes Olesen, also of the University of Copenhagen, was skeptical of the findings, however, noting that they contrast with those of large studies in which careful histories were taken. "Always when you find something that is clearly in contrast to what is sort of conventional wisdom, we have to think about possible sources of error. ... My idea is it could be because people are mixing up a little bit attacks with and without aura ... because patients tend to mix these things up if you don’t instruct them very, very carefully," he said.
"The good thing is, for [patients] to report anything during the study, they should have an aura that they were familiar with to include an attack. I think it’s highly unlikely that people were having a migraine attack without aura. They were asked in the electronic diary, ‘Do you have an aura right now?’ " Dr. Hansen explained. "Of course it’s possible that they answered, ‘Yes, I do,’ because we reminded them. But I think it’s unlikely that so many patients would respond wrongly to a very simple question like that."
Dr. Werner Becker of the University of Calgary (Alta.), who also attended the session, commented that "migraine patients who have premonitory symptoms will often report nausea or photophobia or phonophobia even during their premonitory phase, so I’m not all that surprised that maybe symptoms are occurring during the aura as well.
"Having said that, your findings of so much headache during the aura are very interesting. But I suppose your results are consistent with the idea that the hypothalamus activation is perhaps the first part of the migraine attack," he added.
Dr. Hansen and his coinvestigators studied patients who were enrolled in a randomized therapeutic trial and had migraine with aura.
In the first phase of the study (456 attacks), patients reported the time elapsed since aura onset in quarter hours, as well as pain intensity and associated symptoms. In the second phase (405 attacks), they reported baseline pain and associated symptoms within 1 hour of aura onset, immediately before treatment.
Results showed that for 61% of attacks in the study’s first phase, headache was already present at 0-15 minutes after aura onset, Dr. Hansen reported. Patients also commonly had nausea (40%), photophobia (84%), and phonophobia (67%) at this very early phase.
Additionally, a large proportion of attacks met criteria for migraine with aura within 15 minutes of the onset of aura: 22% with use of the stricter ICHD-2 criteria for migraine with aura, and 54% with use of less strict, pragmatic criteria for probable migraine with aura (defined as migraine aura plus any-intensity headache plus at least one associated symptom among nausea/vomiting, photophobia, and phonophobia).
"These results were, of course, somewhat surprising to us because of the conflict with many of the firmly held beliefs" on migraine with aura, Dr. Hansen commented. Nonetheless, "it seems that headache and migraine symptoms are present during the aura phase."
(For all attacks studied, headache occurred within an hour of aura onset in 73%; some 31% met the ICHD-2 criteria for migraine with aura, whereas 65% met the pragmatic criteria for probable migraine with aura.)
Dr. Hansen disclosed no relevant financial conflicts of interest.
AT THE ANNUAL MEETING OF THE AMERICAN HEADACHE SOCIETY
Major Finding: In 61% of attacks, headache was already present within 15 minutes of the onset of aura.
Data Source: This was a prospective, diary-based study of 201 adult patients experiencing 861 attacks of migraine with aura.
Disclosures: Dr. Hansen disclosed no relevant financial conflicts of interest.
Environment Modifies ApoE e4-Related Risk of Alzheimer's Disease
VANCOUVER, B.C. – Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.
In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.
Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.
Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.
"Here, we show evidence that man can conquer nature," commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.
"The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk," she maintained.
"As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance," she added.
The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. "What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives," said Dr. Lipton of Albert Einstein College of Medicine, New York.
And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset "seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented." He speculated that "this might have been due to age being such a dominant factor."
Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.
After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.
In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).
In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.
In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.
Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).
Dr. Xu disclosed no relevant conflicts of interest.
VANCOUVER, B.C. – Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.
In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.
Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.
Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.
"Here, we show evidence that man can conquer nature," commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.
"The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk," she maintained.
"As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance," she added.
The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. "What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives," said Dr. Lipton of Albert Einstein College of Medicine, New York.
And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset "seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented." He speculated that "this might have been due to age being such a dominant factor."
Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.
After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.
In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).
In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.
In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.
Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).
Dr. Xu disclosed no relevant conflicts of interest.
VANCOUVER, B.C. – Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.
In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.
Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.
Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.
"Here, we show evidence that man can conquer nature," commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.
"The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk," she maintained.
"As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance," she added.
The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. "What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives," said Dr. Lipton of Albert Einstein College of Medicine, New York.
And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset "seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented." He speculated that "this might have been due to age being such a dominant factor."
Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.
After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.
In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).
In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.
In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.
Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).
Dr. Xu disclosed no relevant conflicts of interest.
AT THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE 2012
Major Finding: Among ApoE e4 carriers, the risk of Alzheimer’s disease was lower for those having more education (hazard ratio, 0.55), a high level of leisure-time activities (0.49), and no vascular risk factors (0.61).
Data Source: A sample of 932 cognitively healthy adults aged 75 years or older from a population-based cohort study (the Kungsholmen Project).
Disclosures: Dr. Xu disclosed no relevant conflicts of interest.
Coffee Consumption Linked to Lower Dementia Risk in Elderly
VANCOUVER, B.C. – Long-term coffee consumption may protect against dementia in the elderly, according to an Italian study presented at the Alzheimer’s Association International Conference 2012.
In the prospective population-based cohort study of adults aged 80 years or older, about three-fourths drank coffee, having started on average at the age of 19 years.
Among those who were dementia-free at baseline, coffee drinkers were 32% less likely to develop dementia over the next 5½ years, compared with their counterparts who had never consumed the beverage, reported lead investigator Ugo Lucca, M.Sc., head of the laboratory of geriatric neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milan.
"Recent findings have suggested that coffee consumption may have neuroprotective effects," he noted. "Long-term caffeine consumption could, in fact, reduce amyloid beta production and aggregation through suppression of both beta- and gamma-secretase activities."
"What about reverse causality, with dementia causing a decrease in coffee consumption?" one attendee asked.
Mr. Lucca acknowledged that coffee consumption did indeed fall with increasing severity of dementia at baseline, but he also noted that 41% of participants with severe dementia still drank at least some. "The only explanation could be that, even in this population, drinking coffee is protective for survival," he said. "In a subpopulation of those with dementia, probably drinking coffee is not protective for survival."
The investigators studied 2,198 participants in the Monzino 80-Plus Study, conducted in the Varese province of Italy. Participants or relatives reported the number of cups of coffee consumed daily, in the past and at present.
Study participants were 90 years old and had 5 years of education, on average, and 73% were women. Their mean Mini-Mental State Examination score was 20.5.
Overall, about three-fourths of participants reported drinking coffee, with about one-third drinking two or more cups daily.
"Though the average daily coffee intake tends to decrease from midlife, coffee consumption remains common in the very old," Mr. Lucca observed. The average intake was 2.3 cups daily at the age of 50 years, but still 1.5 cups daily at the age of 87 years.
In the cross-sectional part of the study, the prevalence of dementia was about 51% among participants who drank less than one cup of coffee daily, 34% among those drinking one cup daily, and 23% among those drinking two or more cups daily, he reported.
In a multivariate analysis, participants who drank coffee were 29% less likely to have dementia (odds ratio, 0.71; P = .008).
In the longitudinal part of the study, the incidence of dementia over 5.5 years among the 1,097 participants who were free of dementia at baseline was significantly lower for coffee drinkers than for never-drinkers (P less than .0001), with a widening gap over time.
The incidence was 45% among participants drinking less than one cup of coffee daily, 31% among those drinking one cup daily, and 29% among those drinking two or more cups daily, Mr. Lucca reported.
In a multivariate analysis, compared with never-drinkers, coffee drinkers as a whole were about one-third less likely to develop dementia (hazard ratio [HR], 0.68; P = .006). The benefit was similar whether they consumed one cup daily (HR, 0.68; P = .01) or two or more cups daily (HR, 0.66; P = .02).
Mr. Lucca disclosed no conflicts of interest related to the research.
VANCOUVER, B.C. – Long-term coffee consumption may protect against dementia in the elderly, according to an Italian study presented at the Alzheimer’s Association International Conference 2012.
In the prospective population-based cohort study of adults aged 80 years or older, about three-fourths drank coffee, having started on average at the age of 19 years.
Among those who were dementia-free at baseline, coffee drinkers were 32% less likely to develop dementia over the next 5½ years, compared with their counterparts who had never consumed the beverage, reported lead investigator Ugo Lucca, M.Sc., head of the laboratory of geriatric neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milan.
"Recent findings have suggested that coffee consumption may have neuroprotective effects," he noted. "Long-term caffeine consumption could, in fact, reduce amyloid beta production and aggregation through suppression of both beta- and gamma-secretase activities."
"What about reverse causality, with dementia causing a decrease in coffee consumption?" one attendee asked.
Mr. Lucca acknowledged that coffee consumption did indeed fall with increasing severity of dementia at baseline, but he also noted that 41% of participants with severe dementia still drank at least some. "The only explanation could be that, even in this population, drinking coffee is protective for survival," he said. "In a subpopulation of those with dementia, probably drinking coffee is not protective for survival."
The investigators studied 2,198 participants in the Monzino 80-Plus Study, conducted in the Varese province of Italy. Participants or relatives reported the number of cups of coffee consumed daily, in the past and at present.
Study participants were 90 years old and had 5 years of education, on average, and 73% were women. Their mean Mini-Mental State Examination score was 20.5.
Overall, about three-fourths of participants reported drinking coffee, with about one-third drinking two or more cups daily.
"Though the average daily coffee intake tends to decrease from midlife, coffee consumption remains common in the very old," Mr. Lucca observed. The average intake was 2.3 cups daily at the age of 50 years, but still 1.5 cups daily at the age of 87 years.
In the cross-sectional part of the study, the prevalence of dementia was about 51% among participants who drank less than one cup of coffee daily, 34% among those drinking one cup daily, and 23% among those drinking two or more cups daily, he reported.
In a multivariate analysis, participants who drank coffee were 29% less likely to have dementia (odds ratio, 0.71; P = .008).
In the longitudinal part of the study, the incidence of dementia over 5.5 years among the 1,097 participants who were free of dementia at baseline was significantly lower for coffee drinkers than for never-drinkers (P less than .0001), with a widening gap over time.
The incidence was 45% among participants drinking less than one cup of coffee daily, 31% among those drinking one cup daily, and 29% among those drinking two or more cups daily, Mr. Lucca reported.
In a multivariate analysis, compared with never-drinkers, coffee drinkers as a whole were about one-third less likely to develop dementia (hazard ratio [HR], 0.68; P = .006). The benefit was similar whether they consumed one cup daily (HR, 0.68; P = .01) or two or more cups daily (HR, 0.66; P = .02).
Mr. Lucca disclosed no conflicts of interest related to the research.
VANCOUVER, B.C. – Long-term coffee consumption may protect against dementia in the elderly, according to an Italian study presented at the Alzheimer’s Association International Conference 2012.
In the prospective population-based cohort study of adults aged 80 years or older, about three-fourths drank coffee, having started on average at the age of 19 years.
Among those who were dementia-free at baseline, coffee drinkers were 32% less likely to develop dementia over the next 5½ years, compared with their counterparts who had never consumed the beverage, reported lead investigator Ugo Lucca, M.Sc., head of the laboratory of geriatric neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milan.
"Recent findings have suggested that coffee consumption may have neuroprotective effects," he noted. "Long-term caffeine consumption could, in fact, reduce amyloid beta production and aggregation through suppression of both beta- and gamma-secretase activities."
"What about reverse causality, with dementia causing a decrease in coffee consumption?" one attendee asked.
Mr. Lucca acknowledged that coffee consumption did indeed fall with increasing severity of dementia at baseline, but he also noted that 41% of participants with severe dementia still drank at least some. "The only explanation could be that, even in this population, drinking coffee is protective for survival," he said. "In a subpopulation of those with dementia, probably drinking coffee is not protective for survival."
The investigators studied 2,198 participants in the Monzino 80-Plus Study, conducted in the Varese province of Italy. Participants or relatives reported the number of cups of coffee consumed daily, in the past and at present.
Study participants were 90 years old and had 5 years of education, on average, and 73% were women. Their mean Mini-Mental State Examination score was 20.5.
Overall, about three-fourths of participants reported drinking coffee, with about one-third drinking two or more cups daily.
"Though the average daily coffee intake tends to decrease from midlife, coffee consumption remains common in the very old," Mr. Lucca observed. The average intake was 2.3 cups daily at the age of 50 years, but still 1.5 cups daily at the age of 87 years.
In the cross-sectional part of the study, the prevalence of dementia was about 51% among participants who drank less than one cup of coffee daily, 34% among those drinking one cup daily, and 23% among those drinking two or more cups daily, he reported.
In a multivariate analysis, participants who drank coffee were 29% less likely to have dementia (odds ratio, 0.71; P = .008).
In the longitudinal part of the study, the incidence of dementia over 5.5 years among the 1,097 participants who were free of dementia at baseline was significantly lower for coffee drinkers than for never-drinkers (P less than .0001), with a widening gap over time.
The incidence was 45% among participants drinking less than one cup of coffee daily, 31% among those drinking one cup daily, and 29% among those drinking two or more cups daily, Mr. Lucca reported.
In a multivariate analysis, compared with never-drinkers, coffee drinkers as a whole were about one-third less likely to develop dementia (hazard ratio [HR], 0.68; P = .006). The benefit was similar whether they consumed one cup daily (HR, 0.68; P = .01) or two or more cups daily (HR, 0.66; P = .02).
Mr. Lucca disclosed no conflicts of interest related to the research.
AT THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE 2012
Major Finding: In a multivariate analysis, cognitively healthy participants drinking coffee daily had a significant 32% reduction in the risk of developing dementia relative to never-drinkers.
Data Source: A prospective population-based cohort study of 2,198 adults aged 80 years or older (the Monzino 80-Plus Study).
Disclosures: Mr. Lucca disclosed no relevant conflicts of interest.
Posttraumatic Headache More Common When Injury Is Mild
LOS ANGELES – The likelihood of headache after traumatic brain injury was inversely related to the severity of injury in a longitudinal study of 598 patients.
The patients with mild injury were about 70% more likely than were their counterparts with moderate or severe injury to develop new headache or have a worsening of preexisting headache over the next year, first author Dr. Sylvia Lucas reported at the annual meeting of the American Headache Society.
The majority of headaches were migraine or probable migraine according to the ICHD-2 (International Classification of Headache Disorders, second edition) system, but a large share – roughly a quarter – had features that defied classification. Patients with preexisting headache and female patients had a higher risk of posttraumatic headache.
"Using symptom-based criteria for headache after TBI [traumatic brain injury] hopefully may serve as a framework from which to provide evidence-based treatment," commented Dr. Lucas, clinical professor of neurology, rehabilitation medicine, and neurosurgery at the University of Washington in Seattle.
Session attendee Dr. Werner Becker of the University of Calgary (Alta.) asked, "Any thoughts as to why the patients with milder injuries have more headache?"
"I don’t know. It has to have something to do with the mechanics of the hit, I suspect," Dr. Lucas replied. "We’re just now trying to look at the types of injury. We’re trying to separate subarachnoid hemorrhage, depressed skull fracture, intracerebral hemorrhage, and trying to look at how they relate to the chronicity of the headache. But, as of now, I can’t answer that."
Dr. James R. Couch of the University of Oklahoma, Oklahoma City, who also attended the session, noted that he and his colleagues found a similar pattern in a previous study. "I was very gratified to see that what you are finding is the less severely injured people seem to have a greater propensity for headache," he said. "Maybe the severe brain injury takes out some kind of center that is involved in generating headache, whereas the mild head injury just irritates it."
The investigators studied a single-center cohort of 220 patients with mild TBI who were enrolled within a week of injury and a seven-center cohort of 378 patients with moderate to severe TBI who were admitted to inpatient rehabilitation facilities. All patients were evaluated with the same questionnaire, in person at baseline, and prospectively by telephone over a year, to gain a better understanding of headache incidence, characteristics, and predictors, and treatment effectiveness.
"We feel that the ICHD-2 criteria, both in the civilian and military populations, really don’t contribute to treatment planning," Dr. Lucas commented. "They also don’t account for the latency of posttraumatic headache following trauma," with experience suggesting that almost a third of headache cases do not come to clinical attention until more than 1 week after the injury, even though that is the window typically used to define posttraumatic headache.
Patients in both groups were about 43 years old, on average, and roughly three-quarters each were male and white, and had completed high school. The leading cause of injury was vehicular accident (58%) followed by falls (25%).
Study results showed that the mild TBI group and the moderate or severe TBI group had an identical prevalence of headache before injury (17%). But the former had a higher incidence of new or worsened headache at baseline (56% vs. 40%), at 3 months (63% vs. 37%), at 6 months (69% vs. 33%), and at 12 months (58% vs. 34%).
Headache was classified according to ICHD-2 criteria for primary headache, with only a single class permitted per patient, based on the predominant features, according to Dr. Lucas. "The idea behind classification of a secondary headache using primary headache criteria is really to try to find some defining features that may allow us to do what we want in the future, which is to get some evidence-based medicine treatment or management protocols," she explained.
At all time points and in both groups, the largest share of headaches (39%-67%) was of the migraine or probable migraine type. Tension headaches were the next most common type. "Surprisingly, cervicogenic was not very [common], particularly considering that many of these were motor vehicle accidents and probably involved whiplash-type injuries," she observed.
Roughly a quarter of headaches were unclassifiable. "We felt that rather than trying to use a shoehorn to fit the headache into a classification, if it didn’t fit, we just stayed with it and deemed it unclassifiable," Dr. Lucas commented.
In both the mild TBI group and the moderate to severe TBI group, the migraine and probable migraine headaches, in addition to being most common, were more likely than the other types of headache to occur daily or several times weekly.
Also, in both groups, patients who had a prior history of headache and female patients were more likely to have headache at follow-up. For example, in the mild TBI group, about 70% of patients who had preexisting headache had headache at all time points during follow-up, compared with about 50% of patients who did not have preexisting headache.
Dr. Lucas disclosed no relevant conflicts of interest.
LOS ANGELES – The likelihood of headache after traumatic brain injury was inversely related to the severity of injury in a longitudinal study of 598 patients.
The patients with mild injury were about 70% more likely than were their counterparts with moderate or severe injury to develop new headache or have a worsening of preexisting headache over the next year, first author Dr. Sylvia Lucas reported at the annual meeting of the American Headache Society.
The majority of headaches were migraine or probable migraine according to the ICHD-2 (International Classification of Headache Disorders, second edition) system, but a large share – roughly a quarter – had features that defied classification. Patients with preexisting headache and female patients had a higher risk of posttraumatic headache.
"Using symptom-based criteria for headache after TBI [traumatic brain injury] hopefully may serve as a framework from which to provide evidence-based treatment," commented Dr. Lucas, clinical professor of neurology, rehabilitation medicine, and neurosurgery at the University of Washington in Seattle.
Session attendee Dr. Werner Becker of the University of Calgary (Alta.) asked, "Any thoughts as to why the patients with milder injuries have more headache?"
"I don’t know. It has to have something to do with the mechanics of the hit, I suspect," Dr. Lucas replied. "We’re just now trying to look at the types of injury. We’re trying to separate subarachnoid hemorrhage, depressed skull fracture, intracerebral hemorrhage, and trying to look at how they relate to the chronicity of the headache. But, as of now, I can’t answer that."
Dr. James R. Couch of the University of Oklahoma, Oklahoma City, who also attended the session, noted that he and his colleagues found a similar pattern in a previous study. "I was very gratified to see that what you are finding is the less severely injured people seem to have a greater propensity for headache," he said. "Maybe the severe brain injury takes out some kind of center that is involved in generating headache, whereas the mild head injury just irritates it."
The investigators studied a single-center cohort of 220 patients with mild TBI who were enrolled within a week of injury and a seven-center cohort of 378 patients with moderate to severe TBI who were admitted to inpatient rehabilitation facilities. All patients were evaluated with the same questionnaire, in person at baseline, and prospectively by telephone over a year, to gain a better understanding of headache incidence, characteristics, and predictors, and treatment effectiveness.
"We feel that the ICHD-2 criteria, both in the civilian and military populations, really don’t contribute to treatment planning," Dr. Lucas commented. "They also don’t account for the latency of posttraumatic headache following trauma," with experience suggesting that almost a third of headache cases do not come to clinical attention until more than 1 week after the injury, even though that is the window typically used to define posttraumatic headache.
Patients in both groups were about 43 years old, on average, and roughly three-quarters each were male and white, and had completed high school. The leading cause of injury was vehicular accident (58%) followed by falls (25%).
Study results showed that the mild TBI group and the moderate or severe TBI group had an identical prevalence of headache before injury (17%). But the former had a higher incidence of new or worsened headache at baseline (56% vs. 40%), at 3 months (63% vs. 37%), at 6 months (69% vs. 33%), and at 12 months (58% vs. 34%).
Headache was classified according to ICHD-2 criteria for primary headache, with only a single class permitted per patient, based on the predominant features, according to Dr. Lucas. "The idea behind classification of a secondary headache using primary headache criteria is really to try to find some defining features that may allow us to do what we want in the future, which is to get some evidence-based medicine treatment or management protocols," she explained.
At all time points and in both groups, the largest share of headaches (39%-67%) was of the migraine or probable migraine type. Tension headaches were the next most common type. "Surprisingly, cervicogenic was not very [common], particularly considering that many of these were motor vehicle accidents and probably involved whiplash-type injuries," she observed.
Roughly a quarter of headaches were unclassifiable. "We felt that rather than trying to use a shoehorn to fit the headache into a classification, if it didn’t fit, we just stayed with it and deemed it unclassifiable," Dr. Lucas commented.
In both the mild TBI group and the moderate to severe TBI group, the migraine and probable migraine headaches, in addition to being most common, were more likely than the other types of headache to occur daily or several times weekly.
Also, in both groups, patients who had a prior history of headache and female patients were more likely to have headache at follow-up. For example, in the mild TBI group, about 70% of patients who had preexisting headache had headache at all time points during follow-up, compared with about 50% of patients who did not have preexisting headache.
Dr. Lucas disclosed no relevant conflicts of interest.
LOS ANGELES – The likelihood of headache after traumatic brain injury was inversely related to the severity of injury in a longitudinal study of 598 patients.
The patients with mild injury were about 70% more likely than were their counterparts with moderate or severe injury to develop new headache or have a worsening of preexisting headache over the next year, first author Dr. Sylvia Lucas reported at the annual meeting of the American Headache Society.
The majority of headaches were migraine or probable migraine according to the ICHD-2 (International Classification of Headache Disorders, second edition) system, but a large share – roughly a quarter – had features that defied classification. Patients with preexisting headache and female patients had a higher risk of posttraumatic headache.
"Using symptom-based criteria for headache after TBI [traumatic brain injury] hopefully may serve as a framework from which to provide evidence-based treatment," commented Dr. Lucas, clinical professor of neurology, rehabilitation medicine, and neurosurgery at the University of Washington in Seattle.
Session attendee Dr. Werner Becker of the University of Calgary (Alta.) asked, "Any thoughts as to why the patients with milder injuries have more headache?"
"I don’t know. It has to have something to do with the mechanics of the hit, I suspect," Dr. Lucas replied. "We’re just now trying to look at the types of injury. We’re trying to separate subarachnoid hemorrhage, depressed skull fracture, intracerebral hemorrhage, and trying to look at how they relate to the chronicity of the headache. But, as of now, I can’t answer that."
Dr. James R. Couch of the University of Oklahoma, Oklahoma City, who also attended the session, noted that he and his colleagues found a similar pattern in a previous study. "I was very gratified to see that what you are finding is the less severely injured people seem to have a greater propensity for headache," he said. "Maybe the severe brain injury takes out some kind of center that is involved in generating headache, whereas the mild head injury just irritates it."
The investigators studied a single-center cohort of 220 patients with mild TBI who were enrolled within a week of injury and a seven-center cohort of 378 patients with moderate to severe TBI who were admitted to inpatient rehabilitation facilities. All patients were evaluated with the same questionnaire, in person at baseline, and prospectively by telephone over a year, to gain a better understanding of headache incidence, characteristics, and predictors, and treatment effectiveness.
"We feel that the ICHD-2 criteria, both in the civilian and military populations, really don’t contribute to treatment planning," Dr. Lucas commented. "They also don’t account for the latency of posttraumatic headache following trauma," with experience suggesting that almost a third of headache cases do not come to clinical attention until more than 1 week after the injury, even though that is the window typically used to define posttraumatic headache.
Patients in both groups were about 43 years old, on average, and roughly three-quarters each were male and white, and had completed high school. The leading cause of injury was vehicular accident (58%) followed by falls (25%).
Study results showed that the mild TBI group and the moderate or severe TBI group had an identical prevalence of headache before injury (17%). But the former had a higher incidence of new or worsened headache at baseline (56% vs. 40%), at 3 months (63% vs. 37%), at 6 months (69% vs. 33%), and at 12 months (58% vs. 34%).
Headache was classified according to ICHD-2 criteria for primary headache, with only a single class permitted per patient, based on the predominant features, according to Dr. Lucas. "The idea behind classification of a secondary headache using primary headache criteria is really to try to find some defining features that may allow us to do what we want in the future, which is to get some evidence-based medicine treatment or management protocols," she explained.
At all time points and in both groups, the largest share of headaches (39%-67%) was of the migraine or probable migraine type. Tension headaches were the next most common type. "Surprisingly, cervicogenic was not very [common], particularly considering that many of these were motor vehicle accidents and probably involved whiplash-type injuries," she observed.
Roughly a quarter of headaches were unclassifiable. "We felt that rather than trying to use a shoehorn to fit the headache into a classification, if it didn’t fit, we just stayed with it and deemed it unclassifiable," Dr. Lucas commented.
In both the mild TBI group and the moderate to severe TBI group, the migraine and probable migraine headaches, in addition to being most common, were more likely than the other types of headache to occur daily or several times weekly.
Also, in both groups, patients who had a prior history of headache and female patients were more likely to have headache at follow-up. For example, in the mild TBI group, about 70% of patients who had preexisting headache had headache at all time points during follow-up, compared with about 50% of patients who did not have preexisting headache.
Dr. Lucas disclosed no relevant conflicts of interest.
AT THE ANNUAL MEETING OF THE AMERICAN HEADACHE SOCIETY
Major Finding: The prevalence of new or worsened headache at 1 year after TBI was 58% in the cohort with mild injury, compared with 34% in the cohort with moderate or severe injury.
Data Source: This was a longitudinal study of two cohorts having a total of 598 patients with TBI.
Disclosures: Dr. Lucas disclosed no relevant conflicts of interest.
Acute Use of Rizatriptan for Migraine Safe, Effective in Teens
LOS ANGELES – Rizatriptan is safe and effective when used for intermittent treatment of migraine in adolescents on a long-term basis, according to a year-long, multicenter, open-label trial presented at the annual meeting of the American Headache Society.
Less than 1% of the 606 patients studied experienced serious drug-related adverse events. And all of these events were classified as serious because they occurred after accidental use of an extra dose of rizatriptan in a 24-hour period.
Additionally, in 46% of treated attacks, the patients were pain free at 2 hours after taking the medication, reported lead investigator Dr. Eric M. Pearlman of Children’s Hospital at Memorial University Medical Center, Savannah, Ga.
"Rizatriptan was generally safe and well tolerated in the long-term acute treatment of migraine in this adolescent population," he maintained. And "at least in an open-label fashion, it was effective."
Session attendee Dr. James R. Couch of the University of Oklahoma, Oklahoma City, commented, "That’s a very impressive pain-free number. ... The usual triptan gives us between 25% and 30% pain freedom. Do you have any comments on why children seem to respond much better?"
"I think it was because it was open label," Dr. Pearlman replied. "But this was done in conjunction with a single-attack, double-blind, placebo-controlled trial," he added. That trial, which led to regulatory approval of the drug for adolescents, had a run-in phase aimed at identifying and excluding placebo responders; the rate of pain freedom at 2 hours was 31% with rizatriptan.
Dr. Pearlman and his colleagues studied 12- to 17-years-olds in the United States and Europe who met diagnostic criteria for migraine and had not achieved a satisfactory response to treatment with nonsteroidal anti-inflammatory drugs or acetaminophen.
They were assigned to the orally disintegrating tablet formulation of rizatriptan (Maxalt-MLT) based on weight: 5 mg if they weighed less than 40 kg, and 10 mg if they weighed 40 kg or more.
Patients were instructed to use the medication to treat up to eight migraines of any severity per month. But they also were told to use only a single dose of the medication in a 24-hour period (additional nontriptan rescue medication was permitted if necessary).
Overall, 23 patients were treated with the 5-mg dose, and 583 were treated with the 10-mg dose. The average age was about 13 years in the former group and 15 years in the latter group.
As far as migraine history, in the 3 months before the study, the patients had experienced on average four attacks monthly. The majority had migraines lasting more than 6 hours. Twelve percent were on preventive therapies. "For an adolescent trial, these are fairly disabling characteristics," Dr. Pearlman noted.
A total of 12,284 attacks (most either moderate or severe) were treated during the study. The mean number of doses of study medication taken by treated patients was 20.
The leading adverse event by far was accidental overdose (seen in 24% of patients overall), defined as taking more than one dose of rizatriptan in 24 hours. Possible reasons for these overdoses may have been previous experience with triptans for which two doses are allowed in this time period, and confusing a 24-hour day with a calendar day, Dr. Pearlman speculated. The next most common adverse events were dizziness (8%), somnolence (7%), and nausea (6%).
The rate of serious drug-related adverse events was 0% in the 5-mg group and 0.5% in the 10-mg group. "All three adverse events that were classified as serious occurred in the setting of an accidental overdose, and any adverse event that occurred in conjunction with an overdose per protocol was defined as serious," he explained.
In terms of efficacy, the rate of freedom from pain at 2 hours was 46% for all treated attacks, and it appeared to be consistent over time. In a post hoc analysis, the rate of pain relief at 2 hours was 65% for treated attacks. Rescue medications were used in only 6% of treated attacks.
Dr. Pearlman disclosed that he has received consulting fees from Merck, maker of Maxalt. The study was funded by Merck.
LOS ANGELES – Rizatriptan is safe and effective when used for intermittent treatment of migraine in adolescents on a long-term basis, according to a year-long, multicenter, open-label trial presented at the annual meeting of the American Headache Society.
Less than 1% of the 606 patients studied experienced serious drug-related adverse events. And all of these events were classified as serious because they occurred after accidental use of an extra dose of rizatriptan in a 24-hour period.
Additionally, in 46% of treated attacks, the patients were pain free at 2 hours after taking the medication, reported lead investigator Dr. Eric M. Pearlman of Children’s Hospital at Memorial University Medical Center, Savannah, Ga.
"Rizatriptan was generally safe and well tolerated in the long-term acute treatment of migraine in this adolescent population," he maintained. And "at least in an open-label fashion, it was effective."
Session attendee Dr. James R. Couch of the University of Oklahoma, Oklahoma City, commented, "That’s a very impressive pain-free number. ... The usual triptan gives us between 25% and 30% pain freedom. Do you have any comments on why children seem to respond much better?"
"I think it was because it was open label," Dr. Pearlman replied. "But this was done in conjunction with a single-attack, double-blind, placebo-controlled trial," he added. That trial, which led to regulatory approval of the drug for adolescents, had a run-in phase aimed at identifying and excluding placebo responders; the rate of pain freedom at 2 hours was 31% with rizatriptan.
Dr. Pearlman and his colleagues studied 12- to 17-years-olds in the United States and Europe who met diagnostic criteria for migraine and had not achieved a satisfactory response to treatment with nonsteroidal anti-inflammatory drugs or acetaminophen.
They were assigned to the orally disintegrating tablet formulation of rizatriptan (Maxalt-MLT) based on weight: 5 mg if they weighed less than 40 kg, and 10 mg if they weighed 40 kg or more.
Patients were instructed to use the medication to treat up to eight migraines of any severity per month. But they also were told to use only a single dose of the medication in a 24-hour period (additional nontriptan rescue medication was permitted if necessary).
Overall, 23 patients were treated with the 5-mg dose, and 583 were treated with the 10-mg dose. The average age was about 13 years in the former group and 15 years in the latter group.
As far as migraine history, in the 3 months before the study, the patients had experienced on average four attacks monthly. The majority had migraines lasting more than 6 hours. Twelve percent were on preventive therapies. "For an adolescent trial, these are fairly disabling characteristics," Dr. Pearlman noted.
A total of 12,284 attacks (most either moderate or severe) were treated during the study. The mean number of doses of study medication taken by treated patients was 20.
The leading adverse event by far was accidental overdose (seen in 24% of patients overall), defined as taking more than one dose of rizatriptan in 24 hours. Possible reasons for these overdoses may have been previous experience with triptans for which two doses are allowed in this time period, and confusing a 24-hour day with a calendar day, Dr. Pearlman speculated. The next most common adverse events were dizziness (8%), somnolence (7%), and nausea (6%).
The rate of serious drug-related adverse events was 0% in the 5-mg group and 0.5% in the 10-mg group. "All three adverse events that were classified as serious occurred in the setting of an accidental overdose, and any adverse event that occurred in conjunction with an overdose per protocol was defined as serious," he explained.
In terms of efficacy, the rate of freedom from pain at 2 hours was 46% for all treated attacks, and it appeared to be consistent over time. In a post hoc analysis, the rate of pain relief at 2 hours was 65% for treated attacks. Rescue medications were used in only 6% of treated attacks.
Dr. Pearlman disclosed that he has received consulting fees from Merck, maker of Maxalt. The study was funded by Merck.
LOS ANGELES – Rizatriptan is safe and effective when used for intermittent treatment of migraine in adolescents on a long-term basis, according to a year-long, multicenter, open-label trial presented at the annual meeting of the American Headache Society.
Less than 1% of the 606 patients studied experienced serious drug-related adverse events. And all of these events were classified as serious because they occurred after accidental use of an extra dose of rizatriptan in a 24-hour period.
Additionally, in 46% of treated attacks, the patients were pain free at 2 hours after taking the medication, reported lead investigator Dr. Eric M. Pearlman of Children’s Hospital at Memorial University Medical Center, Savannah, Ga.
"Rizatriptan was generally safe and well tolerated in the long-term acute treatment of migraine in this adolescent population," he maintained. And "at least in an open-label fashion, it was effective."
Session attendee Dr. James R. Couch of the University of Oklahoma, Oklahoma City, commented, "That’s a very impressive pain-free number. ... The usual triptan gives us between 25% and 30% pain freedom. Do you have any comments on why children seem to respond much better?"
"I think it was because it was open label," Dr. Pearlman replied. "But this was done in conjunction with a single-attack, double-blind, placebo-controlled trial," he added. That trial, which led to regulatory approval of the drug for adolescents, had a run-in phase aimed at identifying and excluding placebo responders; the rate of pain freedom at 2 hours was 31% with rizatriptan.
Dr. Pearlman and his colleagues studied 12- to 17-years-olds in the United States and Europe who met diagnostic criteria for migraine and had not achieved a satisfactory response to treatment with nonsteroidal anti-inflammatory drugs or acetaminophen.
They were assigned to the orally disintegrating tablet formulation of rizatriptan (Maxalt-MLT) based on weight: 5 mg if they weighed less than 40 kg, and 10 mg if they weighed 40 kg or more.
Patients were instructed to use the medication to treat up to eight migraines of any severity per month. But they also were told to use only a single dose of the medication in a 24-hour period (additional nontriptan rescue medication was permitted if necessary).
Overall, 23 patients were treated with the 5-mg dose, and 583 were treated with the 10-mg dose. The average age was about 13 years in the former group and 15 years in the latter group.
As far as migraine history, in the 3 months before the study, the patients had experienced on average four attacks monthly. The majority had migraines lasting more than 6 hours. Twelve percent were on preventive therapies. "For an adolescent trial, these are fairly disabling characteristics," Dr. Pearlman noted.
A total of 12,284 attacks (most either moderate or severe) were treated during the study. The mean number of doses of study medication taken by treated patients was 20.
The leading adverse event by far was accidental overdose (seen in 24% of patients overall), defined as taking more than one dose of rizatriptan in 24 hours. Possible reasons for these overdoses may have been previous experience with triptans for which two doses are allowed in this time period, and confusing a 24-hour day with a calendar day, Dr. Pearlman speculated. The next most common adverse events were dizziness (8%), somnolence (7%), and nausea (6%).
The rate of serious drug-related adverse events was 0% in the 5-mg group and 0.5% in the 10-mg group. "All three adverse events that were classified as serious occurred in the setting of an accidental overdose, and any adverse event that occurred in conjunction with an overdose per protocol was defined as serious," he explained.
In terms of efficacy, the rate of freedom from pain at 2 hours was 46% for all treated attacks, and it appeared to be consistent over time. In a post hoc analysis, the rate of pain relief at 2 hours was 65% for treated attacks. Rescue medications were used in only 6% of treated attacks.
Dr. Pearlman disclosed that he has received consulting fees from Merck, maker of Maxalt. The study was funded by Merck.
AT THE ANNUAL MEETING OF THE AMERICAN HEADACHE SOCIETY
Neuropsychological Data Endorse Preclinical Alzheimer's
VANCOUVER, B.C. – The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.
So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. "Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers]."
The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. "One gets the sense that there are newer, better tests ... that might have picked up cross-sectionally the differences," said Dr. Howard Chertkow of McGill University in Montreal.
Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.
"The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. ... Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease," said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.
Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.
Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. "Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years," he said.
"Extrapolating from these group analyses," Dr. Caselli said, "neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like ... the lorazepam challenge," for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).
A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.
The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).
Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.
"Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills," Dr. Caselli commented.
In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.
Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.
Dr. Caselli disclosed no relevant conflicts of interest.
VANCOUVER, B.C. – The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.
So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. "Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers]."
The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. "One gets the sense that there are newer, better tests ... that might have picked up cross-sectionally the differences," said Dr. Howard Chertkow of McGill University in Montreal.
Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.
"The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. ... Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease," said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.
Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.
Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. "Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years," he said.
"Extrapolating from these group analyses," Dr. Caselli said, "neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like ... the lorazepam challenge," for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).
A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.
The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).
Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.
"Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills," Dr. Caselli commented.
In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.
Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.
Dr. Caselli disclosed no relevant conflicts of interest.
VANCOUVER, B.C. – The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.
So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. "Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers]."
The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. "One gets the sense that there are newer, better tests ... that might have picked up cross-sectionally the differences," said Dr. Howard Chertkow of McGill University in Montreal.
Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.
"The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. ... Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease," said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.
Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.
Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. "Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years," he said.
"Extrapolating from these group analyses," Dr. Caselli said, "neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like ... the lorazepam challenge," for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).
A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.
The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).
Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.
"Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills," Dr. Caselli commented.
In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.
Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.
Dr. Caselli disclosed no relevant conflicts of interest.
AT THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE 2012
Major Finding: Participants who didn’t carry the apo E allele had a greater-than-1% annual improvement in scores on the SRT. Carriers of apo E did not improve their scores over time.
Data Source: A longitudinal study of 813 cognitively healthy individuals from the Arizona apo E cohort and the Arizona Alzheimer’s Disease Center cohort.
Disclosures: Dr. Caselli disclosed no relevant conflicts of interest.
'Visual Snow' May Be a Distinct Clinical Entity
LOS ANGELES – So-called visual snow, characterized by myriad persistent tiny dots throughout the visual field, commonly occurs in patients with migraine, but it is usually accompanied by other visual symptoms and appears to be a distinct entity, according to combined data from two cross-sectional studies.
In a two-part study among 240 patients with visual snow, nearly all had other visual symptoms such as after-images or poor night vision, reported lead investigator Christoph Schankin, Ph.D., a postdoctoral clinical research fellow at the University of California at San Francisco Headache Center. Slightly more than half also had migraine, but the visual snow did not have any of the features of typical aura. Also, only a small minority of affected patients had used illicit drugs.
"Visual snow is almost always associated with additional visual symptoms. It therefore represents a unique clinical syndrome – the visual snow syndrome," he said at the annual meeting of the American Headache Society. "It is distinct from visual aura in migraine; migraine with and without aura are common comorbidities, but we don’t actually know at the moment what is the pathological link between those two conditions. And the intake of illicit drugs is not relevant."
Dr. Schankin went one step further, proposing new diagnostic criteria for the visual snow syndrome: visual snow plus at least three additional visual symptoms out of nine identified in the study, in the context where these symptoms are not consistent with typical migraine aura and cannot be attributed to some other disorder.
A session attendee congratulated the investigators on the research, noting, "These patients, for those who haven’t seen them, are devastated and lonely. Some can’t drive, some can’t work, some can’t read books, some can’t use computers. They are a wreck ... and there is nobody out there who is owning this condition – I don’t know if it falls in the realm of neuro-ophthalmology or neurology or headache, and what to do with these poor folks. ...They have been banished to the realms of psychiatry and have been told they have functional disorders and other things, when it is very clearly a widespread neurological perceptual disturbance."
He said his own experience with affected patients affirms the existence of the visual snow syndrome. "The more you talk to them, the more you appreciate that they really do have these features in common ... So I just want to thank you for bringing attention to this sort of orphan disorder, and hope it raises awareness, and that some people will take interest in it and studying the biophysiology and treatment options."
Session chair Dr. R. Allan Purdy, a neurologist at Dalhousie University in Halifax, N.S., asked the neuro-ophthalmologists present to weigh in with their thoughts on the possible pathophysiology of visual snow.
"I think this is a somewhat migrainous phenomenon in people with very sensitive brains," one replied. "We have done EEGs on these people and they are normal, at least in adults that we have seen with this. It is definitely real – these people are not making this up. And we have seen quite a few of these cases in neuro-ophthalmology."
Another concurred, saying "I think it’s real." Moreover, in her opinion, the presence of visual snow alone would be sufficient for diagnosis. "I suspect it’s migrainous because most of these people have migraines. But it’s not aura. I don’t know really what it is. It’s incredibly frustrating because nothing works. You can try every antiepileptic known to mankind, and nothing works. So I agree that this is something we need to pay attention to and help these people."
Dr. Schankin noted that research on visual snow is scarce, and affected individuals suffer in part because of a lack of knowledge about the condition in the medical community. "Patients are commonly given the diagnosis of persistent migraine aura or a posthallucinogen perceptual disorder, especially after LSD intake," he noted.
He and his coinvestigators studied members of an online support group for visual snow (Eye on Vision). In the first part of the study, they analyzed data from an Internet survey among 120 patients that asked about visual symptoms. They were 26 years old on average and about two-thirds were men.
Results showed that in addition to visual snow, nearly all patients reported other visual symptoms, such floaters (73%); persistent visual images (63%); difficulty seeing at night (58%); tiny objects moving on the blue sky (57%); sensitivity to light (54%); trails behind moving objects (48%); bright flashes (44%); and colored swirls, clouds, or waves when their eyes were closed (41%).
Dr. Schankin noted that some of these symptoms map onto the well defined clinical phenomena of palinopsia (trailing and prolonged after-images), photophobia, and impaired night vision.
And others fall into a category of entoptic phenomena, or visual symptoms originating in the eyes themselves, namely, floaters (likely protein aggregations in the vitreous fluid that cast a shadow on photoreceptors); photopsia (bright flashes typically elicited by mechanical stimulation of the eyes); Scheerer’s phenomenon (small moving objects against the sky thought to be due to blood cells moving in the retinal vessels that cast a shadow on the photoreceptors); and self-light of the eye (the colored swirls, clouds, and waves), whose etiology is unknown.
In the second part of the study, the investigators conducted telephone interviews with another 120 patients with visual snow to further explore the nature of symptoms and antecedent events. These patients were 31 years old on average and nearly evenly split between men and women.
Results showed that the textural patterns described for the snow varied considerably. The most common pattern reported was dots alternating from black (on light backgrounds) to white (on dark backgrounds) (48%), while some patients reported flashing dots, transparent dots, or other patterns. "We don’t know what that means – whether that has some pathophysiologic relevance," Dr. Schankin commented.
Analyses restricted to the subset reporting black and white dots showed that 98% had at least one additional visual symptom, and 93% had three or more. In this part of the study, another symptom identified was halos or starbursts, seen in 65% of cases.
Of the 40 patients with onset of visual snow later in life, 54% had a history of migraine. However, when asked about events in the week before the onset of visual snow, only 33% reported headache, and just 10% reported aura symptoms. But none had classic features of visual aura, such as unilaterality, zig-zag lines, or scotoma, during visual snow. Additionally, only 8% had used illicit drugs, mainly marijuana, in the week leading up to the start of visual snow, and none had significant ophthalmologic findings.
Dr. Schankin disclosed no relevant conflicts of interest.
LOS ANGELES – So-called visual snow, characterized by myriad persistent tiny dots throughout the visual field, commonly occurs in patients with migraine, but it is usually accompanied by other visual symptoms and appears to be a distinct entity, according to combined data from two cross-sectional studies.
In a two-part study among 240 patients with visual snow, nearly all had other visual symptoms such as after-images or poor night vision, reported lead investigator Christoph Schankin, Ph.D., a postdoctoral clinical research fellow at the University of California at San Francisco Headache Center. Slightly more than half also had migraine, but the visual snow did not have any of the features of typical aura. Also, only a small minority of affected patients had used illicit drugs.
"Visual snow is almost always associated with additional visual symptoms. It therefore represents a unique clinical syndrome – the visual snow syndrome," he said at the annual meeting of the American Headache Society. "It is distinct from visual aura in migraine; migraine with and without aura are common comorbidities, but we don’t actually know at the moment what is the pathological link between those two conditions. And the intake of illicit drugs is not relevant."
Dr. Schankin went one step further, proposing new diagnostic criteria for the visual snow syndrome: visual snow plus at least three additional visual symptoms out of nine identified in the study, in the context where these symptoms are not consistent with typical migraine aura and cannot be attributed to some other disorder.
A session attendee congratulated the investigators on the research, noting, "These patients, for those who haven’t seen them, are devastated and lonely. Some can’t drive, some can’t work, some can’t read books, some can’t use computers. They are a wreck ... and there is nobody out there who is owning this condition – I don’t know if it falls in the realm of neuro-ophthalmology or neurology or headache, and what to do with these poor folks. ...They have been banished to the realms of psychiatry and have been told they have functional disorders and other things, when it is very clearly a widespread neurological perceptual disturbance."
He said his own experience with affected patients affirms the existence of the visual snow syndrome. "The more you talk to them, the more you appreciate that they really do have these features in common ... So I just want to thank you for bringing attention to this sort of orphan disorder, and hope it raises awareness, and that some people will take interest in it and studying the biophysiology and treatment options."
Session chair Dr. R. Allan Purdy, a neurologist at Dalhousie University in Halifax, N.S., asked the neuro-ophthalmologists present to weigh in with their thoughts on the possible pathophysiology of visual snow.
"I think this is a somewhat migrainous phenomenon in people with very sensitive brains," one replied. "We have done EEGs on these people and they are normal, at least in adults that we have seen with this. It is definitely real – these people are not making this up. And we have seen quite a few of these cases in neuro-ophthalmology."
Another concurred, saying "I think it’s real." Moreover, in her opinion, the presence of visual snow alone would be sufficient for diagnosis. "I suspect it’s migrainous because most of these people have migraines. But it’s not aura. I don’t know really what it is. It’s incredibly frustrating because nothing works. You can try every antiepileptic known to mankind, and nothing works. So I agree that this is something we need to pay attention to and help these people."
Dr. Schankin noted that research on visual snow is scarce, and affected individuals suffer in part because of a lack of knowledge about the condition in the medical community. "Patients are commonly given the diagnosis of persistent migraine aura or a posthallucinogen perceptual disorder, especially after LSD intake," he noted.
He and his coinvestigators studied members of an online support group for visual snow (Eye on Vision). In the first part of the study, they analyzed data from an Internet survey among 120 patients that asked about visual symptoms. They were 26 years old on average and about two-thirds were men.
Results showed that in addition to visual snow, nearly all patients reported other visual symptoms, such floaters (73%); persistent visual images (63%); difficulty seeing at night (58%); tiny objects moving on the blue sky (57%); sensitivity to light (54%); trails behind moving objects (48%); bright flashes (44%); and colored swirls, clouds, or waves when their eyes were closed (41%).
Dr. Schankin noted that some of these symptoms map onto the well defined clinical phenomena of palinopsia (trailing and prolonged after-images), photophobia, and impaired night vision.
And others fall into a category of entoptic phenomena, or visual symptoms originating in the eyes themselves, namely, floaters (likely protein aggregations in the vitreous fluid that cast a shadow on photoreceptors); photopsia (bright flashes typically elicited by mechanical stimulation of the eyes); Scheerer’s phenomenon (small moving objects against the sky thought to be due to blood cells moving in the retinal vessels that cast a shadow on the photoreceptors); and self-light of the eye (the colored swirls, clouds, and waves), whose etiology is unknown.
In the second part of the study, the investigators conducted telephone interviews with another 120 patients with visual snow to further explore the nature of symptoms and antecedent events. These patients were 31 years old on average and nearly evenly split between men and women.
Results showed that the textural patterns described for the snow varied considerably. The most common pattern reported was dots alternating from black (on light backgrounds) to white (on dark backgrounds) (48%), while some patients reported flashing dots, transparent dots, or other patterns. "We don’t know what that means – whether that has some pathophysiologic relevance," Dr. Schankin commented.
Analyses restricted to the subset reporting black and white dots showed that 98% had at least one additional visual symptom, and 93% had three or more. In this part of the study, another symptom identified was halos or starbursts, seen in 65% of cases.
Of the 40 patients with onset of visual snow later in life, 54% had a history of migraine. However, when asked about events in the week before the onset of visual snow, only 33% reported headache, and just 10% reported aura symptoms. But none had classic features of visual aura, such as unilaterality, zig-zag lines, or scotoma, during visual snow. Additionally, only 8% had used illicit drugs, mainly marijuana, in the week leading up to the start of visual snow, and none had significant ophthalmologic findings.
Dr. Schankin disclosed no relevant conflicts of interest.
LOS ANGELES – So-called visual snow, characterized by myriad persistent tiny dots throughout the visual field, commonly occurs in patients with migraine, but it is usually accompanied by other visual symptoms and appears to be a distinct entity, according to combined data from two cross-sectional studies.
In a two-part study among 240 patients with visual snow, nearly all had other visual symptoms such as after-images or poor night vision, reported lead investigator Christoph Schankin, Ph.D., a postdoctoral clinical research fellow at the University of California at San Francisco Headache Center. Slightly more than half also had migraine, but the visual snow did not have any of the features of typical aura. Also, only a small minority of affected patients had used illicit drugs.
"Visual snow is almost always associated with additional visual symptoms. It therefore represents a unique clinical syndrome – the visual snow syndrome," he said at the annual meeting of the American Headache Society. "It is distinct from visual aura in migraine; migraine with and without aura are common comorbidities, but we don’t actually know at the moment what is the pathological link between those two conditions. And the intake of illicit drugs is not relevant."
Dr. Schankin went one step further, proposing new diagnostic criteria for the visual snow syndrome: visual snow plus at least three additional visual symptoms out of nine identified in the study, in the context where these symptoms are not consistent with typical migraine aura and cannot be attributed to some other disorder.
A session attendee congratulated the investigators on the research, noting, "These patients, for those who haven’t seen them, are devastated and lonely. Some can’t drive, some can’t work, some can’t read books, some can’t use computers. They are a wreck ... and there is nobody out there who is owning this condition – I don’t know if it falls in the realm of neuro-ophthalmology or neurology or headache, and what to do with these poor folks. ...They have been banished to the realms of psychiatry and have been told they have functional disorders and other things, when it is very clearly a widespread neurological perceptual disturbance."
He said his own experience with affected patients affirms the existence of the visual snow syndrome. "The more you talk to them, the more you appreciate that they really do have these features in common ... So I just want to thank you for bringing attention to this sort of orphan disorder, and hope it raises awareness, and that some people will take interest in it and studying the biophysiology and treatment options."
Session chair Dr. R. Allan Purdy, a neurologist at Dalhousie University in Halifax, N.S., asked the neuro-ophthalmologists present to weigh in with their thoughts on the possible pathophysiology of visual snow.
"I think this is a somewhat migrainous phenomenon in people with very sensitive brains," one replied. "We have done EEGs on these people and they are normal, at least in adults that we have seen with this. It is definitely real – these people are not making this up. And we have seen quite a few of these cases in neuro-ophthalmology."
Another concurred, saying "I think it’s real." Moreover, in her opinion, the presence of visual snow alone would be sufficient for diagnosis. "I suspect it’s migrainous because most of these people have migraines. But it’s not aura. I don’t know really what it is. It’s incredibly frustrating because nothing works. You can try every antiepileptic known to mankind, and nothing works. So I agree that this is something we need to pay attention to and help these people."
Dr. Schankin noted that research on visual snow is scarce, and affected individuals suffer in part because of a lack of knowledge about the condition in the medical community. "Patients are commonly given the diagnosis of persistent migraine aura or a posthallucinogen perceptual disorder, especially after LSD intake," he noted.
He and his coinvestigators studied members of an online support group for visual snow (Eye on Vision). In the first part of the study, they analyzed data from an Internet survey among 120 patients that asked about visual symptoms. They were 26 years old on average and about two-thirds were men.
Results showed that in addition to visual snow, nearly all patients reported other visual symptoms, such floaters (73%); persistent visual images (63%); difficulty seeing at night (58%); tiny objects moving on the blue sky (57%); sensitivity to light (54%); trails behind moving objects (48%); bright flashes (44%); and colored swirls, clouds, or waves when their eyes were closed (41%).
Dr. Schankin noted that some of these symptoms map onto the well defined clinical phenomena of palinopsia (trailing and prolonged after-images), photophobia, and impaired night vision.
And others fall into a category of entoptic phenomena, or visual symptoms originating in the eyes themselves, namely, floaters (likely protein aggregations in the vitreous fluid that cast a shadow on photoreceptors); photopsia (bright flashes typically elicited by mechanical stimulation of the eyes); Scheerer’s phenomenon (small moving objects against the sky thought to be due to blood cells moving in the retinal vessels that cast a shadow on the photoreceptors); and self-light of the eye (the colored swirls, clouds, and waves), whose etiology is unknown.
In the second part of the study, the investigators conducted telephone interviews with another 120 patients with visual snow to further explore the nature of symptoms and antecedent events. These patients were 31 years old on average and nearly evenly split between men and women.
Results showed that the textural patterns described for the snow varied considerably. The most common pattern reported was dots alternating from black (on light backgrounds) to white (on dark backgrounds) (48%), while some patients reported flashing dots, transparent dots, or other patterns. "We don’t know what that means – whether that has some pathophysiologic relevance," Dr. Schankin commented.
Analyses restricted to the subset reporting black and white dots showed that 98% had at least one additional visual symptom, and 93% had three or more. In this part of the study, another symptom identified was halos or starbursts, seen in 65% of cases.
Of the 40 patients with onset of visual snow later in life, 54% had a history of migraine. However, when asked about events in the week before the onset of visual snow, only 33% reported headache, and just 10% reported aura symptoms. But none had classic features of visual aura, such as unilaterality, zig-zag lines, or scotoma, during visual snow. Additionally, only 8% had used illicit drugs, mainly marijuana, in the week leading up to the start of visual snow, and none had significant ophthalmologic findings.
Dr. Schankin disclosed no relevant conflicts of interest.
AT THE ANNUAL MEETING OF THE AMERICAN HEADACHE SOCIETY
Major Finding: Slightly more than half of patients with ‘visual snow’ have migraine, and the patients nearly always have other visual symptoms, such as floaters (73%); persistent visual images (63%); difficulty seeing at night (58%); tiny objects moving on the blue sky (57%); sensitivity to light (54%); trails behind moving objects (48%); bright flashes (44%); and colored swirls, clouds, or waves when their eyes were closed (41%).
Data Source: A pair of cross-sectional studies among 240 patients with visual snow.
Disclosures: Dr. Schankin disclosed no relevant conflicts of interest.
Superiority of Dose-Dense Chemo Upheld for Ovarian Cancer
CHICAGO – The superiority of dose-dense paclitaxel-plus-carboplatin chemotherapy stood up in the long term for women with ovarian or related cancers in a randomized trial.
Investigators from the Japanese Gynecologic Oncology Group 3016 study reported statistically significant reductions in risks of progression and of death with dose-dense chemotherapy, compared with a conventional regimen, at a median follow-up of 6.4 years.
Women who were given dose-dense chemotherapy had the risk of progression or death cut by 24% and the risk of death cut by 21%, according to results reported at the annual meeting of the American Society of Clinical Oncology. This followed respective reductions of 29% and 25% at a median follow-up of 2.4 years (Lancet 2009;374:1331-8).
In subgroup analyses, the survival benefit of dose-dense chemotherapy was significant only among women who had residual disease after debulking surgery measuring greater than 1 cm, or serous histology.
"Dose-dense [paclitaxel plus carboplatin] improved long-term progression-free survival and overall survival in patients with advanced epithelial ovarian cancer," said first author Dr. Noriyuki Katsumata of the Nippon Medical School–Musashi-Kosugi Hospital in Kawasaki, Japan.
"Neither dose-dense nor conventional treatment seemed effective against clear-cell or mucinous ovarian carcinoma, which suggests that other treatment strategies are needed," he added.
The study "is a major contribution to our understanding of dose-dense therapy and whether or not it should be used," said the invited discussant, Dr. Jonathan S. Berek, director of the Stanford (Calif.) Women’s Cancer Center. In particular, the overall survival benefit "is a very important observation for our patients and our specialty."
However, the trial was done in a Japanese population, he cautioned. "Maybe there are racial differences. We’ll have to wait for confirmatory trials to see whether there is any difference. There may be none, but we’ll see."
"One of the questions I’d like to raise is, how does this compare to the advantage that we saw with intraperitoneal therapy, and what should we recommend to our patients while we await more confirmatory and comparative data?" Dr. Berek said.
He noted that a variety of trials – GOG (Gynecologic Oncology Group)–0252, GOG-0262, ICON8, MITO-7, and iPocc – will better clarify and compare the merits of dose-dense and intraperitoneal approaches, sometimes in combination with the antiangiogenic agent bevacizumab (Avastin).
"I suspect in the next 2-3 years, the head-to-head comparison of the dose-dense regimens and the intraperitoneal regimens will emerge, and we will probably have at least some clear answers about whether it’s route of administration or frequency of administration, or in some cases, both" that optimizes efficacy, Dr. Berek concluded.
The 637 women accrued to the Japanese trial, also known as the NOVEL study, had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer and had undergone debulking surgery. The large majority (84%) had serous tumor histology.
They were randomly assigned to paclitaxel (Taxol) plus carboplatin given according to a conventional schedule (paclitaxel, 180 mg/m2; carboplatin, AUC [area under the curve] = 6; each given once every 3 weeks) or according to a dose-dense schedule (paclitaxel, 80 mg/m2 weekly; carboplatin, AUC = 6 once every 3 weeks), in both arms for six to nine cycles.
The updated results showed that relative to conventional chemotherapy, dose-dense chemotherapy conferred better median progression-free survival (28.2 vs. 17.5 months, respectively; hazard ratio, 0.76; P = .004) and overall survival (not reached vs. 62.2 months; HR, 0.79; P = .04). At this point, 58.7% of the dose-dense group and 51.1% of the conventional therapy group were alive.
In analyses stratified by the extent of residual disease after debulking surgery, the overall survival benefit of dose-dense chemotherapy was significant only for women who had residual disease measuring greater than 1 cm (median, 51.2 months vs. 33.5 months; HR, 0.75; P = .03) or serous histology (median, not reached vs. 61.2 months; HR, 0.76; P = .03).
In a multivariate analysis, dose-dense chemotherapy was a significant independent predictor of overall survival, along with ovarian disease site, earlier stage, less residual disease, better performance status, and a paclitaxel relative dose intensity of at least 80%.
Dr. Katsumata disclosed no relevant conflicts of interest. Dr. Berek disclosed no relevant conflicts of interest.
CHICAGO – The superiority of dose-dense paclitaxel-plus-carboplatin chemotherapy stood up in the long term for women with ovarian or related cancers in a randomized trial.
Investigators from the Japanese Gynecologic Oncology Group 3016 study reported statistically significant reductions in risks of progression and of death with dose-dense chemotherapy, compared with a conventional regimen, at a median follow-up of 6.4 years.
Women who were given dose-dense chemotherapy had the risk of progression or death cut by 24% and the risk of death cut by 21%, according to results reported at the annual meeting of the American Society of Clinical Oncology. This followed respective reductions of 29% and 25% at a median follow-up of 2.4 years (Lancet 2009;374:1331-8).
In subgroup analyses, the survival benefit of dose-dense chemotherapy was significant only among women who had residual disease after debulking surgery measuring greater than 1 cm, or serous histology.
"Dose-dense [paclitaxel plus carboplatin] improved long-term progression-free survival and overall survival in patients with advanced epithelial ovarian cancer," said first author Dr. Noriyuki Katsumata of the Nippon Medical School–Musashi-Kosugi Hospital in Kawasaki, Japan.
"Neither dose-dense nor conventional treatment seemed effective against clear-cell or mucinous ovarian carcinoma, which suggests that other treatment strategies are needed," he added.
The study "is a major contribution to our understanding of dose-dense therapy and whether or not it should be used," said the invited discussant, Dr. Jonathan S. Berek, director of the Stanford (Calif.) Women’s Cancer Center. In particular, the overall survival benefit "is a very important observation for our patients and our specialty."
However, the trial was done in a Japanese population, he cautioned. "Maybe there are racial differences. We’ll have to wait for confirmatory trials to see whether there is any difference. There may be none, but we’ll see."
"One of the questions I’d like to raise is, how does this compare to the advantage that we saw with intraperitoneal therapy, and what should we recommend to our patients while we await more confirmatory and comparative data?" Dr. Berek said.
He noted that a variety of trials – GOG (Gynecologic Oncology Group)–0252, GOG-0262, ICON8, MITO-7, and iPocc – will better clarify and compare the merits of dose-dense and intraperitoneal approaches, sometimes in combination with the antiangiogenic agent bevacizumab (Avastin).
"I suspect in the next 2-3 years, the head-to-head comparison of the dose-dense regimens and the intraperitoneal regimens will emerge, and we will probably have at least some clear answers about whether it’s route of administration or frequency of administration, or in some cases, both" that optimizes efficacy, Dr. Berek concluded.
The 637 women accrued to the Japanese trial, also known as the NOVEL study, had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer and had undergone debulking surgery. The large majority (84%) had serous tumor histology.
They were randomly assigned to paclitaxel (Taxol) plus carboplatin given according to a conventional schedule (paclitaxel, 180 mg/m2; carboplatin, AUC [area under the curve] = 6; each given once every 3 weeks) or according to a dose-dense schedule (paclitaxel, 80 mg/m2 weekly; carboplatin, AUC = 6 once every 3 weeks), in both arms for six to nine cycles.
The updated results showed that relative to conventional chemotherapy, dose-dense chemotherapy conferred better median progression-free survival (28.2 vs. 17.5 months, respectively; hazard ratio, 0.76; P = .004) and overall survival (not reached vs. 62.2 months; HR, 0.79; P = .04). At this point, 58.7% of the dose-dense group and 51.1% of the conventional therapy group were alive.
In analyses stratified by the extent of residual disease after debulking surgery, the overall survival benefit of dose-dense chemotherapy was significant only for women who had residual disease measuring greater than 1 cm (median, 51.2 months vs. 33.5 months; HR, 0.75; P = .03) or serous histology (median, not reached vs. 61.2 months; HR, 0.76; P = .03).
In a multivariate analysis, dose-dense chemotherapy was a significant independent predictor of overall survival, along with ovarian disease site, earlier stage, less residual disease, better performance status, and a paclitaxel relative dose intensity of at least 80%.
Dr. Katsumata disclosed no relevant conflicts of interest. Dr. Berek disclosed no relevant conflicts of interest.
CHICAGO – The superiority of dose-dense paclitaxel-plus-carboplatin chemotherapy stood up in the long term for women with ovarian or related cancers in a randomized trial.
Investigators from the Japanese Gynecologic Oncology Group 3016 study reported statistically significant reductions in risks of progression and of death with dose-dense chemotherapy, compared with a conventional regimen, at a median follow-up of 6.4 years.
Women who were given dose-dense chemotherapy had the risk of progression or death cut by 24% and the risk of death cut by 21%, according to results reported at the annual meeting of the American Society of Clinical Oncology. This followed respective reductions of 29% and 25% at a median follow-up of 2.4 years (Lancet 2009;374:1331-8).
In subgroup analyses, the survival benefit of dose-dense chemotherapy was significant only among women who had residual disease after debulking surgery measuring greater than 1 cm, or serous histology.
"Dose-dense [paclitaxel plus carboplatin] improved long-term progression-free survival and overall survival in patients with advanced epithelial ovarian cancer," said first author Dr. Noriyuki Katsumata of the Nippon Medical School–Musashi-Kosugi Hospital in Kawasaki, Japan.
"Neither dose-dense nor conventional treatment seemed effective against clear-cell or mucinous ovarian carcinoma, which suggests that other treatment strategies are needed," he added.
The study "is a major contribution to our understanding of dose-dense therapy and whether or not it should be used," said the invited discussant, Dr. Jonathan S. Berek, director of the Stanford (Calif.) Women’s Cancer Center. In particular, the overall survival benefit "is a very important observation for our patients and our specialty."
However, the trial was done in a Japanese population, he cautioned. "Maybe there are racial differences. We’ll have to wait for confirmatory trials to see whether there is any difference. There may be none, but we’ll see."
"One of the questions I’d like to raise is, how does this compare to the advantage that we saw with intraperitoneal therapy, and what should we recommend to our patients while we await more confirmatory and comparative data?" Dr. Berek said.
He noted that a variety of trials – GOG (Gynecologic Oncology Group)–0252, GOG-0262, ICON8, MITO-7, and iPocc – will better clarify and compare the merits of dose-dense and intraperitoneal approaches, sometimes in combination with the antiangiogenic agent bevacizumab (Avastin).
"I suspect in the next 2-3 years, the head-to-head comparison of the dose-dense regimens and the intraperitoneal regimens will emerge, and we will probably have at least some clear answers about whether it’s route of administration or frequency of administration, or in some cases, both" that optimizes efficacy, Dr. Berek concluded.
The 637 women accrued to the Japanese trial, also known as the NOVEL study, had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer and had undergone debulking surgery. The large majority (84%) had serous tumor histology.
They were randomly assigned to paclitaxel (Taxol) plus carboplatin given according to a conventional schedule (paclitaxel, 180 mg/m2; carboplatin, AUC [area under the curve] = 6; each given once every 3 weeks) or according to a dose-dense schedule (paclitaxel, 80 mg/m2 weekly; carboplatin, AUC = 6 once every 3 weeks), in both arms for six to nine cycles.
The updated results showed that relative to conventional chemotherapy, dose-dense chemotherapy conferred better median progression-free survival (28.2 vs. 17.5 months, respectively; hazard ratio, 0.76; P = .004) and overall survival (not reached vs. 62.2 months; HR, 0.79; P = .04). At this point, 58.7% of the dose-dense group and 51.1% of the conventional therapy group were alive.
In analyses stratified by the extent of residual disease after debulking surgery, the overall survival benefit of dose-dense chemotherapy was significant only for women who had residual disease measuring greater than 1 cm (median, 51.2 months vs. 33.5 months; HR, 0.75; P = .03) or serous histology (median, not reached vs. 61.2 months; HR, 0.76; P = .03).
In a multivariate analysis, dose-dense chemotherapy was a significant independent predictor of overall survival, along with ovarian disease site, earlier stage, less residual disease, better performance status, and a paclitaxel relative dose intensity of at least 80%.
Dr. Katsumata disclosed no relevant conflicts of interest. Dr. Berek disclosed no relevant conflicts of interest.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: With a median follow-up of 6.4 years, median overall survival was not reached with dose-dense paclitaxel-plus-carboplatin chemotherapy vs. 62.2 months with a conventional schedule (HR, 0.79; P = .04).
Data Source: The randomized JGOG 3016/NOVEL randomized trial evaluated 637 women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Disclosures: Dr. Katsumata disclosed no relevant conflicts of interest. Dr. Berek disclosed no relevant conflicts of interest.