Michele G. Sullivan

Testosterone supplementation is not recommended for women, unless they have a clinical diagnosis of hypoactive sexual desire disorder, a joint task force led by the Endocrine Society has determined.

While a number of studies have shown that testosterone supplementation helps improve sexual desire, cognition, and other outcomes, most are either too small, too short, or confounded by other factors to provide irrefutable evidence of the hormone’s benefit for any indication other than hypoactive sexual desire disorder (HSDD), Dr. Margaret E. Wierman and her colleagues wrote in the Journal of Clinical Endocrinology and Metabolism (J. Clin. Endocrinol. Metab. 2014;99:3489-510).

A trial of testosterone is only appropriate for postmenopausal women with a diagnosed HSDD, wrote the task force, which also noted that libido and response improvements don’t necessarily correlate with testosterone serum levels. If there’s no clinical response after a 6-month trial, the hormone should be discontinued.

The hormone-health connection is clearly important to women, and many have already done Internet research on the topic, said Dr. Margery Gass, executive director of the North American Menopause Society. A Google query for “hormones to control aging” turned up 9.5 million results, she said.

Although NAMS was not involved in creating the new clinical guideline, the society supports it, she said in an interview.

“The Endocrine Society has published an excellent set of guidelines on the use of androgen therapy in women. These guidelines are in harmony with NAMS’ comments on the use of testosterone and dehydroepiandrosterones,” included in the group’s clinical practice guideline for the care of midlife women (Menopause 2014;21:1038-62). That paper also recommends a trial of testosterone therapy “in carefully selected postmenopausal women with female sexual interest/arousal disorder and no other etiology for their sexual problems.”

Dr. Gass continued, “I encourage clinicians to use both publications to help women understand the misinformation about testosterone and other androgens that they are seeing on the Internet.”

Dr. Wierman, chief of endocrinology at the University of Colorado, Aurora, led the task force, composed of representatives from the American Society for Reproductive Medicine, the American Congress of Obstetricians and Gynecologists, the European Society of Endocrinology, and the International Menopause Society. Together, they reviewed the extant literature and, in addition, commissioned meta-analyses to examine the issue of androgen supplementation in premenopausal and postmenopausal women – either healthy or with specific conditions. Evidence was graded as level 1 (strong) or level 2 (weak).

The group considered androgen supplementation for a number of indications: infertility; sexual dysfunction; cognition; cardiovascular, metabolic, and bone health; and general well-being. It found little strong data to support the practice in any of these except HSDD.

As a basic tenet, the task force agreed that androgen testing for most women is inaccurate, and thus virtually incapable of providing useful diagnostic information. Testosterone levels vary among women and within their different hormonal life stages, and there are no validated reference ranges.

Sexual function

A controversial issue, women’s sexual health remains somewhat of a mystery, the team noted – a complex web of physical, emotional, and psychological factors. Evidence derived from testosterone therapy in postmenopausal women shows that the hormone may influence all aspects of sexual response by improving desire, subjective arousal, and vaginal blood flow, and increasing frequency of orgasm.

However, decreasing sexuality is a common phenomenon for women, and is not dependent on physiologic testosterone levels. While response to testosterone therapy didn’t always correlate with plasma levels, most trials found that a daily dose of 300 mcg provided optimal benefit. One study found a more than 115% increase in reported orgasms, compared with a 38% increase in the placebo group, and another found 2.12 more satisfactory sexual events per month, compared with 0.73 per month with placebo.

One trial of a testosterone gel was negative, but was only available as an abstract. A large randomized trial of transdermal testosterone gel that recruited 3,565 naturally and surgically postmenopausal women, and accrued several thousand women-years of data, has yet to be published.

For postmenopausal women with properly diagnosed HSDD, the task force recommended a 3- to 6-month trial of testosterone for those who request therapy and in whom it is not contraindicated.

Testosterone levels should be measured at baseline and after 3-6 weeks of initial treatment to assess patient overuse. In cases of ongoing testosterone therapy, levels should be reviewed every 6 months to monitor for excessive use and signs of androgen excess.

Other indications

The task force noted insufficient evidence for the following indications:

• Infertility. One meta-analysis reported an overall 11% increase in live births; another found no benefit. The individual studies were marred by methodological issues, the team said.

• Bone. Several small studies showed increased bone density in some locations after testosterone therapy. However, many women received concomitant estrogens, so the studies were confounded, the team noted.

• Cognition. Several studies have hinted that testosterone may be protective against Alzheimer’s and other dementias in women, possibly by mediating the accumulation of neurotoxic amyloid beta brain plaques. Women taking the hormone scored better on cognitive tests, including verbal memory, as well as spatial and mathematical reasoning. “In addition to having neuroprotective effects, testosterone has positive effects on endothelial function and acts as a vasodilator, providing another potential pathway through which testosterone may confer neuroprotection,” the investigators said. Again, however, they felt that the body and quality of evidence were not enough to justify a recommendation.

• Cardiovascular. Higher endogenous testosterone in women has been associated with better endothelial function and lower carotid intima-medial thickness; exogenous testosterone has not been adequately studied. However, testosterone supplementation does not seem to negatively affect lipids or increase other cardiovascular risk markers.

• Body composition. Several large studies of women with testosterone-alone and testosterone-estradiol therapy found increased lean muscle mass and lower body fat mass. These results were seen in healthy women as well as those with Turner syndrome, anorexia nervosa, and HIV infections. “Thus,” the investigators concluded, “testosterone increases lean body mass and may decrease fat mass in women, but effects are less dramatic than in men.”

• Mood. Testosterone therapy resulted in improved mood and lower depression scores in several studies, but subjects in some were not screened for comorbidities, including sexual dysfunction.

• Side effects. The potential for masculinizing effects – acne, hirsutism, deepening of the voice, and androgenic alopecia – exists. They are dose dependent, uncommon, and short-lived once supraphysiologic levels are decreased. Findings on breast cancer risk are contradictory; the team said more study is necessary.

The task force commissioned a testosterone therapy meta-analysis of published randomized trials of testosterone-alone or in addition to hormone replacement therapy. “Across all trials, testosterone use was associated with a statistically significant improvement in satisfaction, pleasure, orgasm, and libido. The quality of evidence was moderate to high for pleasure and orgasm outcomes, and moderate for satisfaction and libido outcomes,” with minimal effect on lipids and none on hair growth or loss.

“However,” the task force wrote, “data on adverse effects were not extensive, particularly for long-term use,” with a follow-up of 6 weeks to 2 years.

Dr. Wierman had no financial disclosures. However, several coauthors had numerous disclosures, including financial ties with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

Testosterone supplementation is not recommended for women, unless they have a clinical diagnosis of hypoactive sexual desire disorder, a joint task force led by the Endocrine Society has determined.

While a number of studies have shown that testosterone supplementation helps improve sexual desire, cognition, and other outcomes, most are either too small, too short, or confounded by other factors to provide irrefutable evidence of the hormone’s benefit for any indication other than hypoactive sexual desire disorder (HSDD), Dr. Margaret E. Wierman and her colleagues wrote in the Journal of Clinical Endocrinology and Metabolism (J. Clin. Endocrinol. Metab. 2014;99:3489-510).

A trial of testosterone is only appropriate for postmenopausal women with a diagnosed HSDD, wrote the task force, which also noted that libido and response improvements don’t necessarily correlate with testosterone serum levels. If there’s no clinical response after a 6-month trial, the hormone should be discontinued.

The hormone-health connection is clearly important to women, and many have already done Internet research on the topic, said Dr. Margery Gass, executive director of the North American Menopause Society. A Google query for “hormones to control aging” turned up 9.5 million results, she said.

Although NAMS was not involved in creating the new clinical guideline, the society supports it, she said in an interview.

“The Endocrine Society has published an excellent set of guidelines on the use of androgen therapy in women. These guidelines are in harmony with NAMS’ comments on the use of testosterone and dehydroepiandrosterones,” included in the group’s clinical practice guideline for the care of midlife women (Menopause 2014;21:1038-62). That paper also recommends a trial of testosterone therapy “in carefully selected postmenopausal women with female sexual interest/arousal disorder and no other etiology for their sexual problems.”

Dr. Gass continued, “I encourage clinicians to use both publications to help women understand the misinformation about testosterone and other androgens that they are seeing on the Internet.”

Dr. Wierman, chief of endocrinology at the University of Colorado, Aurora, led the task force, composed of representatives from the American Society for Reproductive Medicine, the American Congress of Obstetricians and Gynecologists, the European Society of Endocrinology, and the International Menopause Society. Together, they reviewed the extant literature and, in addition, commissioned meta-analyses to examine the issue of androgen supplementation in premenopausal and postmenopausal women – either healthy or with specific conditions. Evidence was graded as level 1 (strong) or level 2 (weak).

The group considered androgen supplementation for a number of indications: infertility; sexual dysfunction; cognition; cardiovascular, metabolic, and bone health; and general well-being. It found little strong data to support the practice in any of these except HSDD.

As a basic tenet, the task force agreed that androgen testing for most women is inaccurate, and thus virtually incapable of providing useful diagnostic information. Testosterone levels vary among women and within their different hormonal life stages, and there are no validated reference ranges.

Sexual function

A controversial issue, women’s sexual health remains somewhat of a mystery, the team noted – a complex web of physical, emotional, and psychological factors. Evidence derived from testosterone therapy in postmenopausal women shows that the hormone may influence all aspects of sexual response by improving desire, subjective arousal, and vaginal blood flow, and increasing frequency of orgasm.

However, decreasing sexuality is a common phenomenon for women, and is not dependent on physiologic testosterone levels. While response to testosterone therapy didn’t always correlate with plasma levels, most trials found that a daily dose of 300 mcg provided optimal benefit. One study found a more than 115% increase in reported orgasms, compared with a 38% increase in the placebo group, and another found 2.12 more satisfactory sexual events per month, compared with 0.73 per month with placebo.

One trial of a testosterone gel was negative, but was only available as an abstract. A large randomized trial of transdermal testosterone gel that recruited 3,565 naturally and surgically postmenopausal women, and accrued several thousand women-years of data, has yet to be published.

For postmenopausal women with properly diagnosed HSDD, the task force recommended a 3- to 6-month trial of testosterone for those who request therapy and in whom it is not contraindicated.

Testosterone levels should be measured at baseline and after 3-6 weeks of initial treatment to assess patient overuse. In cases of ongoing testosterone therapy, levels should be reviewed every 6 months to monitor for excessive use and signs of androgen excess.

Other indications

The task force noted insufficient evidence for the following indications:

• Infertility. One meta-analysis reported an overall 11% increase in live births; another found no benefit. The individual studies were marred by methodological issues, the team said.

• Bone. Several small studies showed increased bone density in some locations after testosterone therapy. However, many women received concomitant estrogens, so the studies were confounded, the team noted.

• Cognition. Several studies have hinted that testosterone may be protective against Alzheimer’s and other dementias in women, possibly by mediating the accumulation of neurotoxic amyloid beta brain plaques. Women taking the hormone scored better on cognitive tests, including verbal memory, as well as spatial and mathematical reasoning. “In addition to having neuroprotective effects, testosterone has positive effects on endothelial function and acts as a vasodilator, providing another potential pathway through which testosterone may confer neuroprotection,” the investigators said. Again, however, they felt that the body and quality of evidence were not enough to justify a recommendation.

• Cardiovascular. Higher endogenous testosterone in women has been associated with better endothelial function and lower carotid intima-medial thickness; exogenous testosterone has not been adequately studied. However, testosterone supplementation does not seem to negatively affect lipids or increase other cardiovascular risk markers.

• Body composition. Several large studies of women with testosterone-alone and testosterone-estradiol therapy found increased lean muscle mass and lower body fat mass. These results were seen in healthy women as well as those with Turner syndrome, anorexia nervosa, and HIV infections. “Thus,” the investigators concluded, “testosterone increases lean body mass and may decrease fat mass in women, but effects are less dramatic than in men.”

• Mood. Testosterone therapy resulted in improved mood and lower depression scores in several studies, but subjects in some were not screened for comorbidities, including sexual dysfunction.

• Side effects. The potential for masculinizing effects – acne, hirsutism, deepening of the voice, and androgenic alopecia – exists. They are dose dependent, uncommon, and short-lived once supraphysiologic levels are decreased. Findings on breast cancer risk are contradictory; the team said more study is necessary.

The task force commissioned a testosterone therapy meta-analysis of published randomized trials of testosterone-alone or in addition to hormone replacement therapy. “Across all trials, testosterone use was associated with a statistically significant improvement in satisfaction, pleasure, orgasm, and libido. The quality of evidence was moderate to high for pleasure and orgasm outcomes, and moderate for satisfaction and libido outcomes,” with minimal effect on lipids and none on hair growth or loss.

“However,” the task force wrote, “data on adverse effects were not extensive, particularly for long-term use,” with a follow-up of 6 weeks to 2 years.

Dr. Wierman had no financial disclosures. However, several coauthors had numerous disclosures, including financial ties with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

Testosterone supplementation is not recommended for women, unless they have a clinical diagnosis of hypoactive sexual desire disorder, a joint task force led by the Endocrine Society has determined.

While a number of studies have shown that testosterone supplementation helps improve sexual desire, cognition, and other outcomes, most are either too small, too short, or confounded by other factors to provide irrefutable evidence of the hormone’s benefit for any indication other than hypoactive sexual desire disorder (HSDD), Dr. Margaret E. Wierman and her colleagues wrote in the Journal of Clinical Endocrinology and Metabolism (J. Clin. Endocrinol. Metab. 2014;99:3489-510).

A trial of testosterone is only appropriate for postmenopausal women with a diagnosed HSDD, wrote the task force, which also noted that libido and response improvements don’t necessarily correlate with testosterone serum levels. If there’s no clinical response after a 6-month trial, the hormone should be discontinued.

The hormone-health connection is clearly important to women, and many have already done Internet research on the topic, said Dr. Margery Gass, executive director of the North American Menopause Society. A Google query for “hormones to control aging” turned up 9.5 million results, she said.

Although NAMS was not involved in creating the new clinical guideline, the society supports it, she said in an interview.

“The Endocrine Society has published an excellent set of guidelines on the use of androgen therapy in women. These guidelines are in harmony with NAMS’ comments on the use of testosterone and dehydroepiandrosterones,” included in the group’s clinical practice guideline for the care of midlife women (Menopause 2014;21:1038-62). That paper also recommends a trial of testosterone therapy “in carefully selected postmenopausal women with female sexual interest/arousal disorder and no other etiology for their sexual problems.”

Dr. Gass continued, “I encourage clinicians to use both publications to help women understand the misinformation about testosterone and other androgens that they are seeing on the Internet.”

Dr. Wierman, chief of endocrinology at the University of Colorado, Aurora, led the task force, composed of representatives from the American Society for Reproductive Medicine, the American Congress of Obstetricians and Gynecologists, the European Society of Endocrinology, and the International Menopause Society. Together, they reviewed the extant literature and, in addition, commissioned meta-analyses to examine the issue of androgen supplementation in premenopausal and postmenopausal women – either healthy or with specific conditions. Evidence was graded as level 1 (strong) or level 2 (weak).

The group considered androgen supplementation for a number of indications: infertility; sexual dysfunction; cognition; cardiovascular, metabolic, and bone health; and general well-being. It found little strong data to support the practice in any of these except HSDD.

As a basic tenet, the task force agreed that androgen testing for most women is inaccurate, and thus virtually incapable of providing useful diagnostic information. Testosterone levels vary among women and within their different hormonal life stages, and there are no validated reference ranges.

Sexual function

A controversial issue, women’s sexual health remains somewhat of a mystery, the team noted – a complex web of physical, emotional, and psychological factors. Evidence derived from testosterone therapy in postmenopausal women shows that the hormone may influence all aspects of sexual response by improving desire, subjective arousal, and vaginal blood flow, and increasing frequency of orgasm.

However, decreasing sexuality is a common phenomenon for women, and is not dependent on physiologic testosterone levels. While response to testosterone therapy didn’t always correlate with plasma levels, most trials found that a daily dose of 300 mcg provided optimal benefit. One study found a more than 115% increase in reported orgasms, compared with a 38% increase in the placebo group, and another found 2.12 more satisfactory sexual events per month, compared with 0.73 per month with placebo.

One trial of a testosterone gel was negative, but was only available as an abstract. A large randomized trial of transdermal testosterone gel that recruited 3,565 naturally and surgically postmenopausal women, and accrued several thousand women-years of data, has yet to be published.

For postmenopausal women with properly diagnosed HSDD, the task force recommended a 3- to 6-month trial of testosterone for those who request therapy and in whom it is not contraindicated.

Testosterone levels should be measured at baseline and after 3-6 weeks of initial treatment to assess patient overuse. In cases of ongoing testosterone therapy, levels should be reviewed every 6 months to monitor for excessive use and signs of androgen excess.

Other indications

The task force noted insufficient evidence for the following indications:

• Infertility. One meta-analysis reported an overall 11% increase in live births; another found no benefit. The individual studies were marred by methodological issues, the team said.

• Bone. Several small studies showed increased bone density in some locations after testosterone therapy. However, many women received concomitant estrogens, so the studies were confounded, the team noted.

• Cognition. Several studies have hinted that testosterone may be protective against Alzheimer’s and other dementias in women, possibly by mediating the accumulation of neurotoxic amyloid beta brain plaques. Women taking the hormone scored better on cognitive tests, including verbal memory, as well as spatial and mathematical reasoning. “In addition to having neuroprotective effects, testosterone has positive effects on endothelial function and acts as a vasodilator, providing another potential pathway through which testosterone may confer neuroprotection,” the investigators said. Again, however, they felt that the body and quality of evidence were not enough to justify a recommendation.

• Cardiovascular. Higher endogenous testosterone in women has been associated with better endothelial function and lower carotid intima-medial thickness; exogenous testosterone has not been adequately studied. However, testosterone supplementation does not seem to negatively affect lipids or increase other cardiovascular risk markers.

• Body composition. Several large studies of women with testosterone-alone and testosterone-estradiol therapy found increased lean muscle mass and lower body fat mass. These results were seen in healthy women as well as those with Turner syndrome, anorexia nervosa, and HIV infections. “Thus,” the investigators concluded, “testosterone increases lean body mass and may decrease fat mass in women, but effects are less dramatic than in men.”

• Mood. Testosterone therapy resulted in improved mood and lower depression scores in several studies, but subjects in some were not screened for comorbidities, including sexual dysfunction.

• Side effects. The potential for masculinizing effects – acne, hirsutism, deepening of the voice, and androgenic alopecia – exists. They are dose dependent, uncommon, and short-lived once supraphysiologic levels are decreased. Findings on breast cancer risk are contradictory; the team said more study is necessary.

The task force commissioned a testosterone therapy meta-analysis of published randomized trials of testosterone-alone or in addition to hormone replacement therapy. “Across all trials, testosterone use was associated with a statistically significant improvement in satisfaction, pleasure, orgasm, and libido. The quality of evidence was moderate to high for pleasure and orgasm outcomes, and moderate for satisfaction and libido outcomes,” with minimal effect on lipids and none on hair growth or loss.

“However,” the task force wrote, “data on adverse effects were not extensive, particularly for long-term use,” with a follow-up of 6 weeks to 2 years.

Dr. Wierman had no financial disclosures. However, several coauthors had numerous disclosures, including financial ties with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

PHILADELPHIA – Despite some tantalizing hints of efficacy, the antiamyloid antibody crenezumab failed overall to post significant imaging and biomarker results in a phase II study.

The drug did not effect any statistically significant changes in amyloid plaque burden on PET imaging in the prespecified analysis, Dr. Steven Salloway said at the Clinical Trials Conference on Alzheimer’s Disease. A secondary assessment using a different technique yielded slightly better, although still nonsignificant, results.

There was a slight increase in serum amyloid beta 42 (Abeta42), but no effect at all on serum total or phosphorylated tau, said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I.

The lackluster findings, combined with crenezumab’s failure to meet cognitive and functional endpoints in this and a companion study announced last July, are prompting questions about the antibody’s future, Dr. Salloway said. “As a result of these clinical trials ... the company is in discussion with regulators about further development of crenezumab, although no decision has been made.”

These new data will not, however, endanger the landmark API (Alzheimer’s Prevention Initiative–Autosomal Dominant Alzheimer’s Disease Treatment Trial), now launching in Colombia. Crenezumab is the active treatment in this first-ever primary prevention trial.

In fact, these new imaging and biomarker data have led to a dosing protocol change for the API study. Originally, the study called for the 300-mg bimonthly subcutaneous dose; instead, it will use the IV dosing equivalent, a company spokesperson said in an interview.

“Based on the learnings from the crenezumab exploratory data, which may suggest greater benefit in [patients with mild Alzheimer’s disease] treated with the higher IV dose, Genentech is taking next steps to enable use of a higher subcutaneous dose in the API study,” said Carole Ho. She noted that the ongoing extension studies will also drop the subcutaneous dose in favor of IV dosing.

The 69-week study, dubbed BLAZE, looked at 91 patients with mild to moderate, imaging-proven Alzheimer’s disease. They were randomized to either crenezumab 300 mg subcutaneously every other week, 15 mg/kg intravenously once a month, or matching placebo in each arm.

The study group was a typical Alzheimer’s cohort, with a mean age of about 69 years. The Mini-Mental State Exam scores ranged from 18 to 26 (mean score, about 21).

At baseline, all patients had amyloid PET imaging, fluorodeoxyglucose (FDG)-PET imaging, cerebrospinal fluid (CSF) sampling, and brain MRI. Amyloid PET was repeated at week 47, and all of the tests were repeated again at study completion.

Dropout rates in each treatment group – especially the intravenous group – were rather high. In the subcutaneous group, 77% of the placebo arm and 88% of the active arm completed treatment. In the intravenous arms, 59% of the placebo group and 60% of the active group finished the study. There were two deaths, both in the active intravenous group.

The prespecified amyloid imaging used a cerebellar gray matter reference region. With this method, there were no significant differences in amyloid plaque burden by the end of the study.

Serial scans showed some odd variability that led researchers to question whether the reference region was accurately picking up any changes, Dr. Salloway said. In the subcutaneous group, the placebo group measurement stayed flat, as expected, but the active group measure took a significant dip at the interim scan, and then returned to baseline for the last scan, suggesting that amyloid dispersed and then reformed. In the IV arm, the placebo group took a significant dive from the interim scan to the final scan, suggesting that those patients were spontaneously clearing amyloid. The active IV group seemed to stay flat.

That prompted the investigators to reassess the results with a different reference region, a white matter region closer to the corpus callosum and centrum semiovale, Dr. Salloway said. This region is being used in the Alzheimer’s Disease Neuroimaging Initiative longitudinal cohort study. Data were sent to an independent investigator for a blinded reassessment.

The results obtained using this reference region were more in line with expectations, although not spectacular, Dr. Salloway said.

In the subcutaneous group, amyloid burden rose from baseline, with no difference at all between placebo and crenezumab. In the IV group, amyloid burden also rose in both arms. However, the curves showed some nonsignificant separation at the interim scan, which continued to the end of the study. The difference was still not significant at the final scan (P = .169).

When assessed by yet another white matter reference region, the results were similar, with no difference in the subcutaneous arm and a nonsignificant separation in the IV arm (P = .131).

“The suggestion of a separation with a relative reduction of amyloid in the IV group [in both of the alternate assessments] was very encouraging,” Dr. Salloway said.

In a small subset of patients with complete CSF data (30 subcutaneous and 25 IV patients), crenezumab was associated with a significant increase in Abeta₄₂, suggesting that it was interacting with amyloid brain plaques.

However, there was no movement in tau or phosphorylated tau, no changes in brain volume on MRI, and no changes in FDG-PET results.

The negative results may seem disappointing, but they don’t necessarily mean failure, Dr. Maria Carillo said in an interview.

Although disappointing in some ways, the BLAZE study did exactly what a phase II study should, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. It provided good safety data and just enough efficacy data to strengthen the phase III API trial.

“Yes, BLAZE was a negative trial, but it informed the Colombian team,” she said. “It told them that the IV dosing was better. It told them that higher doses would be better. That’s critical, regardless of this study’s negative results.”

Alzheimer’s researcher Peter Davies, Ph.D., said in an interview, “I’m disappointed. It is hard to understand how the high dose of crenezumab does not move the amyloid imaging signal – unless of course this is just too crude a measure. The CSF data did appear promising, but the lack of effect on cognitive function is what is going to decide the fate of this treatment.” Dr. Davies is the director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at Hofstra North Shore-Long Island Jewish School of Medicine.

Both BLAZE and API are sponsored by Genentech. Dr. Salloway has been a consultant for Roche, Lilly, and Genentech, and disclosed a number of other financial relationships with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

PHILADELPHIA – Despite some tantalizing hints of efficacy, the antiamyloid antibody crenezumab failed overall to post significant imaging and biomarker results in a phase II study.

The drug did not effect any statistically significant changes in amyloid plaque burden on PET imaging in the prespecified analysis, Dr. Steven Salloway said at the Clinical Trials Conference on Alzheimer’s Disease. A secondary assessment using a different technique yielded slightly better, although still nonsignificant, results.

There was a slight increase in serum amyloid beta 42 (Abeta42), but no effect at all on serum total or phosphorylated tau, said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I.

The lackluster findings, combined with crenezumab’s failure to meet cognitive and functional endpoints in this and a companion study announced last July, are prompting questions about the antibody’s future, Dr. Salloway said. “As a result of these clinical trials ... the company is in discussion with regulators about further development of crenezumab, although no decision has been made.”

These new data will not, however, endanger the landmark API (Alzheimer’s Prevention Initiative–Autosomal Dominant Alzheimer’s Disease Treatment Trial), now launching in Colombia. Crenezumab is the active treatment in this first-ever primary prevention trial.

In fact, these new imaging and biomarker data have led to a dosing protocol change for the API study. Originally, the study called for the 300-mg bimonthly subcutaneous dose; instead, it will use the IV dosing equivalent, a company spokesperson said in an interview.

“Based on the learnings from the crenezumab exploratory data, which may suggest greater benefit in [patients with mild Alzheimer’s disease] treated with the higher IV dose, Genentech is taking next steps to enable use of a higher subcutaneous dose in the API study,” said Carole Ho. She noted that the ongoing extension studies will also drop the subcutaneous dose in favor of IV dosing.

The 69-week study, dubbed BLAZE, looked at 91 patients with mild to moderate, imaging-proven Alzheimer’s disease. They were randomized to either crenezumab 300 mg subcutaneously every other week, 15 mg/kg intravenously once a month, or matching placebo in each arm.

The study group was a typical Alzheimer’s cohort, with a mean age of about 69 years. The Mini-Mental State Exam scores ranged from 18 to 26 (mean score, about 21).

At baseline, all patients had amyloid PET imaging, fluorodeoxyglucose (FDG)-PET imaging, cerebrospinal fluid (CSF) sampling, and brain MRI. Amyloid PET was repeated at week 47, and all of the tests were repeated again at study completion.

Dropout rates in each treatment group – especially the intravenous group – were rather high. In the subcutaneous group, 77% of the placebo arm and 88% of the active arm completed treatment. In the intravenous arms, 59% of the placebo group and 60% of the active group finished the study. There were two deaths, both in the active intravenous group.

The prespecified amyloid imaging used a cerebellar gray matter reference region. With this method, there were no significant differences in amyloid plaque burden by the end of the study.

Serial scans showed some odd variability that led researchers to question whether the reference region was accurately picking up any changes, Dr. Salloway said. In the subcutaneous group, the placebo group measurement stayed flat, as expected, but the active group measure took a significant dip at the interim scan, and then returned to baseline for the last scan, suggesting that amyloid dispersed and then reformed. In the IV arm, the placebo group took a significant dive from the interim scan to the final scan, suggesting that those patients were spontaneously clearing amyloid. The active IV group seemed to stay flat.

That prompted the investigators to reassess the results with a different reference region, a white matter region closer to the corpus callosum and centrum semiovale, Dr. Salloway said. This region is being used in the Alzheimer’s Disease Neuroimaging Initiative longitudinal cohort study. Data were sent to an independent investigator for a blinded reassessment.

The results obtained using this reference region were more in line with expectations, although not spectacular, Dr. Salloway said.

In the subcutaneous group, amyloid burden rose from baseline, with no difference at all between placebo and crenezumab. In the IV group, amyloid burden also rose in both arms. However, the curves showed some nonsignificant separation at the interim scan, which continued to the end of the study. The difference was still not significant at the final scan (P = .169).

When assessed by yet another white matter reference region, the results were similar, with no difference in the subcutaneous arm and a nonsignificant separation in the IV arm (P = .131).

“The suggestion of a separation with a relative reduction of amyloid in the IV group [in both of the alternate assessments] was very encouraging,” Dr. Salloway said.

In a small subset of patients with complete CSF data (30 subcutaneous and 25 IV patients), crenezumab was associated with a significant increase in Abeta₄₂, suggesting that it was interacting with amyloid brain plaques.

However, there was no movement in tau or phosphorylated tau, no changes in brain volume on MRI, and no changes in FDG-PET results.

The negative results may seem disappointing, but they don’t necessarily mean failure, Dr. Maria Carillo said in an interview.

Although disappointing in some ways, the BLAZE study did exactly what a phase II study should, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. It provided good safety data and just enough efficacy data to strengthen the phase III API trial.

“Yes, BLAZE was a negative trial, but it informed the Colombian team,” she said. “It told them that the IV dosing was better. It told them that higher doses would be better. That’s critical, regardless of this study’s negative results.”

Alzheimer’s researcher Peter Davies, Ph.D., said in an interview, “I’m disappointed. It is hard to understand how the high dose of crenezumab does not move the amyloid imaging signal – unless of course this is just too crude a measure. The CSF data did appear promising, but the lack of effect on cognitive function is what is going to decide the fate of this treatment.” Dr. Davies is the director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at Hofstra North Shore-Long Island Jewish School of Medicine.

Both BLAZE and API are sponsored by Genentech. Dr. Salloway has been a consultant for Roche, Lilly, and Genentech, and disclosed a number of other financial relationships with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

PHILADELPHIA – Despite some tantalizing hints of efficacy, the antiamyloid antibody crenezumab failed overall to post significant imaging and biomarker results in a phase II study.

The drug did not effect any statistically significant changes in amyloid plaque burden on PET imaging in the prespecified analysis, Dr. Steven Salloway said at the Clinical Trials Conference on Alzheimer’s Disease. A secondary assessment using a different technique yielded slightly better, although still nonsignificant, results.

There was a slight increase in serum amyloid beta 42 (Abeta42), but no effect at all on serum total or phosphorylated tau, said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I.

The lackluster findings, combined with crenezumab’s failure to meet cognitive and functional endpoints in this and a companion study announced last July, are prompting questions about the antibody’s future, Dr. Salloway said. “As a result of these clinical trials ... the company is in discussion with regulators about further development of crenezumab, although no decision has been made.”

These new data will not, however, endanger the landmark API (Alzheimer’s Prevention Initiative–Autosomal Dominant Alzheimer’s Disease Treatment Trial), now launching in Colombia. Crenezumab is the active treatment in this first-ever primary prevention trial.

In fact, these new imaging and biomarker data have led to a dosing protocol change for the API study. Originally, the study called for the 300-mg bimonthly subcutaneous dose; instead, it will use the IV dosing equivalent, a company spokesperson said in an interview.

“Based on the learnings from the crenezumab exploratory data, which may suggest greater benefit in [patients with mild Alzheimer’s disease] treated with the higher IV dose, Genentech is taking next steps to enable use of a higher subcutaneous dose in the API study,” said Carole Ho. She noted that the ongoing extension studies will also drop the subcutaneous dose in favor of IV dosing.

The 69-week study, dubbed BLAZE, looked at 91 patients with mild to moderate, imaging-proven Alzheimer’s disease. They were randomized to either crenezumab 300 mg subcutaneously every other week, 15 mg/kg intravenously once a month, or matching placebo in each arm.

The study group was a typical Alzheimer’s cohort, with a mean age of about 69 years. The Mini-Mental State Exam scores ranged from 18 to 26 (mean score, about 21).

At baseline, all patients had amyloid PET imaging, fluorodeoxyglucose (FDG)-PET imaging, cerebrospinal fluid (CSF) sampling, and brain MRI. Amyloid PET was repeated at week 47, and all of the tests were repeated again at study completion.

Dropout rates in each treatment group – especially the intravenous group – were rather high. In the subcutaneous group, 77% of the placebo arm and 88% of the active arm completed treatment. In the intravenous arms, 59% of the placebo group and 60% of the active group finished the study. There were two deaths, both in the active intravenous group.

The prespecified amyloid imaging used a cerebellar gray matter reference region. With this method, there were no significant differences in amyloid plaque burden by the end of the study.

Serial scans showed some odd variability that led researchers to question whether the reference region was accurately picking up any changes, Dr. Salloway said. In the subcutaneous group, the placebo group measurement stayed flat, as expected, but the active group measure took a significant dip at the interim scan, and then returned to baseline for the last scan, suggesting that amyloid dispersed and then reformed. In the IV arm, the placebo group took a significant dive from the interim scan to the final scan, suggesting that those patients were spontaneously clearing amyloid. The active IV group seemed to stay flat.

That prompted the investigators to reassess the results with a different reference region, a white matter region closer to the corpus callosum and centrum semiovale, Dr. Salloway said. This region is being used in the Alzheimer’s Disease Neuroimaging Initiative longitudinal cohort study. Data were sent to an independent investigator for a blinded reassessment.

The results obtained using this reference region were more in line with expectations, although not spectacular, Dr. Salloway said.

In the subcutaneous group, amyloid burden rose from baseline, with no difference at all between placebo and crenezumab. In the IV group, amyloid burden also rose in both arms. However, the curves showed some nonsignificant separation at the interim scan, which continued to the end of the study. The difference was still not significant at the final scan (P = .169).

When assessed by yet another white matter reference region, the results were similar, with no difference in the subcutaneous arm and a nonsignificant separation in the IV arm (P = .131).

“The suggestion of a separation with a relative reduction of amyloid in the IV group [in both of the alternate assessments] was very encouraging,” Dr. Salloway said.

In a small subset of patients with complete CSF data (30 subcutaneous and 25 IV patients), crenezumab was associated with a significant increase in Abeta₄₂, suggesting that it was interacting with amyloid brain plaques.

However, there was no movement in tau or phosphorylated tau, no changes in brain volume on MRI, and no changes in FDG-PET results.

The negative results may seem disappointing, but they don’t necessarily mean failure, Dr. Maria Carillo said in an interview.

Although disappointing in some ways, the BLAZE study did exactly what a phase II study should, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. It provided good safety data and just enough efficacy data to strengthen the phase III API trial.

“Yes, BLAZE was a negative trial, but it informed the Colombian team,” she said. “It told them that the IV dosing was better. It told them that higher doses would be better. That’s critical, regardless of this study’s negative results.”

Alzheimer’s researcher Peter Davies, Ph.D., said in an interview, “I’m disappointed. It is hard to understand how the high dose of crenezumab does not move the amyloid imaging signal – unless of course this is just too crude a measure. The CSF data did appear promising, but the lack of effect on cognitive function is what is going to decide the fate of this treatment.” Dr. Davies is the director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at Hofstra North Shore-Long Island Jewish School of Medicine.

Both BLAZE and API are sponsored by Genentech. Dr. Salloway has been a consultant for Roche, Lilly, and Genentech, and disclosed a number of other financial relationships with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

PHILADELPHIA- Neither perioperative aspirin nor clonidine reduced the risk of an acute kidney injury in patients who underwent major noncardiac surgery, a large randomized trial has determined.

The risk of an acute kidney injury (AKI) associated with aspirin was 10% more than placebo, and the risk with clonidine, 3% more, but those differences were not statistically significant, Dr. Amit X. Garg and associates wrote online in JAMA (JAMA 2015; doi:10.1001/jama.2014.15284).

Both drugs increased the risk of postoperative conditions that are associated with AKI, Dr. Garg of the London Health Sciences Centre and Western University, London, Ontario, and his co-authors noted. The study was simultaneously presented at Kidney Week 2014, which was sponsored by the American Society of Nephrology.

In fact, there was some suggestion that the drugs increased the risk of severe AKI, he said at the meeting. “But these were secondary measures and need to be interpreted cautiosuly, because the absolute number of severe AKIs was quite small.”

The AKI investigation was a substudy of the Perioperative Ischemia Evaluation-2, (POISE-2) trial, which evaluated the risk of 30-day mortality or nonfatal myocardial infarction among 6,905 surgical patients with a moderate to high risk of a perioperative cardiac event. The aspirin regimen called for 200 mg before surgery and then 100 mg daily for up to 30 days after surgery. The clonidine regimen was 0.2 mg orally 2-4 hours before surgery, followed by a 0.3 mg/day transdermal patch worn for 72 hours after surgery. Both groups also had a placebo arm.

The patients were a mean of 69 years old. Cardiovascular disease was present in about 30%; these included coronary artery disease, stroke, and peripheral vascular disease. About a quarter smoked; 36% had diabetes; 86% had hypertension; 2% had atrial fibrillation. Medications included COX-2 inhibitors; statins; ACE, ARB or direct renin inhibitors; and antihypertensives.

At baseline about 24% had an estimated glomerular filtration rate of 60 ml/min or lower per 1.73 m².

Surgical procedures were urgent or emergent, major vascular, major thoracic, major urological or gynecologic, and other unspecified procedures.

Aspirin did not reduce the risk of an AKI compared to placebo. AKI occurred in 462 patients taking aspirin and 426 taking placebo (13.4% vs. 12.3% respectively; adjusted risk ratio 1.10). Nor did clonidine reduce the risk of AKI compared to placebo. AKI occurred in 449 taking aspirin and 439 taking placebo (13% and 12.7% respectively; adjusted risk ratio 1.03). Neither of these findings was statistically significant.

AKI-related dialysis within 30 days occurred in 0.6% those taking aspirin and 0.3% of the matched placebo patients - a nonsignificant difference. Serum creatinine increased a mean of 11% with aspirin vs. 11% with placebo.

Dialysis was necessary in 0.5% of those taking clonidine and 0.3% of the matched placebo patients - another nonsignificant finding. A history of preoperative chronic kidney disease did not alter either of these findings.

A post hoc analysis determined that both drugs increased the incidence of conditions known to boost the risk of kidney injury. Aspirin increased the risk of major bleeding, which was associated with a greater risk of AKI (23.3% when bleeding occurred vs 12.3% when it did not; adjusted risk ratio 2.20).

Because of this doubling of risk, Dr. Garg suggested moderating pre-operative aspirin exposure in these patients.

“Among patients taking aspirin as part of a long-term regimen, these results support holding it for at least 3 days before surgery and then restarting it a week after surgery,” he recommended.

Clonidine increased the risk of clinically important hypotension, which was also related in turn to AKI (14.3% when hypotension was present vs. 11.8% when it was not; adjusted risk ratio for AKI 1.34).

Dr. Garg had no financial disclosures. A number of the POISE-2 investigators reported financial relationships with pharmaceutical companies.

[email protected]

PHILADELPHIA- Neither perioperative aspirin nor clonidine reduced the risk of an acute kidney injury in patients who underwent major noncardiac surgery, a large randomized trial has determined.

The risk of an acute kidney injury (AKI) associated with aspirin was 10% more than placebo, and the risk with clonidine, 3% more, but those differences were not statistically significant, Dr. Amit X. Garg and associates wrote online in JAMA (JAMA 2015; doi:10.1001/jama.2014.15284).

Both drugs increased the risk of postoperative conditions that are associated with AKI, Dr. Garg of the London Health Sciences Centre and Western University, London, Ontario, and his co-authors noted. The study was simultaneously presented at Kidney Week 2014, which was sponsored by the American Society of Nephrology.

In fact, there was some suggestion that the drugs increased the risk of severe AKI, he said at the meeting. “But these were secondary measures and need to be interpreted cautiosuly, because the absolute number of severe AKIs was quite small.”

The AKI investigation was a substudy of the Perioperative Ischemia Evaluation-2, (POISE-2) trial, which evaluated the risk of 30-day mortality or nonfatal myocardial infarction among 6,905 surgical patients with a moderate to high risk of a perioperative cardiac event. The aspirin regimen called for 200 mg before surgery and then 100 mg daily for up to 30 days after surgery. The clonidine regimen was 0.2 mg orally 2-4 hours before surgery, followed by a 0.3 mg/day transdermal patch worn for 72 hours after surgery. Both groups also had a placebo arm.

The patients were a mean of 69 years old. Cardiovascular disease was present in about 30%; these included coronary artery disease, stroke, and peripheral vascular disease. About a quarter smoked; 36% had diabetes; 86% had hypertension; 2% had atrial fibrillation. Medications included COX-2 inhibitors; statins; ACE, ARB or direct renin inhibitors; and antihypertensives.

At baseline about 24% had an estimated glomerular filtration rate of 60 ml/min or lower per 1.73 m².

Surgical procedures were urgent or emergent, major vascular, major thoracic, major urological or gynecologic, and other unspecified procedures.

Aspirin did not reduce the risk of an AKI compared to placebo. AKI occurred in 462 patients taking aspirin and 426 taking placebo (13.4% vs. 12.3% respectively; adjusted risk ratio 1.10). Nor did clonidine reduce the risk of AKI compared to placebo. AKI occurred in 449 taking aspirin and 439 taking placebo (13% and 12.7% respectively; adjusted risk ratio 1.03). Neither of these findings was statistically significant.

AKI-related dialysis within 30 days occurred in 0.6% those taking aspirin and 0.3% of the matched placebo patients - a nonsignificant difference. Serum creatinine increased a mean of 11% with aspirin vs. 11% with placebo.

Dialysis was necessary in 0.5% of those taking clonidine and 0.3% of the matched placebo patients - another nonsignificant finding. A history of preoperative chronic kidney disease did not alter either of these findings.

A post hoc analysis determined that both drugs increased the incidence of conditions known to boost the risk of kidney injury. Aspirin increased the risk of major bleeding, which was associated with a greater risk of AKI (23.3% when bleeding occurred vs 12.3% when it did not; adjusted risk ratio 2.20).

Because of this doubling of risk, Dr. Garg suggested moderating pre-operative aspirin exposure in these patients.

“Among patients taking aspirin as part of a long-term regimen, these results support holding it for at least 3 days before surgery and then restarting it a week after surgery,” he recommended.

Clonidine increased the risk of clinically important hypotension, which was also related in turn to AKI (14.3% when hypotension was present vs. 11.8% when it was not; adjusted risk ratio for AKI 1.34).

Dr. Garg had no financial disclosures. A number of the POISE-2 investigators reported financial relationships with pharmaceutical companies.

[email protected]

PHILADELPHIA- Neither perioperative aspirin nor clonidine reduced the risk of an acute kidney injury in patients who underwent major noncardiac surgery, a large randomized trial has determined.

The risk of an acute kidney injury (AKI) associated with aspirin was 10% more than placebo, and the risk with clonidine, 3% more, but those differences were not statistically significant, Dr. Amit X. Garg and associates wrote online in JAMA (JAMA 2015; doi:10.1001/jama.2014.15284).

Both drugs increased the risk of postoperative conditions that are associated with AKI, Dr. Garg of the London Health Sciences Centre and Western University, London, Ontario, and his co-authors noted. The study was simultaneously presented at Kidney Week 2014, which was sponsored by the American Society of Nephrology.

In fact, there was some suggestion that the drugs increased the risk of severe AKI, he said at the meeting. “But these were secondary measures and need to be interpreted cautiosuly, because the absolute number of severe AKIs was quite small.”

The AKI investigation was a substudy of the Perioperative Ischemia Evaluation-2, (POISE-2) trial, which evaluated the risk of 30-day mortality or nonfatal myocardial infarction among 6,905 surgical patients with a moderate to high risk of a perioperative cardiac event. The aspirin regimen called for 200 mg before surgery and then 100 mg daily for up to 30 days after surgery. The clonidine regimen was 0.2 mg orally 2-4 hours before surgery, followed by a 0.3 mg/day transdermal patch worn for 72 hours after surgery. Both groups also had a placebo arm.

The patients were a mean of 69 years old. Cardiovascular disease was present in about 30%; these included coronary artery disease, stroke, and peripheral vascular disease. About a quarter smoked; 36% had diabetes; 86% had hypertension; 2% had atrial fibrillation. Medications included COX-2 inhibitors; statins; ACE, ARB or direct renin inhibitors; and antihypertensives.

At baseline about 24% had an estimated glomerular filtration rate of 60 ml/min or lower per 1.73 m².

Surgical procedures were urgent or emergent, major vascular, major thoracic, major urological or gynecologic, and other unspecified procedures.

Aspirin did not reduce the risk of an AKI compared to placebo. AKI occurred in 462 patients taking aspirin and 426 taking placebo (13.4% vs. 12.3% respectively; adjusted risk ratio 1.10). Nor did clonidine reduce the risk of AKI compared to placebo. AKI occurred in 449 taking aspirin and 439 taking placebo (13% and 12.7% respectively; adjusted risk ratio 1.03). Neither of these findings was statistically significant.

AKI-related dialysis within 30 days occurred in 0.6% those taking aspirin and 0.3% of the matched placebo patients - a nonsignificant difference. Serum creatinine increased a mean of 11% with aspirin vs. 11% with placebo.

Dialysis was necessary in 0.5% of those taking clonidine and 0.3% of the matched placebo patients - another nonsignificant finding. A history of preoperative chronic kidney disease did not alter either of these findings.

A post hoc analysis determined that both drugs increased the incidence of conditions known to boost the risk of kidney injury. Aspirin increased the risk of major bleeding, which was associated with a greater risk of AKI (23.3% when bleeding occurred vs 12.3% when it did not; adjusted risk ratio 2.20).

Because of this doubling of risk, Dr. Garg suggested moderating pre-operative aspirin exposure in these patients.

“Among patients taking aspirin as part of a long-term regimen, these results support holding it for at least 3 days before surgery and then restarting it a week after surgery,” he recommended.

Clonidine increased the risk of clinically important hypotension, which was also related in turn to AKI (14.3% when hypotension was present vs. 11.8% when it was not; adjusted risk ratio for AKI 1.34).

Dr. Garg had no financial disclosures. A number of the POISE-2 investigators reported financial relationships with pharmaceutical companies.

[email protected]

BALTIMORE – Patients with seemingly desperate illnesses of the central nervous system can make a dramatic recovery if they receive appropriate, early antimicrobials and have enough time to respond.

When these illnesses strike, “Without timely, appropriate antimicrobials, we are in trouble,” Dr. Claude Hemphill said at the annual meeting of the American Neurological Association. “All is usually lost. But patients can look very sick and still make a good recovery if we treat early. However, good neurocritical care is crucial.”

As an example, he cited the case of a 28-year-old nurse who had symptoms of an upper respiratory infection, including fever and headache. Her mother found her unresponsive and with left arm flexure. She required suctioning, which revealed pus in her throat. She did open her eyes to loud voices, but couldn’t follow commands. She had severe right-sided hemiparesis.

Michele G. Sullivan/Frontline Medical News

Imaging showed a severe empyema with brain inflammation and cerebral venous sinus thrombosis. Further testing revealed an Staphylococcus aureus brain infection.

“This was an emergency neurosurgical situation and she went emergently to the operating room,” where she had a decompressive craniectomy and postoperative angiography, said Dr. Hemphill, the Kenneth Rainin Chair in Neurocritical Care at the University of California, San Francisco. She was started on antibiotics and had several days of tissue plasminogen activator infusion into the superior sagittal sinus. But she remained in a coma.”

Intracranial pressure (ICP) monitoring and brain oxygen monitoring were not favorable. By hospital day 29, “You could see swelling everywhere. The middle cerebral artery was pushed up, and there was brain herniation through the craniectomy. At this time, we were weaning her off barbiturates and strongly urged to give up. But we didn’t. We finished her treatment and sent her to a rehab facility.”

Ten weeks later, Dr. Hemphill got a call from the young woman, requesting a note to return to work as soon as her craniectomy skull flap healed. “I wrote the note and chalked it up to a good lesson for both me and my team.”

In addition to discovering the root cause of the primary injury (in this case, infective illness), a key to the nurse’s good recovery was the limiting of secondary brain injury, he said. ICP monitoring was crucial during treatment and the long waiting period, Dr. Hemphill said. But ICP monitoring for these patients is often viewed as an unusual tactic.

“If you ask the neurosurgeon for an ICP, you might get a funny look,” he warned. “In the U.S. at least, not doing so is merely an accepted practice pattern – it’s not anything based on the pathophysiology of the disease.”

Even if the situation looks grim, Dr. Hemphill advised optimizing treatment to give patients with encephalitis a fighting chance. Antimicrobials may be helpful even if no infective agent can be identified. Corticosteroids, especially dexamethasone, appear beneficial if given concomitantly. “The reason we shouldn’t defer dexamethasone is that the blood-brain barrier may be less permeable after antibiotics,” Dr. Hemphill noted.

Glycerol, anti-inflammatory drugs, and paracetamol have not been proven helpful.

Because nonconvulsive status epilepticus isn’t uncommon, he also recommended continuous EEG monitoring, although prophylactic anticonvulsants are not usually indicated.

Dr. Hemphill had no financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – Patients with seemingly desperate illnesses of the central nervous system can make a dramatic recovery if they receive appropriate, early antimicrobials and have enough time to respond.

When these illnesses strike, “Without timely, appropriate antimicrobials, we are in trouble,” Dr. Claude Hemphill said at the annual meeting of the American Neurological Association. “All is usually lost. But patients can look very sick and still make a good recovery if we treat early. However, good neurocritical care is crucial.”

As an example, he cited the case of a 28-year-old nurse who had symptoms of an upper respiratory infection, including fever and headache. Her mother found her unresponsive and with left arm flexure. She required suctioning, which revealed pus in her throat. She did open her eyes to loud voices, but couldn’t follow commands. She had severe right-sided hemiparesis.

Michele G. Sullivan/Frontline Medical News

Imaging showed a severe empyema with brain inflammation and cerebral venous sinus thrombosis. Further testing revealed an Staphylococcus aureus brain infection.

“This was an emergency neurosurgical situation and she went emergently to the operating room,” where she had a decompressive craniectomy and postoperative angiography, said Dr. Hemphill, the Kenneth Rainin Chair in Neurocritical Care at the University of California, San Francisco. She was started on antibiotics and had several days of tissue plasminogen activator infusion into the superior sagittal sinus. But she remained in a coma.”

Intracranial pressure (ICP) monitoring and brain oxygen monitoring were not favorable. By hospital day 29, “You could see swelling everywhere. The middle cerebral artery was pushed up, and there was brain herniation through the craniectomy. At this time, we were weaning her off barbiturates and strongly urged to give up. But we didn’t. We finished her treatment and sent her to a rehab facility.”

Ten weeks later, Dr. Hemphill got a call from the young woman, requesting a note to return to work as soon as her craniectomy skull flap healed. “I wrote the note and chalked it up to a good lesson for both me and my team.”

In addition to discovering the root cause of the primary injury (in this case, infective illness), a key to the nurse’s good recovery was the limiting of secondary brain injury, he said. ICP monitoring was crucial during treatment and the long waiting period, Dr. Hemphill said. But ICP monitoring for these patients is often viewed as an unusual tactic.

“If you ask the neurosurgeon for an ICP, you might get a funny look,” he warned. “In the U.S. at least, not doing so is merely an accepted practice pattern – it’s not anything based on the pathophysiology of the disease.”

Even if the situation looks grim, Dr. Hemphill advised optimizing treatment to give patients with encephalitis a fighting chance. Antimicrobials may be helpful even if no infective agent can be identified. Corticosteroids, especially dexamethasone, appear beneficial if given concomitantly. “The reason we shouldn’t defer dexamethasone is that the blood-brain barrier may be less permeable after antibiotics,” Dr. Hemphill noted.

Glycerol, anti-inflammatory drugs, and paracetamol have not been proven helpful.

Because nonconvulsive status epilepticus isn’t uncommon, he also recommended continuous EEG monitoring, although prophylactic anticonvulsants are not usually indicated.

Dr. Hemphill had no financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – Patients with seemingly desperate illnesses of the central nervous system can make a dramatic recovery if they receive appropriate, early antimicrobials and have enough time to respond.

When these illnesses strike, “Without timely, appropriate antimicrobials, we are in trouble,” Dr. Claude Hemphill said at the annual meeting of the American Neurological Association. “All is usually lost. But patients can look very sick and still make a good recovery if we treat early. However, good neurocritical care is crucial.”

As an example, he cited the case of a 28-year-old nurse who had symptoms of an upper respiratory infection, including fever and headache. Her mother found her unresponsive and with left arm flexure. She required suctioning, which revealed pus in her throat. She did open her eyes to loud voices, but couldn’t follow commands. She had severe right-sided hemiparesis.

Michele G. Sullivan/Frontline Medical News

Imaging showed a severe empyema with brain inflammation and cerebral venous sinus thrombosis. Further testing revealed an Staphylococcus aureus brain infection.

“This was an emergency neurosurgical situation and she went emergently to the operating room,” where she had a decompressive craniectomy and postoperative angiography, said Dr. Hemphill, the Kenneth Rainin Chair in Neurocritical Care at the University of California, San Francisco. She was started on antibiotics and had several days of tissue plasminogen activator infusion into the superior sagittal sinus. But she remained in a coma.”

Intracranial pressure (ICP) monitoring and brain oxygen monitoring were not favorable. By hospital day 29, “You could see swelling everywhere. The middle cerebral artery was pushed up, and there was brain herniation through the craniectomy. At this time, we were weaning her off barbiturates and strongly urged to give up. But we didn’t. We finished her treatment and sent her to a rehab facility.”

Ten weeks later, Dr. Hemphill got a call from the young woman, requesting a note to return to work as soon as her craniectomy skull flap healed. “I wrote the note and chalked it up to a good lesson for both me and my team.”

In addition to discovering the root cause of the primary injury (in this case, infective illness), a key to the nurse’s good recovery was the limiting of secondary brain injury, he said. ICP monitoring was crucial during treatment and the long waiting period, Dr. Hemphill said. But ICP monitoring for these patients is often viewed as an unusual tactic.

“If you ask the neurosurgeon for an ICP, you might get a funny look,” he warned. “In the U.S. at least, not doing so is merely an accepted practice pattern – it’s not anything based on the pathophysiology of the disease.”

Even if the situation looks grim, Dr. Hemphill advised optimizing treatment to give patients with encephalitis a fighting chance. Antimicrobials may be helpful even if no infective agent can be identified. Corticosteroids, especially dexamethasone, appear beneficial if given concomitantly. “The reason we shouldn’t defer dexamethasone is that the blood-brain barrier may be less permeable after antibiotics,” Dr. Hemphill noted.

Glycerol, anti-inflammatory drugs, and paracetamol have not been proven helpful.

Because nonconvulsive status epilepticus isn’t uncommon, he also recommended continuous EEG monitoring, although prophylactic anticonvulsants are not usually indicated.

Dr. Hemphill had no financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – A few days’ delay in prognostication can make the difference between life and death for patients who are treated with hypothermia after cardiac arrest.*

There’s no doubt now that the cooling technique improves survival and neurologic outcomes after cardiac arrest, Dr. Romergryko Geocadin said at the annual meeting of the American Neurological Association. But there isn’t yet firm consensus on the optimal target temperature, how long cooling and rewarming should last, or how long to wait before recovery can be adequately assessed, said Dr. Geocadin of Johns Hopkins University, Baltimore.

Because these questions remain open, both clinicians and families can make what he called a possibly tragic mistake: assuming too early that all hope is lost.

“The concept of waiting and allowing the tincture of time to work is very straightforward,” said Dr. Geocadin, who is also president of the Neurocritical Care Society. “It’s the problem of nihilism that is so immense. Once we as physicians say a disease is fatal – it is. Because if you predict the patient will die, then you will give up. Then patient will die, and then you will be correct.”

Dr. Geocadin argues that many cardiac arrest patients don’t get the time they need to begin recovery after hypothermic treatment. “The forces against this are sadly aligned” against patience, he said in an interview. Families are in distress and crave answers to difficult questions. Doctors feel pressured to give them, and predict outcomes too early. And, unfortunately, medical economics always lurks in the background. “In the ICU, you are always in a bed crunch. People demand to know why we’re waiting on this patient who is obviously going to have a poor outcome. I would say, what’s more unethical? Sentencing a patient to prolonged existence with little hope, or using insufficient information to predict a fatal outcome? I’m not saying sustain someone for 3 months – but just give it a week before making the decision that treatment is futile.”

No one knows exactly why postarrest hypothermia improves overall survival and good neurologic outcomes, Dr. Geocadin said. Treatment guidelines from the American Academy of Neurology and American Heart Association are scheduled to be released sometime in 2015. But for now, some important questions remain. What’s the best target temperature and how long should it be sustained? How about rewarming? The latest research isn’t finding definitive answers.

In 2013, a randomized trial of 950 patients added to the confusion. Mortality and neurologic recovery were similar whether patients had been cooled to 33° C or a near-normothermic 36° C.

The study suggests that cooling itself might not be the only key outcomes driver, Dr. Geocadin said. A combination of several other factors could also be at play. The real benefit could be in avoiding postresuscitation fever, which is associated with poor outcomes. It’s also possible that hypothermia’s therapeutic bang might actually be because of the improved multidisciplinary critical care protocols that accompany it – stabilizing blood pressure and blood glucose, controlling seizures, and increased clinician vigilance. Or it could simply be a marker of facility quality: A hospital equipped to offer hypothermia will likely be offering other advanced care practices and expert personnel as well.

“But one thing needs to be emphasized,” he said. “Temperature management at either 33° C or 36° C is superior to no temperature management [normothermia or more than 36° C] in comatose, postcardiac arrest patients."

Hypothermia slows down everything, including drug metabolism. “It’s not just cell death that slows or stops. Metabolism of drugs, such as sedatives, slows as well, and this could be related to the delayed brain recovery that we saw in the earlier trials, where neurologic function started to return by about 5-6 days. This could be because of the brain itself being slowed, or the being affected by slowly metabolized drugs. And this is why we need that delay before we can make prognostication about outcomes. We just need to give people a chance to come out of it.”

Dr. Geocadin had no financial disclosures. However, he is a member of the task force creating the new American Academy of Neurology/American Heart Association hypothermia treatment guidelines.

*Correction, 11/14/2014: A portion of the article that incorrectly stated the cardiac arrest hypothermia protocol at Johns Hopkins has been deleted.

[email protected]

On Twitter @alz_gal

BALTIMORE – A few days’ delay in prognostication can make the difference between life and death for patients who are treated with hypothermia after cardiac arrest.*

There’s no doubt now that the cooling technique improves survival and neurologic outcomes after cardiac arrest, Dr. Romergryko Geocadin said at the annual meeting of the American Neurological Association. But there isn’t yet firm consensus on the optimal target temperature, how long cooling and rewarming should last, or how long to wait before recovery can be adequately assessed, said Dr. Geocadin of Johns Hopkins University, Baltimore.

Because these questions remain open, both clinicians and families can make what he called a possibly tragic mistake: assuming too early that all hope is lost.

“The concept of waiting and allowing the tincture of time to work is very straightforward,” said Dr. Geocadin, who is also president of the Neurocritical Care Society. “It’s the problem of nihilism that is so immense. Once we as physicians say a disease is fatal – it is. Because if you predict the patient will die, then you will give up. Then patient will die, and then you will be correct.”

Dr. Geocadin argues that many cardiac arrest patients don’t get the time they need to begin recovery after hypothermic treatment. “The forces against this are sadly aligned” against patience, he said in an interview. Families are in distress and crave answers to difficult questions. Doctors feel pressured to give them, and predict outcomes too early. And, unfortunately, medical economics always lurks in the background. “In the ICU, you are always in a bed crunch. People demand to know why we’re waiting on this patient who is obviously going to have a poor outcome. I would say, what’s more unethical? Sentencing a patient to prolonged existence with little hope, or using insufficient information to predict a fatal outcome? I’m not saying sustain someone for 3 months – but just give it a week before making the decision that treatment is futile.”

No one knows exactly why postarrest hypothermia improves overall survival and good neurologic outcomes, Dr. Geocadin said. Treatment guidelines from the American Academy of Neurology and American Heart Association are scheduled to be released sometime in 2015. But for now, some important questions remain. What’s the best target temperature and how long should it be sustained? How about rewarming? The latest research isn’t finding definitive answers.

In 2013, a randomized trial of 950 patients added to the confusion. Mortality and neurologic recovery were similar whether patients had been cooled to 33° C or a near-normothermic 36° C.

The study suggests that cooling itself might not be the only key outcomes driver, Dr. Geocadin said. A combination of several other factors could also be at play. The real benefit could be in avoiding postresuscitation fever, which is associated with poor outcomes. It’s also possible that hypothermia’s therapeutic bang might actually be because of the improved multidisciplinary critical care protocols that accompany it – stabilizing blood pressure and blood glucose, controlling seizures, and increased clinician vigilance. Or it could simply be a marker of facility quality: A hospital equipped to offer hypothermia will likely be offering other advanced care practices and expert personnel as well.

“But one thing needs to be emphasized,” he said. “Temperature management at either 33° C or 36° C is superior to no temperature management [normothermia or more than 36° C] in comatose, postcardiac arrest patients."

Hypothermia slows down everything, including drug metabolism. “It’s not just cell death that slows or stops. Metabolism of drugs, such as sedatives, slows as well, and this could be related to the delayed brain recovery that we saw in the earlier trials, where neurologic function started to return by about 5-6 days. This could be because of the brain itself being slowed, or the being affected by slowly metabolized drugs. And this is why we need that delay before we can make prognostication about outcomes. We just need to give people a chance to come out of it.”

Dr. Geocadin had no financial disclosures. However, he is a member of the task force creating the new American Academy of Neurology/American Heart Association hypothermia treatment guidelines.

*Correction, 11/14/2014: A portion of the article that incorrectly stated the cardiac arrest hypothermia protocol at Johns Hopkins has been deleted.

[email protected]

On Twitter @alz_gal

BALTIMORE – A few days’ delay in prognostication can make the difference between life and death for patients who are treated with hypothermia after cardiac arrest.*

There’s no doubt now that the cooling technique improves survival and neurologic outcomes after cardiac arrest, Dr. Romergryko Geocadin said at the annual meeting of the American Neurological Association. But there isn’t yet firm consensus on the optimal target temperature, how long cooling and rewarming should last, or how long to wait before recovery can be adequately assessed, said Dr. Geocadin of Johns Hopkins University, Baltimore.

Because these questions remain open, both clinicians and families can make what he called a possibly tragic mistake: assuming too early that all hope is lost.

“The concept of waiting and allowing the tincture of time to work is very straightforward,” said Dr. Geocadin, who is also president of the Neurocritical Care Society. “It’s the problem of nihilism that is so immense. Once we as physicians say a disease is fatal – it is. Because if you predict the patient will die, then you will give up. Then patient will die, and then you will be correct.”

Dr. Geocadin argues that many cardiac arrest patients don’t get the time they need to begin recovery after hypothermic treatment. “The forces against this are sadly aligned” against patience, he said in an interview. Families are in distress and crave answers to difficult questions. Doctors feel pressured to give them, and predict outcomes too early. And, unfortunately, medical economics always lurks in the background. “In the ICU, you are always in a bed crunch. People demand to know why we’re waiting on this patient who is obviously going to have a poor outcome. I would say, what’s more unethical? Sentencing a patient to prolonged existence with little hope, or using insufficient information to predict a fatal outcome? I’m not saying sustain someone for 3 months – but just give it a week before making the decision that treatment is futile.”

No one knows exactly why postarrest hypothermia improves overall survival and good neurologic outcomes, Dr. Geocadin said. Treatment guidelines from the American Academy of Neurology and American Heart Association are scheduled to be released sometime in 2015. But for now, some important questions remain. What’s the best target temperature and how long should it be sustained? How about rewarming? The latest research isn’t finding definitive answers.

In 2013, a randomized trial of 950 patients added to the confusion. Mortality and neurologic recovery were similar whether patients had been cooled to 33° C or a near-normothermic 36° C.

The study suggests that cooling itself might not be the only key outcomes driver, Dr. Geocadin said. A combination of several other factors could also be at play. The real benefit could be in avoiding postresuscitation fever, which is associated with poor outcomes. It’s also possible that hypothermia’s therapeutic bang might actually be because of the improved multidisciplinary critical care protocols that accompany it – stabilizing blood pressure and blood glucose, controlling seizures, and increased clinician vigilance. Or it could simply be a marker of facility quality: A hospital equipped to offer hypothermia will likely be offering other advanced care practices and expert personnel as well.

“But one thing needs to be emphasized,” he said. “Temperature management at either 33° C or 36° C is superior to no temperature management [normothermia or more than 36° C] in comatose, postcardiac arrest patients."

Hypothermia slows down everything, including drug metabolism. “It’s not just cell death that slows or stops. Metabolism of drugs, such as sedatives, slows as well, and this could be related to the delayed brain recovery that we saw in the earlier trials, where neurologic function started to return by about 5-6 days. This could be because of the brain itself being slowed, or the being affected by slowly metabolized drugs. And this is why we need that delay before we can make prognostication about outcomes. We just need to give people a chance to come out of it.”

Dr. Geocadin had no financial disclosures. However, he is a member of the task force creating the new American Academy of Neurology/American Heart Association hypothermia treatment guidelines.

*Correction, 11/14/2014: A portion of the article that incorrectly stated the cardiac arrest hypothermia protocol at Johns Hopkins has been deleted.

[email protected]

On Twitter @alz_gal

BALTIMORE – Serotonin syndrome can easily develop in the intensive care unit, particularly when patients receive opiates and antiemetic medications in addition to the serotonin-enhancing medications they may already be taking.

“These medications are pervasively present, and they are notorious for drug-drug interactions,” Dr. Alejandro Rabinstein said at the annual meeting of the American Neurological Association. “And, in the ICU, we often use them without even realizing it. The combination can be enough to cause serotonin syndrome, which is sometimes recognized too late, and can have serious consequences.”

Because there are scant data on the phenomenon, Dr. Rabinstein, a critical care neurologist at the Mayo Clinic, Rochester, Minn., conducted a literature search to identify cases and examine their outcomes. His series comprised 33 patients, 22 of whom were seen at the Mayo facility. The patients were a median of 42 years old. Four of them had been admitted with serotonin syndrome as their primary diagnosis, but it was either unsuspected or had not yet developed in the remainder.

For 17 patients (52%), the primary reason for admission was a change in mental status or altered consciousness. Four were admitted for sepsis syndrome. Other reasons included resuscitation after cardiac arrest (three), severe pneumonia (two), tumor-related complications (two), emergency surgery (two), graft vs. host disease (one), liver failure (one), and trauma (one).

At admission, the mean APACHE-III score was 67, although the range was wide (11-146). A total of 18 patients required mechanical ventilation, and 6 had undergone surgery before serotonin syndrome developed.

All of the patients showed altered mental status, a key characteristic of serotonin syndrome. Agitation was present in 14 patients. Other common signs were tachypnea (23), tachycardia (20), clonus (29), hyperreflexia (24), and rigidity (26). Mydriasis was present in 14 and tremor in 12. Seven patients were markedly diaphoretic. Fever was present in 14.

About 40% of the group (13 patients) developed signs of serotonin syndrome only after they were hospitalized (mean day 4). Dr. Rabinstein said 22 drugs with a direct serotonin-enhancing action were involved in the cases. In fact, almost all were taking at least one such drug on admission, and 70% got new serotonergic medications while in the ICU.

About 75% of the patients were taking a selective serotonin reuptake inhibitor when admitted (citalopram, fluoxetine, sertraline, escitalopram, and paroxetine ). Almost a third were taking a selective norepinephrine reuptake inhibitor (venlafaxine and duloxetine). About a fourth were taking some other antidepressant with serotonergic activity (trazodone, mirtazapine, buspirone, clomipramine). While in the ICU, three patients received a new serotonergic antidepressant.

Four patients were taking an antiemetic upon admission, and seven started a new antiemetic when admitted. Three were taking an opioid upon admission, and 21 started an opioid when admitted.

All of the patients received benzodiazepine treatment, and 24% had to be paralyzed while their serotonergic symptoms resolved. The anticholinergic antihistamine cyproheptadine was given to the 13 most severely affected patients. However, Dr. Rabinstein said, its efficacy couldn’t be reliably assessed because of this selection bias.

It took a mean of 56 hours for patients to recover to the point where they could interact normally, but the range of recovery time was very wide (8-288 hours). Despite some increases in creatinine kinase and lactic acid, none of the patients developed rhabdomyolysis-related kidney failure. Although serotonin syndrome can be fatal, there were no related deaths in this group.

The review points to how easily ICU treatment can precipitate a very serious neurologic disorder. “Almost everyone came into the ICU on one of these medications, and almost everyone got at least one more after arriving,” Dr. Rabinstein said. “It’s something we have to be on the alert for. The reason I did this study was simply to raise awareness, because this diagnosis is blown all the time. You don’t have to be a neurologist to make this diagnosis, but you need to be very attentive to these signs. ”

He had no financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – Serotonin syndrome can easily develop in the intensive care unit, particularly when patients receive opiates and antiemetic medications in addition to the serotonin-enhancing medications they may already be taking.

“These medications are pervasively present, and they are notorious for drug-drug interactions,” Dr. Alejandro Rabinstein said at the annual meeting of the American Neurological Association. “And, in the ICU, we often use them without even realizing it. The combination can be enough to cause serotonin syndrome, which is sometimes recognized too late, and can have serious consequences.”

Because there are scant data on the phenomenon, Dr. Rabinstein, a critical care neurologist at the Mayo Clinic, Rochester, Minn., conducted a literature search to identify cases and examine their outcomes. His series comprised 33 patients, 22 of whom were seen at the Mayo facility. The patients were a median of 42 years old. Four of them had been admitted with serotonin syndrome as their primary diagnosis, but it was either unsuspected or had not yet developed in the remainder.

For 17 patients (52%), the primary reason for admission was a change in mental status or altered consciousness. Four were admitted for sepsis syndrome. Other reasons included resuscitation after cardiac arrest (three), severe pneumonia (two), tumor-related complications (two), emergency surgery (two), graft vs. host disease (one), liver failure (one), and trauma (one).

At admission, the mean APACHE-III score was 67, although the range was wide (11-146). A total of 18 patients required mechanical ventilation, and 6 had undergone surgery before serotonin syndrome developed.

All of the patients showed altered mental status, a key characteristic of serotonin syndrome. Agitation was present in 14 patients. Other common signs were tachypnea (23), tachycardia (20), clonus (29), hyperreflexia (24), and rigidity (26). Mydriasis was present in 14 and tremor in 12. Seven patients were markedly diaphoretic. Fever was present in 14.

About 40% of the group (13 patients) developed signs of serotonin syndrome only after they were hospitalized (mean day 4). Dr. Rabinstein said 22 drugs with a direct serotonin-enhancing action were involved in the cases. In fact, almost all were taking at least one such drug on admission, and 70% got new serotonergic medications while in the ICU.

About 75% of the patients were taking a selective serotonin reuptake inhibitor when admitted (citalopram, fluoxetine, sertraline, escitalopram, and paroxetine ). Almost a third were taking a selective norepinephrine reuptake inhibitor (venlafaxine and duloxetine). About a fourth were taking some other antidepressant with serotonergic activity (trazodone, mirtazapine, buspirone, clomipramine). While in the ICU, three patients received a new serotonergic antidepressant.

Four patients were taking an antiemetic upon admission, and seven started a new antiemetic when admitted. Three were taking an opioid upon admission, and 21 started an opioid when admitted.

All of the patients received benzodiazepine treatment, and 24% had to be paralyzed while their serotonergic symptoms resolved. The anticholinergic antihistamine cyproheptadine was given to the 13 most severely affected patients. However, Dr. Rabinstein said, its efficacy couldn’t be reliably assessed because of this selection bias.

It took a mean of 56 hours for patients to recover to the point where they could interact normally, but the range of recovery time was very wide (8-288 hours). Despite some increases in creatinine kinase and lactic acid, none of the patients developed rhabdomyolysis-related kidney failure. Although serotonin syndrome can be fatal, there were no related deaths in this group.

The review points to how easily ICU treatment can precipitate a very serious neurologic disorder. “Almost everyone came into the ICU on one of these medications, and almost everyone got at least one more after arriving,” Dr. Rabinstein said. “It’s something we have to be on the alert for. The reason I did this study was simply to raise awareness, because this diagnosis is blown all the time. You don’t have to be a neurologist to make this diagnosis, but you need to be very attentive to these signs. ”

He had no financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – Serotonin syndrome can easily develop in the intensive care unit, particularly when patients receive opiates and antiemetic medications in addition to the serotonin-enhancing medications they may already be taking.

“These medications are pervasively present, and they are notorious for drug-drug interactions,” Dr. Alejandro Rabinstein said at the annual meeting of the American Neurological Association. “And, in the ICU, we often use them without even realizing it. The combination can be enough to cause serotonin syndrome, which is sometimes recognized too late, and can have serious consequences.”

Because there are scant data on the phenomenon, Dr. Rabinstein, a critical care neurologist at the Mayo Clinic, Rochester, Minn., conducted a literature search to identify cases and examine their outcomes. His series comprised 33 patients, 22 of whom were seen at the Mayo facility. The patients were a median of 42 years old. Four of them had been admitted with serotonin syndrome as their primary diagnosis, but it was either unsuspected or had not yet developed in the remainder.

For 17 patients (52%), the primary reason for admission was a change in mental status or altered consciousness. Four were admitted for sepsis syndrome. Other reasons included resuscitation after cardiac arrest (three), severe pneumonia (two), tumor-related complications (two), emergency surgery (two), graft vs. host disease (one), liver failure (one), and trauma (one).

At admission, the mean APACHE-III score was 67, although the range was wide (11-146). A total of 18 patients required mechanical ventilation, and 6 had undergone surgery before serotonin syndrome developed.

All of the patients showed altered mental status, a key characteristic of serotonin syndrome. Agitation was present in 14 patients. Other common signs were tachypnea (23), tachycardia (20), clonus (29), hyperreflexia (24), and rigidity (26). Mydriasis was present in 14 and tremor in 12. Seven patients were markedly diaphoretic. Fever was present in 14.

About 40% of the group (13 patients) developed signs of serotonin syndrome only after they were hospitalized (mean day 4). Dr. Rabinstein said 22 drugs with a direct serotonin-enhancing action were involved in the cases. In fact, almost all were taking at least one such drug on admission, and 70% got new serotonergic medications while in the ICU.

About 75% of the patients were taking a selective serotonin reuptake inhibitor when admitted (citalopram, fluoxetine, sertraline, escitalopram, and paroxetine ). Almost a third were taking a selective norepinephrine reuptake inhibitor (venlafaxine and duloxetine). About a fourth were taking some other antidepressant with serotonergic activity (trazodone, mirtazapine, buspirone, clomipramine). While in the ICU, three patients received a new serotonergic antidepressant.

Four patients were taking an antiemetic upon admission, and seven started a new antiemetic when admitted. Three were taking an opioid upon admission, and 21 started an opioid when admitted.

All of the patients received benzodiazepine treatment, and 24% had to be paralyzed while their serotonergic symptoms resolved. The anticholinergic antihistamine cyproheptadine was given to the 13 most severely affected patients. However, Dr. Rabinstein said, its efficacy couldn’t be reliably assessed because of this selection bias.

It took a mean of 56 hours for patients to recover to the point where they could interact normally, but the range of recovery time was very wide (8-288 hours). Despite some increases in creatinine kinase and lactic acid, none of the patients developed rhabdomyolysis-related kidney failure. Although serotonin syndrome can be fatal, there were no related deaths in this group.

The review points to how easily ICU treatment can precipitate a very serious neurologic disorder. “Almost everyone came into the ICU on one of these medications, and almost everyone got at least one more after arriving,” Dr. Rabinstein said. “It’s something we have to be on the alert for. The reason I did this study was simply to raise awareness, because this diagnosis is blown all the time. You don’t have to be a neurologist to make this diagnosis, but you need to be very attentive to these signs. ”

He had no financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – The presence of cerebral microbleeds was not associated with a higher frequency of hemorrhagic transformation among patients who received a loading dose of the antiplatelet drug, compared with patients who had no evidence of microbleeds, in a retrospective study of 1,060 patients who presented with acute ischemic stroke.

“Clopidogrel seems like it can be a safe treatment for patients who are not eligible for tissue plasminogen activator, even if the stroke severity is higher than is being tested in recent clinical trials (CHANCE and POINT, for example),” Melisa Valmoria said at the annual meeting of the American Neurological Association.

Ms. Valmoria, a clinical research assistant at the Tulane University stroke research program, New Orleans, presented a retrospective study of 1,060 patients who presented with acute ischemic stroke. Of 1,060 patients in the study, 324 received a loading dose of at least 300 mg clopidogrel within 6 hours of admission, in addition to aspirin. A total of 51 of those patients had evidence of prior cerebral microbleeds on imaging.

The patients were similar in age (average, 63.5 years). Those with microbleeds were more likely to have had a prior stroke (63% vs. 49%; P = .05). The median NIH Stroke Scale (NIHSS) score was also higher among those patients (6 vs. 4).

There were no significant between-group differences in stroke events, including rates of inpatient complications (33% with microbleeds vs. 28% without), hemorrhagic transformation (6% vs. 8%), and recurrent thrombotic events (16% vs. 14%). Neurologic worsening, defined as an increase of at least 2 points in the NIHSS score over any 24-hour period, was not significantly different between the groups (39% vs. 27%). None of the patients with microbleeds developed a symptomatic hemorrhage.

Patients with microbleeds started off with a higher NIHSS score, but did not have significantly worse discharge outcomes. Poor functional outcome (a modified Rankin Scale score of more than 2) occurred in 59% of those with microbleeds and 47% of those without. An unfavorable discharge disposition (discharge to anywhere except the patient’s home or to inpatient rehabilitation) occurred in 16% of those with microbleeds and 10% of those without, which was not a significant difference.

A subanalysis of patients with more than 10 microbleeds showed that clopidogrel did not increase their risk of hemorrhagic transformation or poor functional outcomes, compared with patients who did not have microbleeds.

“Some trials (MATCH and CHARISMA) have raised concern about bleeding risk, specifically brain bleeding, in patients who receive dual antiplatelets, including clopidogrel, after stroke,” Ms. Valmoria said. “This risk may be higher among patients who have evidence of prior brain bleeding, such as microbleeds. Fortunately, our study did not find support for increased short-term bleeding in patients with ischemic stroke who were treated with a loading dose of clopidogrel with aspirin. Our study included many patients with moderatetosevere strokes, as measured by the NIHSS score who are not wellrepresented in modern clinical trials examining the safety and efficacy of clopidogrel loading, raising the question of whether enrollment criteria could be safely loosened.”

She said she had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – The presence of cerebral microbleeds was not associated with a higher frequency of hemorrhagic transformation among patients who received a loading dose of the antiplatelet drug, compared with patients who had no evidence of microbleeds, in a retrospective study of 1,060 patients who presented with acute ischemic stroke.

“Clopidogrel seems like it can be a safe treatment for patients who are not eligible for tissue plasminogen activator, even if the stroke severity is higher than is being tested in recent clinical trials (CHANCE and POINT, for example),” Melisa Valmoria said at the annual meeting of the American Neurological Association.

Ms. Valmoria, a clinical research assistant at the Tulane University stroke research program, New Orleans, presented a retrospective study of 1,060 patients who presented with acute ischemic stroke. Of 1,060 patients in the study, 324 received a loading dose of at least 300 mg clopidogrel within 6 hours of admission, in addition to aspirin. A total of 51 of those patients had evidence of prior cerebral microbleeds on imaging.

The patients were similar in age (average, 63.5 years). Those with microbleeds were more likely to have had a prior stroke (63% vs. 49%; P = .05). The median NIH Stroke Scale (NIHSS) score was also higher among those patients (6 vs. 4).

There were no significant between-group differences in stroke events, including rates of inpatient complications (33% with microbleeds vs. 28% without), hemorrhagic transformation (6% vs. 8%), and recurrent thrombotic events (16% vs. 14%). Neurologic worsening, defined as an increase of at least 2 points in the NIHSS score over any 24-hour period, was not significantly different between the groups (39% vs. 27%). None of the patients with microbleeds developed a symptomatic hemorrhage.

Patients with microbleeds started off with a higher NIHSS score, but did not have significantly worse discharge outcomes. Poor functional outcome (a modified Rankin Scale score of more than 2) occurred in 59% of those with microbleeds and 47% of those without. An unfavorable discharge disposition (discharge to anywhere except the patient’s home or to inpatient rehabilitation) occurred in 16% of those with microbleeds and 10% of those without, which was not a significant difference.

A subanalysis of patients with more than 10 microbleeds showed that clopidogrel did not increase their risk of hemorrhagic transformation or poor functional outcomes, compared with patients who did not have microbleeds.

“Some trials (MATCH and CHARISMA) have raised concern about bleeding risk, specifically brain bleeding, in patients who receive dual antiplatelets, including clopidogrel, after stroke,” Ms. Valmoria said. “This risk may be higher among patients who have evidence of prior brain bleeding, such as microbleeds. Fortunately, our study did not find support for increased short-term bleeding in patients with ischemic stroke who were treated with a loading dose of clopidogrel with aspirin. Our study included many patients with moderatetosevere strokes, as measured by the NIHSS score who are not wellrepresented in modern clinical trials examining the safety and efficacy of clopidogrel loading, raising the question of whether enrollment criteria could be safely loosened.”

She said she had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – The presence of cerebral microbleeds was not associated with a higher frequency of hemorrhagic transformation among patients who received a loading dose of the antiplatelet drug, compared with patients who had no evidence of microbleeds, in a retrospective study of 1,060 patients who presented with acute ischemic stroke.

“Clopidogrel seems like it can be a safe treatment for patients who are not eligible for tissue plasminogen activator, even if the stroke severity is higher than is being tested in recent clinical trials (CHANCE and POINT, for example),” Melisa Valmoria said at the annual meeting of the American Neurological Association.

Ms. Valmoria, a clinical research assistant at the Tulane University stroke research program, New Orleans, presented a retrospective study of 1,060 patients who presented with acute ischemic stroke. Of 1,060 patients in the study, 324 received a loading dose of at least 300 mg clopidogrel within 6 hours of admission, in addition to aspirin. A total of 51 of those patients had evidence of prior cerebral microbleeds on imaging.

The patients were similar in age (average, 63.5 years). Those with microbleeds were more likely to have had a prior stroke (63% vs. 49%; P = .05). The median NIH Stroke Scale (NIHSS) score was also higher among those patients (6 vs. 4).

There were no significant between-group differences in stroke events, including rates of inpatient complications (33% with microbleeds vs. 28% without), hemorrhagic transformation (6% vs. 8%), and recurrent thrombotic events (16% vs. 14%). Neurologic worsening, defined as an increase of at least 2 points in the NIHSS score over any 24-hour period, was not significantly different between the groups (39% vs. 27%). None of the patients with microbleeds developed a symptomatic hemorrhage.

Patients with microbleeds started off with a higher NIHSS score, but did not have significantly worse discharge outcomes. Poor functional outcome (a modified Rankin Scale score of more than 2) occurred in 59% of those with microbleeds and 47% of those without. An unfavorable discharge disposition (discharge to anywhere except the patient’s home or to inpatient rehabilitation) occurred in 16% of those with microbleeds and 10% of those without, which was not a significant difference.

A subanalysis of patients with more than 10 microbleeds showed that clopidogrel did not increase their risk of hemorrhagic transformation or poor functional outcomes, compared with patients who did not have microbleeds.

“Some trials (MATCH and CHARISMA) have raised concern about bleeding risk, specifically brain bleeding, in patients who receive dual antiplatelets, including clopidogrel, after stroke,” Ms. Valmoria said. “This risk may be higher among patients who have evidence of prior brain bleeding, such as microbleeds. Fortunately, our study did not find support for increased short-term bleeding in patients with ischemic stroke who were treated with a loading dose of clopidogrel with aspirin. Our study included many patients with moderatetosevere strokes, as measured by the NIHSS score who are not wellrepresented in modern clinical trials examining the safety and efficacy of clopidogrel loading, raising the question of whether enrollment criteria could be safely loosened.”

She said she had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE – Two imported mosquito-borne illnesses continue to push into the United States, threatening to take up residence in areas with a favorable environment.

Neither dengue fever nor West Nile virus are naturally endemic to any part of the United States, Dr. Larry Davis said at the annual meeting of the American Neurological Association. But both diseases show some indications of establishing a local infective reservoir.

Dengue remains a rare disease here, with about 650 cases reported in 2013. The majority of those occurred in patients who had just returned from endemic countries. But since 2009, local transmission appears to be occurring in three hot spots: Hawaii, Texas, and south Florida, including Key West and Miami, said Dr. Davis, a professor of neurology at the University of New Mexico, Albuquerque.

Locally acquired disease first popped up during 2009-2010 in Key West, Fla. During that time, 29 residents developed clinical dengue. Many more probably carried the virus, however, since a robust immune response usually tamps down about 80% of first infections. But those asymptomatic carriers provide a potent reservoir for hungry mosquitoes, and dengue is one virus that doesn’t need an intermediate host. Instead, Dr. Davis said, any mosquito that bites an infected person passes the agent directly into the bloodstream of his next meal.

During the Key West outbreak, the Centers for Disease Control and Prevention (CDC) estimated that about 5% of those living on the small island had been infected at some point.

Last year, 53 clinical cases were identified in south Texas. About half of these were locally acquired, which is another sign that the virus may be taking up residence, Dr. Davis said. And, so far this year, four residents of Miami-Dade County, Fla. have been diagnosed with locally acquired disease. The outbreak recently prompted local health officials to issue an alert for mosquito-borne disease, and remind residents to take precautions against being bitten.

In addition to its direct transmissibility, dengue has another neat infective trick, Dr. Davis noted. There are four serotypes, each with their own unique immunogenic profile. Thus, infection with any one confers no protection against any of the others. Any vaccine, therefore, would have to protect against all four serotypes.

In fact, such a tetravalent vaccine is in clinical trials, he said. Last month, Sanofi-Pasteur reported that its candidate vaccine, tested in almost 21,000 children in Latin America and the Caribbean, reduced the risk of disease by more than 60%, and the risk of dengue-related hospitalization by 80%. The results mirror those seen in an earlier Asian trial, the drug company noted.There has been no such progress on a human vaccine against West Nile virus, Dr. Davis said. So far this year, 1,585 cases in 47 states have been reported to the CDC, with the majority occurring in California (563), Colorado (108), and Texas (207). Of these, 917 (58%) were classified as neuroinvasive disease (such as meningitis or encephalitis). Thus far, 54 patients have died; 20 of these in California alone.

The California Department of Public Health has identified 3,282 positive mosquito samples as of Oct. 27. Director Dr. Ron Chapman said in a press statement that the state has never experienced such a severe outbreak.

“The proportion of mosquitoes infected with West Nile virus is at the highest level ever detected in California,” Dr. Chapman said. “We expect to see more people become infected as this is the time of year when the risk of infection is the highest.”

Like dengue, the majority of West Nile cases are asymptomatic, Dr. Davis noted. But in the absence of a robust immune response, the virus can cross the blood-brain barrier and initiate a devastating neuroinvasive illness than can cause a flaccid paralysis, seizures, and death.

Neuroinvasive West Nile carries many clinical and diagnostic similarities to polio, he said. Like polio, the limb weakness has a sudden onset and can be accompanied by pain, although the sensory neurons aren’t apparently involved. Imaging studies show the virus attacking at the anterior horns of the spinal cord; nerve conduction studies show a motor axonopathy, but without much demyelination. Survivors have a variable course of recovery; some may regain full strength of the affected limbs, but many retain persistent weakness.

There is no vaccine against the disease, although several are in early-stage development, including a live, attenuated chimeric vaccine that did well in a phase II, placebo-controlled trial. Within 28 days of vaccination, 98% of subjects experienced seroconversion.

Dr. Davis had no relevant conflicts of interest.

[email protected]

On Twitter @alz_gal

BALTIMORE – Two imported mosquito-borne illnesses continue to push into the United States, threatening to take up residence in areas with a favorable environment.

Neither dengue fever nor West Nile virus are naturally endemic to any part of the United States, Dr. Larry Davis said at the annual meeting of the American Neurological Association. But both diseases show some indications of establishing a local infective reservoir.

Dengue remains a rare disease here, with about 650 cases reported in 2013. The majority of those occurred in patients who had just returned from endemic countries. But since 2009, local transmission appears to be occurring in three hot spots: Hawaii, Texas, and south Florida, including Key West and Miami, said Dr. Davis, a professor of neurology at the University of New Mexico, Albuquerque.

Locally acquired disease first popped up during 2009-2010 in Key West, Fla. During that time, 29 residents developed clinical dengue. Many more probably carried the virus, however, since a robust immune response usually tamps down about 80% of first infections. But those asymptomatic carriers provide a potent reservoir for hungry mosquitoes, and dengue is one virus that doesn’t need an intermediate host. Instead, Dr. Davis said, any mosquito that bites an infected person passes the agent directly into the bloodstream of his next meal.

During the Key West outbreak, the Centers for Disease Control and Prevention (CDC) estimated that about 5% of those living on the small island had been infected at some point.

Last year, 53 clinical cases were identified in south Texas. About half of these were locally acquired, which is another sign that the virus may be taking up residence, Dr. Davis said. And, so far this year, four residents of Miami-Dade County, Fla. have been diagnosed with locally acquired disease. The outbreak recently prompted local health officials to issue an alert for mosquito-borne disease, and remind residents to take precautions against being bitten.

In addition to its direct transmissibility, dengue has another neat infective trick, Dr. Davis noted. There are four serotypes, each with their own unique immunogenic profile. Thus, infection with any one confers no protection against any of the others. Any vaccine, therefore, would have to protect against all four serotypes.

In fact, such a tetravalent vaccine is in clinical trials, he said. Last month, Sanofi-Pasteur reported that its candidate vaccine, tested in almost 21,000 children in Latin America and the Caribbean, reduced the risk of disease by more than 60%, and the risk of dengue-related hospitalization by 80%. The results mirror those seen in an earlier Asian trial, the drug company noted.There has been no such progress on a human vaccine against West Nile virus, Dr. Davis said. So far this year, 1,585 cases in 47 states have been reported to the CDC, with the majority occurring in California (563), Colorado (108), and Texas (207). Of these, 917 (58%) were classified as neuroinvasive disease (such as meningitis or encephalitis). Thus far, 54 patients have died; 20 of these in California alone.

The California Department of Public Health has identified 3,282 positive mosquito samples as of Oct. 27. Director Dr. Ron Chapman said in a press statement that the state has never experienced such a severe outbreak.

“The proportion of mosquitoes infected with West Nile virus is at the highest level ever detected in California,” Dr. Chapman said. “We expect to see more people become infected as this is the time of year when the risk of infection is the highest.”

Like dengue, the majority of West Nile cases are asymptomatic, Dr. Davis noted. But in the absence of a robust immune response, the virus can cross the blood-brain barrier and initiate a devastating neuroinvasive illness than can cause a flaccid paralysis, seizures, and death.

Neuroinvasive West Nile carries many clinical and diagnostic similarities to polio, he said. Like polio, the limb weakness has a sudden onset and can be accompanied by pain, although the sensory neurons aren’t apparently involved. Imaging studies show the virus attacking at the anterior horns of the spinal cord; nerve conduction studies show a motor axonopathy, but without much demyelination. Survivors have a variable course of recovery; some may regain full strength of the affected limbs, but many retain persistent weakness.

There is no vaccine against the disease, although several are in early-stage development, including a live, attenuated chimeric vaccine that did well in a phase II, placebo-controlled trial. Within 28 days of vaccination, 98% of subjects experienced seroconversion.

Dr. Davis had no relevant conflicts of interest.

[email protected]

On Twitter @alz_gal

BALTIMORE – Two imported mosquito-borne illnesses continue to push into the United States, threatening to take up residence in areas with a favorable environment.

Neither dengue fever nor West Nile virus are naturally endemic to any part of the United States, Dr. Larry Davis said at the annual meeting of the American Neurological Association. But both diseases show some indications of establishing a local infective reservoir.

Dengue remains a rare disease here, with about 650 cases reported in 2013. The majority of those occurred in patients who had just returned from endemic countries. But since 2009, local transmission appears to be occurring in three hot spots: Hawaii, Texas, and south Florida, including Key West and Miami, said Dr. Davis, a professor of neurology at the University of New Mexico, Albuquerque.

Locally acquired disease first popped up during 2009-2010 in Key West, Fla. During that time, 29 residents developed clinical dengue. Many more probably carried the virus, however, since a robust immune response usually tamps down about 80% of first infections. But those asymptomatic carriers provide a potent reservoir for hungry mosquitoes, and dengue is one virus that doesn’t need an intermediate host. Instead, Dr. Davis said, any mosquito that bites an infected person passes the agent directly into the bloodstream of his next meal.

During the Key West outbreak, the Centers for Disease Control and Prevention (CDC) estimated that about 5% of those living on the small island had been infected at some point.

Last year, 53 clinical cases were identified in south Texas. About half of these were locally acquired, which is another sign that the virus may be taking up residence, Dr. Davis said. And, so far this year, four residents of Miami-Dade County, Fla. have been diagnosed with locally acquired disease. The outbreak recently prompted local health officials to issue an alert for mosquito-borne disease, and remind residents to take precautions against being bitten.

In addition to its direct transmissibility, dengue has another neat infective trick, Dr. Davis noted. There are four serotypes, each with their own unique immunogenic profile. Thus, infection with any one confers no protection against any of the others. Any vaccine, therefore, would have to protect against all four serotypes.

In fact, such a tetravalent vaccine is in clinical trials, he said. Last month, Sanofi-Pasteur reported that its candidate vaccine, tested in almost 21,000 children in Latin America and the Caribbean, reduced the risk of disease by more than 60%, and the risk of dengue-related hospitalization by 80%. The results mirror those seen in an earlier Asian trial, the drug company noted.There has been no such progress on a human vaccine against West Nile virus, Dr. Davis said. So far this year, 1,585 cases in 47 states have been reported to the CDC, with the majority occurring in California (563), Colorado (108), and Texas (207). Of these, 917 (58%) were classified as neuroinvasive disease (such as meningitis or encephalitis). Thus far, 54 patients have died; 20 of these in California alone.

The California Department of Public Health has identified 3,282 positive mosquito samples as of Oct. 27. Director Dr. Ron Chapman said in a press statement that the state has never experienced such a severe outbreak.

“The proportion of mosquitoes infected with West Nile virus is at the highest level ever detected in California,” Dr. Chapman said. “We expect to see more people become infected as this is the time of year when the risk of infection is the highest.”

Like dengue, the majority of West Nile cases are asymptomatic, Dr. Davis noted. But in the absence of a robust immune response, the virus can cross the blood-brain barrier and initiate a devastating neuroinvasive illness than can cause a flaccid paralysis, seizures, and death.

Neuroinvasive West Nile carries many clinical and diagnostic similarities to polio, he said. Like polio, the limb weakness has a sudden onset and can be accompanied by pain, although the sensory neurons aren’t apparently involved. Imaging studies show the virus attacking at the anterior horns of the spinal cord; nerve conduction studies show a motor axonopathy, but without much demyelination. Survivors have a variable course of recovery; some may regain full strength of the affected limbs, but many retain persistent weakness.

There is no vaccine against the disease, although several are in early-stage development, including a live, attenuated chimeric vaccine that did well in a phase II, placebo-controlled trial. Within 28 days of vaccination, 98% of subjects experienced seroconversion.

Dr. Davis had no relevant conflicts of interest.

[email protected]

On Twitter @alz_gal