M. Alexander Otto

LAS VEGAS – Trauma patients should not get antibiotics after damage control or primarily closed laparotomies because this treatment may increase the risk of postsurgical intra-abdominal infections, according to a study from Virginia Commonwealth University, Richmond, a Level 1 trauma center.

The abdomen is often left open for a while after a damage control laparotomy (DCL), especially when patients are coagulopathic, acidotic, or at risk for an abdominal compartment syndrome. In those cases, "people just automatically assume ‘Open abdomen: Throw on the antibiotics.’ What we are showing here is don’t throw on the antibiotics," said lead investigator Dr. Stephanie Goldberg of the trauma, critical care, and emergency surgery faculty at VCU. The worry is probably the same for primarily closed (PC) laparotomies, when the fascia is closed but skin is sometimes left open.

The findings are important because although – and as the team found – preoperative antibiotics are known to reduce the risk of postsurgical abdominal infections, there’s not much evidence in either direction for their use after trauma laparotomies, so "no one knows what to do." Some surgeons opt for antibiotics, others don’t, Dr. Goldberg said.

To help figure out the right approach, her team analyzed perioperative antibiotic use and infection rates in 28 DCL patients whose abdomens were left open, and 93 PC patients. The PC group had a mean injury severity score of 18; 35.5% (33) had bowel injuries. The DCL group was in worse shape, with a mean severity score of 31.4 and bowel injuries in 53.6% (15).

Everyone should have been dosed with an antibiotic before surgery; 94.6% (88) PC patients, but only 69.2% (19) DCL patients, actually were. "It’s likely," in the DCL cases especially, "that patients were so sick and there was so much chaos in the operating room that giving pre-op antibiotics got missed," Dr. Goldberg said.

Postop antibiotic use differed significantly between the groups; 50.5% (47) of PC patients got no antibiotics, 21.5% (20) got a day’s worth, and 28% (26) were treated for more than a day. In the DCL group, 21.4% (6) got no antibiotics, 25.0% (7) a 1-day course, and 53.6% (15) more than a 1-day course.

As expected, preop antibiotics protected against intra-abdominal infections (odds ratio, 0.20; 95% confidence interval 0.05-0.91; P = .037). Postoperative antibiotics, however, substantially increased the risk (OR, 6.7; 95% CI 1.33 – 33.8; P= .044).

The longer patients were on antibiotics, the greater that risk became. Among the 6 DCL patients who received no postsurgical antibiotics, 16.7% (1) developed an intra-abdominal infection. Among the 7 treated for a day, 28.6% (2) developed an intra-abdominal infection; 40% (6) did so among the 15 treated for more than a day. The trend was similar for PC patients, although the overall infection rates were lower.

Antimicrobial resistance could be to blame. As normal flora were wiped out, maybe the field was cleared for "bugs to cause problems that otherwise would not have," explained senior investigator Dr. Thèrese Duane of the department of surgery at VCU. Surgeons there tend to favor Zosyn or Cefoxitin.

The project was just the first step toward building a robust evidence base about antibiotic use after trauma laparotomies. Next on the team’s agenda is a multicenter, prospective trial.

"We need more numbers," Dr. Duane said.

Dr. Goldberg has no relevant disclosures. Dr. Duane speaks for Pfizer on behalf of its antibiotic, linezolid.

[email protected]

LAS VEGAS – Trauma patients should not get antibiotics after damage control or primarily closed laparotomies because this treatment may increase the risk of postsurgical intra-abdominal infections, according to a study from Virginia Commonwealth University, Richmond, a Level 1 trauma center.

The abdomen is often left open for a while after a damage control laparotomy (DCL), especially when patients are coagulopathic, acidotic, or at risk for an abdominal compartment syndrome. In those cases, "people just automatically assume ‘Open abdomen: Throw on the antibiotics.’ What we are showing here is don’t throw on the antibiotics," said lead investigator Dr. Stephanie Goldberg of the trauma, critical care, and emergency surgery faculty at VCU. The worry is probably the same for primarily closed (PC) laparotomies, when the fascia is closed but skin is sometimes left open.

The findings are important because although – and as the team found – preoperative antibiotics are known to reduce the risk of postsurgical abdominal infections, there’s not much evidence in either direction for their use after trauma laparotomies, so "no one knows what to do." Some surgeons opt for antibiotics, others don’t, Dr. Goldberg said.

To help figure out the right approach, her team analyzed perioperative antibiotic use and infection rates in 28 DCL patients whose abdomens were left open, and 93 PC patients. The PC group had a mean injury severity score of 18; 35.5% (33) had bowel injuries. The DCL group was in worse shape, with a mean severity score of 31.4 and bowel injuries in 53.6% (15).

Everyone should have been dosed with an antibiotic before surgery; 94.6% (88) PC patients, but only 69.2% (19) DCL patients, actually were. "It’s likely," in the DCL cases especially, "that patients were so sick and there was so much chaos in the operating room that giving pre-op antibiotics got missed," Dr. Goldberg said.

Postop antibiotic use differed significantly between the groups; 50.5% (47) of PC patients got no antibiotics, 21.5% (20) got a day’s worth, and 28% (26) were treated for more than a day. In the DCL group, 21.4% (6) got no antibiotics, 25.0% (7) a 1-day course, and 53.6% (15) more than a 1-day course.

As expected, preop antibiotics protected against intra-abdominal infections (odds ratio, 0.20; 95% confidence interval 0.05-0.91; P = .037). Postoperative antibiotics, however, substantially increased the risk (OR, 6.7; 95% CI 1.33 – 33.8; P= .044).

The longer patients were on antibiotics, the greater that risk became. Among the 6 DCL patients who received no postsurgical antibiotics, 16.7% (1) developed an intra-abdominal infection. Among the 7 treated for a day, 28.6% (2) developed an intra-abdominal infection; 40% (6) did so among the 15 treated for more than a day. The trend was similar for PC patients, although the overall infection rates were lower.

Antimicrobial resistance could be to blame. As normal flora were wiped out, maybe the field was cleared for "bugs to cause problems that otherwise would not have," explained senior investigator Dr. Thèrese Duane of the department of surgery at VCU. Surgeons there tend to favor Zosyn or Cefoxitin.

The project was just the first step toward building a robust evidence base about antibiotic use after trauma laparotomies. Next on the team’s agenda is a multicenter, prospective trial.

"We need more numbers," Dr. Duane said.

Dr. Goldberg has no relevant disclosures. Dr. Duane speaks for Pfizer on behalf of its antibiotic, linezolid.

[email protected]

LAS VEGAS – Trauma patients should not get antibiotics after damage control or primarily closed laparotomies because this treatment may increase the risk of postsurgical intra-abdominal infections, according to a study from Virginia Commonwealth University, Richmond, a Level 1 trauma center.

The abdomen is often left open for a while after a damage control laparotomy (DCL), especially when patients are coagulopathic, acidotic, or at risk for an abdominal compartment syndrome. In those cases, "people just automatically assume ‘Open abdomen: Throw on the antibiotics.’ What we are showing here is don’t throw on the antibiotics," said lead investigator Dr. Stephanie Goldberg of the trauma, critical care, and emergency surgery faculty at VCU. The worry is probably the same for primarily closed (PC) laparotomies, when the fascia is closed but skin is sometimes left open.

The findings are important because although – and as the team found – preoperative antibiotics are known to reduce the risk of postsurgical abdominal infections, there’s not much evidence in either direction for their use after trauma laparotomies, so "no one knows what to do." Some surgeons opt for antibiotics, others don’t, Dr. Goldberg said.

To help figure out the right approach, her team analyzed perioperative antibiotic use and infection rates in 28 DCL patients whose abdomens were left open, and 93 PC patients. The PC group had a mean injury severity score of 18; 35.5% (33) had bowel injuries. The DCL group was in worse shape, with a mean severity score of 31.4 and bowel injuries in 53.6% (15).

Everyone should have been dosed with an antibiotic before surgery; 94.6% (88) PC patients, but only 69.2% (19) DCL patients, actually were. "It’s likely," in the DCL cases especially, "that patients were so sick and there was so much chaos in the operating room that giving pre-op antibiotics got missed," Dr. Goldberg said.

Postop antibiotic use differed significantly between the groups; 50.5% (47) of PC patients got no antibiotics, 21.5% (20) got a day’s worth, and 28% (26) were treated for more than a day. In the DCL group, 21.4% (6) got no antibiotics, 25.0% (7) a 1-day course, and 53.6% (15) more than a 1-day course.

As expected, preop antibiotics protected against intra-abdominal infections (odds ratio, 0.20; 95% confidence interval 0.05-0.91; P = .037). Postoperative antibiotics, however, substantially increased the risk (OR, 6.7; 95% CI 1.33 – 33.8; P= .044).

The longer patients were on antibiotics, the greater that risk became. Among the 6 DCL patients who received no postsurgical antibiotics, 16.7% (1) developed an intra-abdominal infection. Among the 7 treated for a day, 28.6% (2) developed an intra-abdominal infection; 40% (6) did so among the 15 treated for more than a day. The trend was similar for PC patients, although the overall infection rates were lower.

Antimicrobial resistance could be to blame. As normal flora were wiped out, maybe the field was cleared for "bugs to cause problems that otherwise would not have," explained senior investigator Dr. Thèrese Duane of the department of surgery at VCU. Surgeons there tend to favor Zosyn or Cefoxitin.

The project was just the first step toward building a robust evidence base about antibiotic use after trauma laparotomies. Next on the team’s agenda is a multicenter, prospective trial.

"We need more numbers," Dr. Duane said.

Dr. Goldberg has no relevant disclosures. Dr. Duane speaks for Pfizer on behalf of its antibiotic, linezolid.

[email protected]

LAS VEGAS – Until recently, residents and surgeons at the University of Cincinnati Medical Center routinely misdiagnosed normal postoperative fever after cesarean section as endometritis, significantly effecting the deep surgical site infection rates reported on websites such as Hospital Compare, according to an investigation by the medical center’s infectious disease experts.

All it took to fix the problem were a few Power Point presentations to make physicians aware of what was going on. Within months, the hospital’s deep-seated c-section infection rate dropped from 2.32 to 0.84 per 100 patients, according to Dr. Madhuri Sopirala, the center’s medical director of infection control, who led the investigation and subsequent educational efforts.

"I don’t believe this is unique to our institution. I am familiar with a lot of other hospitals and practices. This is not uncommon" or limited to c-sections, she said at the annual meeting of the Surgical Infection Society.

"Postoperative fevers happen in a majority of patients," resolve in a day or two, and usually have nothing to do with infection, she noted. Even so, they are often diagnosed and treated as infections out of an abundance of caution.

That’s a problem at a time when surgical site infection rates are among the hospital quality measures reported to the public and, increasingly, affecting the bottom line. Also, "giving antibiotics to patients who don’t need them is not a good thing," Dr. Sopirala added.

The investigation began after she and her colleagues noticed that postcesarean endometritis accounted for a significant proportion of the medical center’s deep surgical site infections.

They found that 78 patients were diagnosed with endometritis after vaginal deliveries or c-sections between January 2011 and June 2012. Forty-four patients were sent home after just a day or two of antibiotics; only 8 patients were readmitted within 30 days.

Most of the 20 post c-section endometritis cases diagnosed between July 2011 and June 2012 got just a few antibiotic doses, too; none of them returned to the hospital.

The numbers just didn’t add up, Dr. Sopirala said. Endometritis is a serious infection; if patients sent home after a dose or two of antibiotics truly had endometritis, more would have been back within a month, seriously ill.

They didn’t come back "because they didn’t need to. It wasn’t really endometritis. These patients most likely had postoperative fever," she said.

"Fever is the most common indication for antibiotics in this country. Whenever a patient has a fever, people give them antibiotics just in case, then find some reason to [justify it]. Endometritis is the most common thing that comes to mind in a patient that’s had a c-section," she said.

Residents and faculty were glad to be made aware of the problem. "The data speak for themselves," Dr. Sopirala said.

Instead of diagnosing postcesarean fevers as endometritis, they "started monitoring temperatures, and could see them coming down on their own. Before, when the fever came down, they assumed it was a response to the antibiotics," she said.

Following the educational efforts, there were no c-section endometritis cases diagnosed at the center between July 2012 and March 2013.

Dr. Sopirala said that she has no disclosures.

[email protected]

LAS VEGAS – Until recently, residents and surgeons at the University of Cincinnati Medical Center routinely misdiagnosed normal postoperative fever after cesarean section as endometritis, significantly effecting the deep surgical site infection rates reported on websites such as Hospital Compare, according to an investigation by the medical center’s infectious disease experts.

All it took to fix the problem were a few Power Point presentations to make physicians aware of what was going on. Within months, the hospital’s deep-seated c-section infection rate dropped from 2.32 to 0.84 per 100 patients, according to Dr. Madhuri Sopirala, the center’s medical director of infection control, who led the investigation and subsequent educational efforts.

"I don’t believe this is unique to our institution. I am familiar with a lot of other hospitals and practices. This is not uncommon" or limited to c-sections, she said at the annual meeting of the Surgical Infection Society.

"Postoperative fevers happen in a majority of patients," resolve in a day or two, and usually have nothing to do with infection, she noted. Even so, they are often diagnosed and treated as infections out of an abundance of caution.

That’s a problem at a time when surgical site infection rates are among the hospital quality measures reported to the public and, increasingly, affecting the bottom line. Also, "giving antibiotics to patients who don’t need them is not a good thing," Dr. Sopirala added.

The investigation began after she and her colleagues noticed that postcesarean endometritis accounted for a significant proportion of the medical center’s deep surgical site infections.

They found that 78 patients were diagnosed with endometritis after vaginal deliveries or c-sections between January 2011 and June 2012. Forty-four patients were sent home after just a day or two of antibiotics; only 8 patients were readmitted within 30 days.

Most of the 20 post c-section endometritis cases diagnosed between July 2011 and June 2012 got just a few antibiotic doses, too; none of them returned to the hospital.

The numbers just didn’t add up, Dr. Sopirala said. Endometritis is a serious infection; if patients sent home after a dose or two of antibiotics truly had endometritis, more would have been back within a month, seriously ill.

They didn’t come back "because they didn’t need to. It wasn’t really endometritis. These patients most likely had postoperative fever," she said.

"Fever is the most common indication for antibiotics in this country. Whenever a patient has a fever, people give them antibiotics just in case, then find some reason to [justify it]. Endometritis is the most common thing that comes to mind in a patient that’s had a c-section," she said.

Residents and faculty were glad to be made aware of the problem. "The data speak for themselves," Dr. Sopirala said.

Instead of diagnosing postcesarean fevers as endometritis, they "started monitoring temperatures, and could see them coming down on their own. Before, when the fever came down, they assumed it was a response to the antibiotics," she said.

Following the educational efforts, there were no c-section endometritis cases diagnosed at the center between July 2012 and March 2013.

Dr. Sopirala said that she has no disclosures.

[email protected]

LAS VEGAS – Until recently, residents and surgeons at the University of Cincinnati Medical Center routinely misdiagnosed normal postoperative fever after cesarean section as endometritis, significantly effecting the deep surgical site infection rates reported on websites such as Hospital Compare, according to an investigation by the medical center’s infectious disease experts.

All it took to fix the problem were a few Power Point presentations to make physicians aware of what was going on. Within months, the hospital’s deep-seated c-section infection rate dropped from 2.32 to 0.84 per 100 patients, according to Dr. Madhuri Sopirala, the center’s medical director of infection control, who led the investigation and subsequent educational efforts.

"I don’t believe this is unique to our institution. I am familiar with a lot of other hospitals and practices. This is not uncommon" or limited to c-sections, she said at the annual meeting of the Surgical Infection Society.

"Postoperative fevers happen in a majority of patients," resolve in a day or two, and usually have nothing to do with infection, she noted. Even so, they are often diagnosed and treated as infections out of an abundance of caution.

That’s a problem at a time when surgical site infection rates are among the hospital quality measures reported to the public and, increasingly, affecting the bottom line. Also, "giving antibiotics to patients who don’t need them is not a good thing," Dr. Sopirala added.

The investigation began after she and her colleagues noticed that postcesarean endometritis accounted for a significant proportion of the medical center’s deep surgical site infections.

They found that 78 patients were diagnosed with endometritis after vaginal deliveries or c-sections between January 2011 and June 2012. Forty-four patients were sent home after just a day or two of antibiotics; only 8 patients were readmitted within 30 days.

Most of the 20 post c-section endometritis cases diagnosed between July 2011 and June 2012 got just a few antibiotic doses, too; none of them returned to the hospital.

The numbers just didn’t add up, Dr. Sopirala said. Endometritis is a serious infection; if patients sent home after a dose or two of antibiotics truly had endometritis, more would have been back within a month, seriously ill.

They didn’t come back "because they didn’t need to. It wasn’t really endometritis. These patients most likely had postoperative fever," she said.

"Fever is the most common indication for antibiotics in this country. Whenever a patient has a fever, people give them antibiotics just in case, then find some reason to [justify it]. Endometritis is the most common thing that comes to mind in a patient that’s had a c-section," she said.

Residents and faculty were glad to be made aware of the problem. "The data speak for themselves," Dr. Sopirala said.

Instead of diagnosing postcesarean fevers as endometritis, they "started monitoring temperatures, and could see them coming down on their own. Before, when the fever came down, they assumed it was a response to the antibiotics," she said.

Following the educational efforts, there were no c-section endometritis cases diagnosed at the center between July 2012 and March 2013.

Dr. Sopirala said that she has no disclosures.

[email protected]

SAN DIEGO – REM sleep behavior disorder is the earliest indication that patients are destined to develop Parkinson’s disease, Lewy body dementia, or another synucleinopathy; it precedes the onset of motor and cognitive problems by years, according to a growing body of research.

Its presence also distinguishes synucleinopathies from Alzheimer’s disease and other problems that can have similar early presentations.

REM sleep behavior disorder (RBD) "diagnoses disease" and "identifies prodromal disease. The rule is very simple: RBD equals synucleinopathy, and it works almost every time," said Dr. Ronald Postuma of the department of neurology at McGill University in Montreal, and a leading researcher in the field.

"The way I explain RBD to patients is that ‘normally, when most people dream, they are paralyzed, but you are not. Therefore, you are capable of acting out the content of your dreams.’ Injury is relatively common," he said, but RBD can be subtle, too, with no more than gestures during sleep.

Dr. Postuma made his comments at the annual meeting of the American Academy of Neurology, following the presentation there of a new addition to the evidence base, an autopsy study led by the Mayo Clinic in Rochester, Minn., and recently published online (Sleep Med. 2013 [doi:10.1016/j.sleep.2012.10.015]).

The Mayo team analyzed neuropathologic findings from 172 patients diagnosed with RBD before death. They found that "among [the 170] neurodegenerative disorders associated with RBD, 160 (94%) were synucleinopathies." Among them were 136 patients with Lewy bodies and 19 with multiple-system atrophy. The remaining few had findings consistent with Alzheimer’s disease or other nonsynucleinopathies.

In life, RBD was diagnosed at a mean age of 62 years of age. It preceded the eventual diagnosis of Parkinsonism in 151 patients by a mean of 6 years. The diagnosis of RBD preceded death by a mean of 13 years.

"Lewy body disease was by far the most common underlying neurologic disorder. The chunk of the rest was multiple-system atrophy. We’ve been looking for [cases of] Alzheimer’s associated with RBD for well over 10 years, and they are just hard to find." The findings "again underscore the selectivity of RBD for synucleinopathy. [They] argue that the selective vulnerability involves ... REM sleep circuitry," said lead investigator Dr. Bradley Boeve, chair of the division of behavioral neurology at Mayo.

Most of the subjects (83%) were men. Eighty-two were diagnosed with RBD by polysomnography, the gold-standard; 98% of the PSG-confirmed cases had a synucleinopathy at autopsy, Dr. Boeve noted.

The remainder had been diagnosed by history, which "can really be quite good" so long as sleep apnea and other confounders are kept in mind, said Dr. Postuma, who was not involved in the project.

The take-home message is that "if you have a patient with a neurodegenerative disorder in front of you, if the patient doesn’t have RBD and that patient is demented, the chances are [that they don’t] have [Lewy body dementia]. In contrast, if you have a pretty good history of RBD but don’t have a PSG [polysomnography] to confirm it, there’s a 94% chance that you have a synucleinopathy. If you do have PSG, there’s a 98% chance of having a synucleinopathy," Dr. Postuma said.

"I don’t think there is any marker in clinical medicine that has anything close to this amount of relative risk for developing a neurodegenerative disease. This is completely unique. Asking about REM sleep behavior disorder in your clinics tomorrow will help you diagnose disease," he said.

Investigators from Barcelona, Spain, came to similar conclusions in a paper published online April 2 in Lancet Neurology (doi:10.1016/S1474-4422[13]70056-5).

For most, RBD "represents the prodromal phase of a Lewy body disorder ... such as Parkinson’s disease (PD) or dementia with Lewy bodies. ... [RBD] is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process," they concluded.

The Spanish team followed 44 RBD cases diagnosed between 1991 and 2003. By 2012, 36 (82%) had developed a synucleinopathy, among them 16 patients with Parkinson’s disease, 14 with Lewy body dementia, and 1 with multiple system atrophy. "The rates of neurological-disease-free survival from time of [RBD] diagnosis were 65.2% at 5 years, 26.6% at 10 years, and 7.5% at 14 years," they reported.

Most RBD patients "developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD," including lesions "in the brainstem nuclei that regulate REM sleep atonia," the Spanish researchers found.

The findings "emphatically confirm the incredible risk that patients with RBD have for developing neurodegenerative disease. This is completely unique, this ability to identify a neurodegenerative disease 10 years before it can be diagnosed. It provides profound opportunities to study early stages of disease and perhaps to test preventative treatments that could be applied to Parkinson’s disease and related disorders," Dr. Postuma said when asked to comment on the Spanish study.

"I don’t think you could imagine a better group to intervene with neuroprotective therapy than this one," he said.

Dr. Boeve’s research has been supported by Cephalon, Allon Therapeutics, and GE Healthcare. Dr. Postuma disclosed personal support from Teva and Novartis.

[email protected]

SAN DIEGO – REM sleep behavior disorder is the earliest indication that patients are destined to develop Parkinson’s disease, Lewy body dementia, or another synucleinopathy; it precedes the onset of motor and cognitive problems by years, according to a growing body of research.

Its presence also distinguishes synucleinopathies from Alzheimer’s disease and other problems that can have similar early presentations.

REM sleep behavior disorder (RBD) "diagnoses disease" and "identifies prodromal disease. The rule is very simple: RBD equals synucleinopathy, and it works almost every time," said Dr. Ronald Postuma of the department of neurology at McGill University in Montreal, and a leading researcher in the field.

"The way I explain RBD to patients is that ‘normally, when most people dream, they are paralyzed, but you are not. Therefore, you are capable of acting out the content of your dreams.’ Injury is relatively common," he said, but RBD can be subtle, too, with no more than gestures during sleep.

Dr. Postuma made his comments at the annual meeting of the American Academy of Neurology, following the presentation there of a new addition to the evidence base, an autopsy study led by the Mayo Clinic in Rochester, Minn., and recently published online (Sleep Med. 2013 [doi:10.1016/j.sleep.2012.10.015]).

The Mayo team analyzed neuropathologic findings from 172 patients diagnosed with RBD before death. They found that "among [the 170] neurodegenerative disorders associated with RBD, 160 (94%) were synucleinopathies." Among them were 136 patients with Lewy bodies and 19 with multiple-system atrophy. The remaining few had findings consistent with Alzheimer’s disease or other nonsynucleinopathies.

In life, RBD was diagnosed at a mean age of 62 years of age. It preceded the eventual diagnosis of Parkinsonism in 151 patients by a mean of 6 years. The diagnosis of RBD preceded death by a mean of 13 years.

"Lewy body disease was by far the most common underlying neurologic disorder. The chunk of the rest was multiple-system atrophy. We’ve been looking for [cases of] Alzheimer’s associated with RBD for well over 10 years, and they are just hard to find." The findings "again underscore the selectivity of RBD for synucleinopathy. [They] argue that the selective vulnerability involves ... REM sleep circuitry," said lead investigator Dr. Bradley Boeve, chair of the division of behavioral neurology at Mayo.

Most of the subjects (83%) were men. Eighty-two were diagnosed with RBD by polysomnography, the gold-standard; 98% of the PSG-confirmed cases had a synucleinopathy at autopsy, Dr. Boeve noted.

The remainder had been diagnosed by history, which "can really be quite good" so long as sleep apnea and other confounders are kept in mind, said Dr. Postuma, who was not involved in the project.

The take-home message is that "if you have a patient with a neurodegenerative disorder in front of you, if the patient doesn’t have RBD and that patient is demented, the chances are [that they don’t] have [Lewy body dementia]. In contrast, if you have a pretty good history of RBD but don’t have a PSG [polysomnography] to confirm it, there’s a 94% chance that you have a synucleinopathy. If you do have PSG, there’s a 98% chance of having a synucleinopathy," Dr. Postuma said.

"I don’t think there is any marker in clinical medicine that has anything close to this amount of relative risk for developing a neurodegenerative disease. This is completely unique. Asking about REM sleep behavior disorder in your clinics tomorrow will help you diagnose disease," he said.

Investigators from Barcelona, Spain, came to similar conclusions in a paper published online April 2 in Lancet Neurology (doi:10.1016/S1474-4422[13]70056-5).

For most, RBD "represents the prodromal phase of a Lewy body disorder ... such as Parkinson’s disease (PD) or dementia with Lewy bodies. ... [RBD] is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process," they concluded.

The Spanish team followed 44 RBD cases diagnosed between 1991 and 2003. By 2012, 36 (82%) had developed a synucleinopathy, among them 16 patients with Parkinson’s disease, 14 with Lewy body dementia, and 1 with multiple system atrophy. "The rates of neurological-disease-free survival from time of [RBD] diagnosis were 65.2% at 5 years, 26.6% at 10 years, and 7.5% at 14 years," they reported.

Most RBD patients "developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD," including lesions "in the brainstem nuclei that regulate REM sleep atonia," the Spanish researchers found.

The findings "emphatically confirm the incredible risk that patients with RBD have for developing neurodegenerative disease. This is completely unique, this ability to identify a neurodegenerative disease 10 years before it can be diagnosed. It provides profound opportunities to study early stages of disease and perhaps to test preventative treatments that could be applied to Parkinson’s disease and related disorders," Dr. Postuma said when asked to comment on the Spanish study.

"I don’t think you could imagine a better group to intervene with neuroprotective therapy than this one," he said.

Dr. Boeve’s research has been supported by Cephalon, Allon Therapeutics, and GE Healthcare. Dr. Postuma disclosed personal support from Teva and Novartis.

[email protected]

SAN DIEGO – REM sleep behavior disorder is the earliest indication that patients are destined to develop Parkinson’s disease, Lewy body dementia, or another synucleinopathy; it precedes the onset of motor and cognitive problems by years, according to a growing body of research.

Its presence also distinguishes synucleinopathies from Alzheimer’s disease and other problems that can have similar early presentations.

REM sleep behavior disorder (RBD) "diagnoses disease" and "identifies prodromal disease. The rule is very simple: RBD equals synucleinopathy, and it works almost every time," said Dr. Ronald Postuma of the department of neurology at McGill University in Montreal, and a leading researcher in the field.

"The way I explain RBD to patients is that ‘normally, when most people dream, they are paralyzed, but you are not. Therefore, you are capable of acting out the content of your dreams.’ Injury is relatively common," he said, but RBD can be subtle, too, with no more than gestures during sleep.

Dr. Postuma made his comments at the annual meeting of the American Academy of Neurology, following the presentation there of a new addition to the evidence base, an autopsy study led by the Mayo Clinic in Rochester, Minn., and recently published online (Sleep Med. 2013 [doi:10.1016/j.sleep.2012.10.015]).

The Mayo team analyzed neuropathologic findings from 172 patients diagnosed with RBD before death. They found that "among [the 170] neurodegenerative disorders associated with RBD, 160 (94%) were synucleinopathies." Among them were 136 patients with Lewy bodies and 19 with multiple-system atrophy. The remaining few had findings consistent with Alzheimer’s disease or other nonsynucleinopathies.

In life, RBD was diagnosed at a mean age of 62 years of age. It preceded the eventual diagnosis of Parkinsonism in 151 patients by a mean of 6 years. The diagnosis of RBD preceded death by a mean of 13 years.

"Lewy body disease was by far the most common underlying neurologic disorder. The chunk of the rest was multiple-system atrophy. We’ve been looking for [cases of] Alzheimer’s associated with RBD for well over 10 years, and they are just hard to find." The findings "again underscore the selectivity of RBD for synucleinopathy. [They] argue that the selective vulnerability involves ... REM sleep circuitry," said lead investigator Dr. Bradley Boeve, chair of the division of behavioral neurology at Mayo.

Most of the subjects (83%) were men. Eighty-two were diagnosed with RBD by polysomnography, the gold-standard; 98% of the PSG-confirmed cases had a synucleinopathy at autopsy, Dr. Boeve noted.

The remainder had been diagnosed by history, which "can really be quite good" so long as sleep apnea and other confounders are kept in mind, said Dr. Postuma, who was not involved in the project.

The take-home message is that "if you have a patient with a neurodegenerative disorder in front of you, if the patient doesn’t have RBD and that patient is demented, the chances are [that they don’t] have [Lewy body dementia]. In contrast, if you have a pretty good history of RBD but don’t have a PSG [polysomnography] to confirm it, there’s a 94% chance that you have a synucleinopathy. If you do have PSG, there’s a 98% chance of having a synucleinopathy," Dr. Postuma said.

"I don’t think there is any marker in clinical medicine that has anything close to this amount of relative risk for developing a neurodegenerative disease. This is completely unique. Asking about REM sleep behavior disorder in your clinics tomorrow will help you diagnose disease," he said.

Investigators from Barcelona, Spain, came to similar conclusions in a paper published online April 2 in Lancet Neurology (doi:10.1016/S1474-4422[13]70056-5).

For most, RBD "represents the prodromal phase of a Lewy body disorder ... such as Parkinson’s disease (PD) or dementia with Lewy bodies. ... [RBD] is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process," they concluded.

The Spanish team followed 44 RBD cases diagnosed between 1991 and 2003. By 2012, 36 (82%) had developed a synucleinopathy, among them 16 patients with Parkinson’s disease, 14 with Lewy body dementia, and 1 with multiple system atrophy. "The rates of neurological-disease-free survival from time of [RBD] diagnosis were 65.2% at 5 years, 26.6% at 10 years, and 7.5% at 14 years," they reported.

Most RBD patients "developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD," including lesions "in the brainstem nuclei that regulate REM sleep atonia," the Spanish researchers found.

The findings "emphatically confirm the incredible risk that patients with RBD have for developing neurodegenerative disease. This is completely unique, this ability to identify a neurodegenerative disease 10 years before it can be diagnosed. It provides profound opportunities to study early stages of disease and perhaps to test preventative treatments that could be applied to Parkinson’s disease and related disorders," Dr. Postuma said when asked to comment on the Spanish study.

"I don’t think you could imagine a better group to intervene with neuroprotective therapy than this one," he said.

Dr. Boeve’s research has been supported by Cephalon, Allon Therapeutics, and GE Healthcare. Dr. Postuma disclosed personal support from Teva and Novartis.

[email protected]

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

[email protected]

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

[email protected]

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

[email protected]

SAN DIEGO – Researchers at Johns Hopkins University are working on a better way to detect fungal meningitis, according to lead investigator, Dr. Jennifer Lyons.

The efforts come in the wake of a recent nationwide outbreak in which hundreds of people were sickened and dozens died from spinal steroid injections contaminated with environmental fungi.

"Many patients developed serious central nervous system complications" following the shots, "but definitive fungal identification [was] elusive," Dr. Lyons and her colleagues noted in their abstract at the annual meeting of the American Academy of Neurology.

Cerebrospinal fluid (CSF) culture is the usual diagnostic test, and sometimes also a CSF polymerase-chain reaction (PCR) assay "that’s largely unvalidated. The CDC has been using it in this [recent] outbreak. It basically amplifies fungal elements, [but it has a] very, very low sensitivity. You can have an infection and be completely missed by this assay," she said in an interview, noting that less than a third of the recent cases were positive by PCR.

A better approach might be to check CSF for Beta D-glucan (BG), a protein in the cell wall of many fungi, including Candida and Aspergillus, and the organism implicated in the outbreak, Exserohilum rostratum.

The hope is that BG testing will help in "the diagnosis and therapeutic monitoring of fungal meningitis, [and that] sequential quantification could assist in determination of therapy duration," the abstract notes.

"CSF is an immune-privileged site, so you should have no BG in your CSF." Even so, "nobody [tests for it] except in research studies, said Dr. Lyons, a fellow in neuroimmunology and neurological infections at Johns Hopkins in Baltimore.

She and her colleagues used the Fungitell assay (Beacon Diagnostic Laboratories), a serum BG test, to check for BG in CSF samples from six patients who were sick after getting the suspect shots. They had been on voriconazole for a few days to a few weeks.

Four patients met the CDC definition for probable meningitis but had negative cultures. PCR testing in three patients was negative. All four patients with probable meningitis had detectable BG in their CSF samples.

One patient was sampled before and after 2 weeks of voriconazole treatment. Treatment corresponded with a drop in her BG titer.

Although sick, the two other patients did not meet the CDC’s criteria for probable meningitis. They had no detectable BG in their CSF.

"For every single [fungal meningitis] case we suspected, [the test] was positive. That said, it’s hard to hang your hat on this. We have a very small N; this is just an observation," Dr. Lyons said.

"The next step is to validate the assay by defining cutoff values and false positives. We are trying to get something in the works," she said.

Dr. Lyons said she has no relevant commercial disclosures.

[email protected]

SAN DIEGO – Researchers at Johns Hopkins University are working on a better way to detect fungal meningitis, according to lead investigator, Dr. Jennifer Lyons.

The efforts come in the wake of a recent nationwide outbreak in which hundreds of people were sickened and dozens died from spinal steroid injections contaminated with environmental fungi.

"Many patients developed serious central nervous system complications" following the shots, "but definitive fungal identification [was] elusive," Dr. Lyons and her colleagues noted in their abstract at the annual meeting of the American Academy of Neurology.

Cerebrospinal fluid (CSF) culture is the usual diagnostic test, and sometimes also a CSF polymerase-chain reaction (PCR) assay "that’s largely unvalidated. The CDC has been using it in this [recent] outbreak. It basically amplifies fungal elements, [but it has a] very, very low sensitivity. You can have an infection and be completely missed by this assay," she said in an interview, noting that less than a third of the recent cases were positive by PCR.

A better approach might be to check CSF for Beta D-glucan (BG), a protein in the cell wall of many fungi, including Candida and Aspergillus, and the organism implicated in the outbreak, Exserohilum rostratum.

The hope is that BG testing will help in "the diagnosis and therapeutic monitoring of fungal meningitis, [and that] sequential quantification could assist in determination of therapy duration," the abstract notes.

"CSF is an immune-privileged site, so you should have no BG in your CSF." Even so, "nobody [tests for it] except in research studies, said Dr. Lyons, a fellow in neuroimmunology and neurological infections at Johns Hopkins in Baltimore.

She and her colleagues used the Fungitell assay (Beacon Diagnostic Laboratories), a serum BG test, to check for BG in CSF samples from six patients who were sick after getting the suspect shots. They had been on voriconazole for a few days to a few weeks.

Four patients met the CDC definition for probable meningitis but had negative cultures. PCR testing in three patients was negative. All four patients with probable meningitis had detectable BG in their CSF samples.

One patient was sampled before and after 2 weeks of voriconazole treatment. Treatment corresponded with a drop in her BG titer.

Although sick, the two other patients did not meet the CDC’s criteria for probable meningitis. They had no detectable BG in their CSF.

"For every single [fungal meningitis] case we suspected, [the test] was positive. That said, it’s hard to hang your hat on this. We have a very small N; this is just an observation," Dr. Lyons said.

"The next step is to validate the assay by defining cutoff values and false positives. We are trying to get something in the works," she said.

Dr. Lyons said she has no relevant commercial disclosures.

[email protected]

SAN DIEGO – Researchers at Johns Hopkins University are working on a better way to detect fungal meningitis, according to lead investigator, Dr. Jennifer Lyons.

The efforts come in the wake of a recent nationwide outbreak in which hundreds of people were sickened and dozens died from spinal steroid injections contaminated with environmental fungi.

"Many patients developed serious central nervous system complications" following the shots, "but definitive fungal identification [was] elusive," Dr. Lyons and her colleagues noted in their abstract at the annual meeting of the American Academy of Neurology.

Cerebrospinal fluid (CSF) culture is the usual diagnostic test, and sometimes also a CSF polymerase-chain reaction (PCR) assay "that’s largely unvalidated. The CDC has been using it in this [recent] outbreak. It basically amplifies fungal elements, [but it has a] very, very low sensitivity. You can have an infection and be completely missed by this assay," she said in an interview, noting that less than a third of the recent cases were positive by PCR.

A better approach might be to check CSF for Beta D-glucan (BG), a protein in the cell wall of many fungi, including Candida and Aspergillus, and the organism implicated in the outbreak, Exserohilum rostratum.

The hope is that BG testing will help in "the diagnosis and therapeutic monitoring of fungal meningitis, [and that] sequential quantification could assist in determination of therapy duration," the abstract notes.

"CSF is an immune-privileged site, so you should have no BG in your CSF." Even so, "nobody [tests for it] except in research studies, said Dr. Lyons, a fellow in neuroimmunology and neurological infections at Johns Hopkins in Baltimore.

She and her colleagues used the Fungitell assay (Beacon Diagnostic Laboratories), a serum BG test, to check for BG in CSF samples from six patients who were sick after getting the suspect shots. They had been on voriconazole for a few days to a few weeks.

Four patients met the CDC definition for probable meningitis but had negative cultures. PCR testing in three patients was negative. All four patients with probable meningitis had detectable BG in their CSF samples.

One patient was sampled before and after 2 weeks of voriconazole treatment. Treatment corresponded with a drop in her BG titer.

Although sick, the two other patients did not meet the CDC’s criteria for probable meningitis. They had no detectable BG in their CSF.

"For every single [fungal meningitis] case we suspected, [the test] was positive. That said, it’s hard to hang your hat on this. We have a very small N; this is just an observation," Dr. Lyons said.

"The next step is to validate the assay by defining cutoff values and false positives. We are trying to get something in the works," she said.

Dr. Lyons said she has no relevant commercial disclosures.

[email protected]

PSA screening should not be done in men younger than 50 years or in those older than 69 years – and men between those ages should be offered the test only if they want to take it after being told that they are more likely to be hurt by it than helped, according to new prostate-specific antigen screening guidelines from the American College of Physicians.

"A man’s chances of being harmed are much greater than his chances of benefiting from the PSA test," caution the guidelines’ authors. Those harms include surgery that risks incontinence, impotency, and other problems to remove harmless tumors, the group said.

"Any absolute mortality risk reduction" from routine screening "is probably small to none," according to the guidelines. "The vast majority of prostate cancer is slow-growing and does not cause death."

That news isn’t likely to surprise many doctors – PSA testing has been suspect for years, and ACP’s guidelines mirror and, in fact, are derived from those from other groups. But it might be a surprise to the general public.

There’s still "a lot of misperception about the accuracy and utility of the test," because it’s been promoted until recently as a kind of "mammography for men," noted Dr. William Golden, a professor of medicine and public health at the University of Arkansas.

With patient demand still high and many physicians fearing malpractice risk if they don’t screen, "it’s been a whole lot easier to just check the box and order the test," Dr. Golden observed. "I think there are still a lot of PSAs being ordered [even for men] over age 75 [years].

"Statements like this from the ACP give doctors a little more ammunition to help educate patients that this is not a real strong diagnostic tool," he said.

To that end, the ACP has also published a one-page patient information sheet that explains the problems with PSA tests. The guidelines themselves include 10 talking points men need to hear before opting to be screened.

Men are open to the message, Dr. Golden said. "I say [to them], ‘Look, if you really want the test, I’ll give it to you.’ " But he lets them know first that he and many other doctors don’t get themselves screened; that the test isn’t very sensitive or specific; and that it often leads to biopsies until something is found and operations regardless of therapeutic value.

"When they hear that kind of framework, a lot of patients don’t want to go near" it, Dr. Golden said. Instead, they say, "Look, I’d rather take my chances. I’d rather not have incontinence, I’d rather have sexual function, and I’d rather not have surgery for something that may or may not make a difference to my health."

That discussion is exactly the approach ACP hopes to foster.

"The key is to talk with your patient and help determine what they value" – preserving continence, sexual function, and peace of mind, or gambling them on a tiny chance of catching a fatal tumor early, said the senior author of ACP’s guidelines, Dr. Paul Shekelle, director of the RAND Corporation’s Southern California Evidence-Based Practice Center. "Do not over-sell the screen-biopsy-surgery approach."

Practice is still "probably tilted toward screening," he said. "The ACP guideline is an attempt to steer this back."

The conversation is much the same even for high-risk men – blacks and those with strong family histories of prostate cancer. But instead of starting at age 50 years, it should come at age 45 or 40. "Screening in high-risk men has not been demonstrated to be associated with different outcomes than screening in average-risk men," the ACP guidelines note.

Up to a third of men are screened without their knowledge during routine physicals; that practice should end, the ACP also said.

The ACP derived its own recommendations from a review of those from the American College of Preventive Medicine, the American Cancer Society, the American Urological Association, and the U.S. Preventive Services Task Force. "ACP believes that it is more valuable to provide clinicians with a rigorous review of available guidelines, rather than develop a new guideline on the same topic when several guidelines are available," it said.

The ACP found the USPSTF’s efforts the most rigorous; that group in 2012 recommended abandoning PSA screening.

"The one nuance [ACP] added is that in the [50-69 ] age range where there is a hint of benefit from one of the large trials, even for them the evidence of harm is much stronger than the evidence of benefit. I think [ACP] has the messaging correct," said Dr. Barry Kramer, director of the National Cancer Institute’s Division of Cancer Prevention.

If they are performed, PSA tests should be conducted no more than every 4 years. "No evidence supports annual screening for prostate cancer," the ACP guidelines note.

The potential benefit of screening is vanishingly small for men older than 69 years – and for those expected to live no more than 15 years – because prostate cancer isn’t likely to cause any problems in the time they have left, the guidelines explain. For men younger than 50 years, the downstream harms "such as erectile dysfunction and urinary incontinence carry even more weight relative to any potential benefit," according to the guidelines.

Dr. Golden, Dr. Kramer, and Dr. Shekelle said they have no relevant financial disclosures.

[email protected]

*This story was updated 4/10/13.

PSA screening should not be done in men younger than 50 years or in those older than 69 years – and men between those ages should be offered the test only if they want to take it after being told that they are more likely to be hurt by it than helped, according to new prostate-specific antigen screening guidelines from the American College of Physicians.

"A man’s chances of being harmed are much greater than his chances of benefiting from the PSA test," caution the guidelines’ authors. Those harms include surgery that risks incontinence, impotency, and other problems to remove harmless tumors, the group said.

"Any absolute mortality risk reduction" from routine screening "is probably small to none," according to the guidelines. "The vast majority of prostate cancer is slow-growing and does not cause death."

That news isn’t likely to surprise many doctors – PSA testing has been suspect for years, and ACP’s guidelines mirror and, in fact, are derived from those from other groups. But it might be a surprise to the general public.

There’s still "a lot of misperception about the accuracy and utility of the test," because it’s been promoted until recently as a kind of "mammography for men," noted Dr. William Golden, a professor of medicine and public health at the University of Arkansas.

With patient demand still high and many physicians fearing malpractice risk if they don’t screen, "it’s been a whole lot easier to just check the box and order the test," Dr. Golden observed. "I think there are still a lot of PSAs being ordered [even for men] over age 75 [years].

"Statements like this from the ACP give doctors a little more ammunition to help educate patients that this is not a real strong diagnostic tool," he said.

To that end, the ACP has also published a one-page patient information sheet that explains the problems with PSA tests. The guidelines themselves include 10 talking points men need to hear before opting to be screened.

Men are open to the message, Dr. Golden said. "I say [to them], ‘Look, if you really want the test, I’ll give it to you.’ " But he lets them know first that he and many other doctors don’t get themselves screened; that the test isn’t very sensitive or specific; and that it often leads to biopsies until something is found and operations regardless of therapeutic value.

"When they hear that kind of framework, a lot of patients don’t want to go near" it, Dr. Golden said. Instead, they say, "Look, I’d rather take my chances. I’d rather not have incontinence, I’d rather have sexual function, and I’d rather not have surgery for something that may or may not make a difference to my health."

That discussion is exactly the approach ACP hopes to foster.

"The key is to talk with your patient and help determine what they value" – preserving continence, sexual function, and peace of mind, or gambling them on a tiny chance of catching a fatal tumor early, said the senior author of ACP’s guidelines, Dr. Paul Shekelle, director of the RAND Corporation’s Southern California Evidence-Based Practice Center. "Do not over-sell the screen-biopsy-surgery approach."

Practice is still "probably tilted toward screening," he said. "The ACP guideline is an attempt to steer this back."

The conversation is much the same even for high-risk men – blacks and those with strong family histories of prostate cancer. But instead of starting at age 50 years, it should come at age 45 or 40. "Screening in high-risk men has not been demonstrated to be associated with different outcomes than screening in average-risk men," the ACP guidelines note.

Up to a third of men are screened without their knowledge during routine physicals; that practice should end, the ACP also said.

The ACP derived its own recommendations from a review of those from the American College of Preventive Medicine, the American Cancer Society, the American Urological Association, and the U.S. Preventive Services Task Force. "ACP believes that it is more valuable to provide clinicians with a rigorous review of available guidelines, rather than develop a new guideline on the same topic when several guidelines are available," it said.

The ACP found the USPSTF’s efforts the most rigorous; that group in 2012 recommended abandoning PSA screening.

"The one nuance [ACP] added is that in the [50-69 ] age range where there is a hint of benefit from one of the large trials, even for them the evidence of harm is much stronger than the evidence of benefit. I think [ACP] has the messaging correct," said Dr. Barry Kramer, director of the National Cancer Institute’s Division of Cancer Prevention.

If they are performed, PSA tests should be conducted no more than every 4 years. "No evidence supports annual screening for prostate cancer," the ACP guidelines note.

The potential benefit of screening is vanishingly small for men older than 69 years – and for those expected to live no more than 15 years – because prostate cancer isn’t likely to cause any problems in the time they have left, the guidelines explain. For men younger than 50 years, the downstream harms "such as erectile dysfunction and urinary incontinence carry even more weight relative to any potential benefit," according to the guidelines.

Dr. Golden, Dr. Kramer, and Dr. Shekelle said they have no relevant financial disclosures.

[email protected]

*This story was updated 4/10/13.

PSA screening should not be done in men younger than 50 years or in those older than 69 years – and men between those ages should be offered the test only if they want to take it after being told that they are more likely to be hurt by it than helped, according to new prostate-specific antigen screening guidelines from the American College of Physicians.

"A man’s chances of being harmed are much greater than his chances of benefiting from the PSA test," caution the guidelines’ authors. Those harms include surgery that risks incontinence, impotency, and other problems to remove harmless tumors, the group said.

"Any absolute mortality risk reduction" from routine screening "is probably small to none," according to the guidelines. "The vast majority of prostate cancer is slow-growing and does not cause death."

That news isn’t likely to surprise many doctors – PSA testing has been suspect for years, and ACP’s guidelines mirror and, in fact, are derived from those from other groups. But it might be a surprise to the general public.

There’s still "a lot of misperception about the accuracy and utility of the test," because it’s been promoted until recently as a kind of "mammography for men," noted Dr. William Golden, a professor of medicine and public health at the University of Arkansas.

With patient demand still high and many physicians fearing malpractice risk if they don’t screen, "it’s been a whole lot easier to just check the box and order the test," Dr. Golden observed. "I think there are still a lot of PSAs being ordered [even for men] over age 75 [years].

"Statements like this from the ACP give doctors a little more ammunition to help educate patients that this is not a real strong diagnostic tool," he said.

To that end, the ACP has also published a one-page patient information sheet that explains the problems with PSA tests. The guidelines themselves include 10 talking points men need to hear before opting to be screened.

Men are open to the message, Dr. Golden said. "I say [to them], ‘Look, if you really want the test, I’ll give it to you.’ " But he lets them know first that he and many other doctors don’t get themselves screened; that the test isn’t very sensitive or specific; and that it often leads to biopsies until something is found and operations regardless of therapeutic value.

"When they hear that kind of framework, a lot of patients don’t want to go near" it, Dr. Golden said. Instead, they say, "Look, I’d rather take my chances. I’d rather not have incontinence, I’d rather have sexual function, and I’d rather not have surgery for something that may or may not make a difference to my health."

That discussion is exactly the approach ACP hopes to foster.

"The key is to talk with your patient and help determine what they value" – preserving continence, sexual function, and peace of mind, or gambling them on a tiny chance of catching a fatal tumor early, said the senior author of ACP’s guidelines, Dr. Paul Shekelle, director of the RAND Corporation’s Southern California Evidence-Based Practice Center. "Do not over-sell the screen-biopsy-surgery approach."

Practice is still "probably tilted toward screening," he said. "The ACP guideline is an attempt to steer this back."

The conversation is much the same even for high-risk men – blacks and those with strong family histories of prostate cancer. But instead of starting at age 50 years, it should come at age 45 or 40. "Screening in high-risk men has not been demonstrated to be associated with different outcomes than screening in average-risk men," the ACP guidelines note.

Up to a third of men are screened without their knowledge during routine physicals; that practice should end, the ACP also said.

The ACP derived its own recommendations from a review of those from the American College of Preventive Medicine, the American Cancer Society, the American Urological Association, and the U.S. Preventive Services Task Force. "ACP believes that it is more valuable to provide clinicians with a rigorous review of available guidelines, rather than develop a new guideline on the same topic when several guidelines are available," it said.

The ACP found the USPSTF’s efforts the most rigorous; that group in 2012 recommended abandoning PSA screening.

"The one nuance [ACP] added is that in the [50-69 ] age range where there is a hint of benefit from one of the large trials, even for them the evidence of harm is much stronger than the evidence of benefit. I think [ACP] has the messaging correct," said Dr. Barry Kramer, director of the National Cancer Institute’s Division of Cancer Prevention.

If they are performed, PSA tests should be conducted no more than every 4 years. "No evidence supports annual screening for prostate cancer," the ACP guidelines note.

The potential benefit of screening is vanishingly small for men older than 69 years – and for those expected to live no more than 15 years – because prostate cancer isn’t likely to cause any problems in the time they have left, the guidelines explain. For men younger than 50 years, the downstream harms "such as erectile dysfunction and urinary incontinence carry even more weight relative to any potential benefit," according to the guidelines.

Dr. Golden, Dr. Kramer, and Dr. Shekelle said they have no relevant financial disclosures.

[email protected]

*This story was updated 4/10/13.

SAN DIEGO – A new adverse event may be emerging for dalfampridine – trigeminal neuralgia in multiple sclerosis patients with a preexisting trigeminal injury, or worsening of the condition in those who already have it, according to Dr. Gary Birnbaum, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology.

Within a month of starting the drug at his clinic, three women with well-controlled trigeminal neuralgia "had very significant increases in the severity of their trigeminal pain," he said.

Stopping the drug brought some temporary relief to two, but they soon relapsed and their pain is now "very, very difficult to control," requiring substantially higher pain medication doses than before, he said.

In the third woman, the pain continued despite stopping the drug and no longer responded to pain medication. It was so severe that she contemplated suicide; she eventually had a trigeminal rhizotomy.

They had "very, very severe pain after" starting dalfampridine (Ampyra), "and it didn’t get better" when it was stopped. "That is what’s disquieting about it," Dr. Birnbaum said at the American Academy of Neurology (AAN) annual meeting.

A fourth patient developed trigeminal neuralgia after 18 months on the drug; the side of his face had only been numb previously. He now requires pain medications for the condition. Brain MRIs of all four patients were stable.

"Irreversible injury [appears] to have occurred in our three patients, and perhaps even in the fourth. Dalfampridine needs to be used with caution in multiple sclerosis patients with preexisting trigeminal neuralgia as well as in those with evidence of preexisting trigeminal nerve injuries," Dr. Birnbaum said.

When prescribing the drug, "I have to tell [patients] now that there’s a possibility that their trigeminal neuralgia may get worse, and it may not get better if they stop [the drug]. They have to take that into consideration," he said in an interview.

The four cases are not the first to be reported since the potassium channel blocker was approved for MS in 2010 to improve walking.

Investigators from the Mayo Clinic in Scottsdale, Ariz., reported two cases at AAN’s 2012 annual conference, both within a month of starting the drug and both in patients whose trigeminal neuralgia had been in remission. One patient responded to pain medications, the other needed a rhizotomy.

"As I talk to [physicians] about these data," people come up and say, "I’ve seen the same thing," Dr. Birnbaum said.

Dalfampridine improves action potential conduction in demyelinated axons. Perhaps when sensory nerves – such as the trigeminal – have a preexisting injury, that effect can lead to a type of "metabolic exhaustion" that makes the injury worse.

"Could there be a similar phenomenon with motor nerves? Perhaps one sees an initial improvement in motor function, but in the long term could this perhaps be deleterious? I have no data to support that, but the implication is that [it’s] a possibility," he said.

Dr. Birnbaum is a paid consultant to TEVA, Serono, Genzyme, Questcor, and Biogen Idec. Biogen Idec and Hoffman-LaRoche have both supported his research.

[email protected]

SAN DIEGO – A new adverse event may be emerging for dalfampridine – trigeminal neuralgia in multiple sclerosis patients with a preexisting trigeminal injury, or worsening of the condition in those who already have it, according to Dr. Gary Birnbaum, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology.

Within a month of starting the drug at his clinic, three women with well-controlled trigeminal neuralgia "had very significant increases in the severity of their trigeminal pain," he said.

Stopping the drug brought some temporary relief to two, but they soon relapsed and their pain is now "very, very difficult to control," requiring substantially higher pain medication doses than before, he said.

In the third woman, the pain continued despite stopping the drug and no longer responded to pain medication. It was so severe that she contemplated suicide; she eventually had a trigeminal rhizotomy.

They had "very, very severe pain after" starting dalfampridine (Ampyra), "and it didn’t get better" when it was stopped. "That is what’s disquieting about it," Dr. Birnbaum said at the American Academy of Neurology (AAN) annual meeting.

A fourth patient developed trigeminal neuralgia after 18 months on the drug; the side of his face had only been numb previously. He now requires pain medications for the condition. Brain MRIs of all four patients were stable.

"Irreversible injury [appears] to have occurred in our three patients, and perhaps even in the fourth. Dalfampridine needs to be used with caution in multiple sclerosis patients with preexisting trigeminal neuralgia as well as in those with evidence of preexisting trigeminal nerve injuries," Dr. Birnbaum said.

When prescribing the drug, "I have to tell [patients] now that there’s a possibility that their trigeminal neuralgia may get worse, and it may not get better if they stop [the drug]. They have to take that into consideration," he said in an interview.

The four cases are not the first to be reported since the potassium channel blocker was approved for MS in 2010 to improve walking.

Investigators from the Mayo Clinic in Scottsdale, Ariz., reported two cases at AAN’s 2012 annual conference, both within a month of starting the drug and both in patients whose trigeminal neuralgia had been in remission. One patient responded to pain medications, the other needed a rhizotomy.

"As I talk to [physicians] about these data," people come up and say, "I’ve seen the same thing," Dr. Birnbaum said.

Dalfampridine improves action potential conduction in demyelinated axons. Perhaps when sensory nerves – such as the trigeminal – have a preexisting injury, that effect can lead to a type of "metabolic exhaustion" that makes the injury worse.

"Could there be a similar phenomenon with motor nerves? Perhaps one sees an initial improvement in motor function, but in the long term could this perhaps be deleterious? I have no data to support that, but the implication is that [it’s] a possibility," he said.

Dr. Birnbaum is a paid consultant to TEVA, Serono, Genzyme, Questcor, and Biogen Idec. Biogen Idec and Hoffman-LaRoche have both supported his research.

[email protected]

SAN DIEGO – A new adverse event may be emerging for dalfampridine – trigeminal neuralgia in multiple sclerosis patients with a preexisting trigeminal injury, or worsening of the condition in those who already have it, according to Dr. Gary Birnbaum, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology.

Within a month of starting the drug at his clinic, three women with well-controlled trigeminal neuralgia "had very significant increases in the severity of their trigeminal pain," he said.

Stopping the drug brought some temporary relief to two, but they soon relapsed and their pain is now "very, very difficult to control," requiring substantially higher pain medication doses than before, he said.

In the third woman, the pain continued despite stopping the drug and no longer responded to pain medication. It was so severe that she contemplated suicide; she eventually had a trigeminal rhizotomy.

They had "very, very severe pain after" starting dalfampridine (Ampyra), "and it didn’t get better" when it was stopped. "That is what’s disquieting about it," Dr. Birnbaum said at the American Academy of Neurology (AAN) annual meeting.

A fourth patient developed trigeminal neuralgia after 18 months on the drug; the side of his face had only been numb previously. He now requires pain medications for the condition. Brain MRIs of all four patients were stable.

"Irreversible injury [appears] to have occurred in our three patients, and perhaps even in the fourth. Dalfampridine needs to be used with caution in multiple sclerosis patients with preexisting trigeminal neuralgia as well as in those with evidence of preexisting trigeminal nerve injuries," Dr. Birnbaum said.

When prescribing the drug, "I have to tell [patients] now that there’s a possibility that their trigeminal neuralgia may get worse, and it may not get better if they stop [the drug]. They have to take that into consideration," he said in an interview.

The four cases are not the first to be reported since the potassium channel blocker was approved for MS in 2010 to improve walking.

Investigators from the Mayo Clinic in Scottsdale, Ariz., reported two cases at AAN’s 2012 annual conference, both within a month of starting the drug and both in patients whose trigeminal neuralgia had been in remission. One patient responded to pain medications, the other needed a rhizotomy.

"As I talk to [physicians] about these data," people come up and say, "I’ve seen the same thing," Dr. Birnbaum said.

Dalfampridine improves action potential conduction in demyelinated axons. Perhaps when sensory nerves – such as the trigeminal – have a preexisting injury, that effect can lead to a type of "metabolic exhaustion" that makes the injury worse.

"Could there be a similar phenomenon with motor nerves? Perhaps one sees an initial improvement in motor function, but in the long term could this perhaps be deleterious? I have no data to support that, but the implication is that [it’s] a possibility," he said.

Dr. Birnbaum is a paid consultant to TEVA, Serono, Genzyme, Questcor, and Biogen Idec. Biogen Idec and Hoffman-LaRoche have both supported his research.

[email protected]

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

[email protected]

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

[email protected]

SAN DIEGO – Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

He and his team reviewed 38 natalizumab (Tysabri)-induced progressive multifocal leukoencephalopathy (PML) cases – 11.5% of the current global total – and found that 24 of the patients were 70 kg or less and 29 were 80 kg or less. The median weight of the PML patients was 64 kg, substantially lower than the weight of the average MS patient, at least at the Rocky Mountain clinic.

At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

To further explore the issue, his team also analyzed clinical data from 301 of its own natalizumab patients, plus data from 826 patients in the Swedish Natalizumab Registry, 799 patients from phase III trials, and patients from other sources.

In doing so, they also found that patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.

Patients who weighed no more than 70 kg had mean plasma concentrations of about 45 mcg/mL, whereas those over 150 kg had a mean level of less than 10 mcg/mL. Meanwhile, saturations appeared to escalate with concentration per patient-kilogram in a linear fashion from a mean of 85%-95%. "When you look at 95%-plus saturators, you see stratification into this real high-concentration and low-weight group," Dr. Foley said at the annual meeting of the American Academy of Neurology.

The findings led him to theorize that thinner patients are more at risk for PML because the higher saturations they develop block not only myelin-destroying lymphocytes from entering the central nervous system, as intended, but also lymphocytes that fight the JC virus, the cause of PML in those who carry it.

"We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said.

At the Rocky Mountain clinic, 14 patients who took natalizumab every 6 weeks had mean concentrations of 18.7 mcg/mL and saturations of 83.5%, whereas a group of about 160 patients on a 4-week dosing schedule had mean concentrations of 33.6 mcg/mL and saturations of 89.3%.

"You really want to avoid these high-concentration, high-saturation environments," he said.

The work was funded by the maker of natalizumab, Biogen Idec, and its distributor, Elan Pharmaceuticals. Dr. Foley is a scientific adviser to and a speaker for Biogen.

[email protected]

A small, swallowed, laser imaging capsule provides full-thickness imaging of the upper gastro- intestinal tract without biopsy, and is quicker and less invasive than traditional endoscopy, according to the Harvard University research-ers who are developing it.

About the size of a large multivitamin pill, the transparent capsule generates a near-infrared beam that spins rapidly about its circumference during transit. Changes in the reflected light allow cross-sectional imaging of the esophagus in a few minutes. Sequential cross-sections can be compiled into three-dimensional models of the entire lumen (Nat. Med. 2013 Jan. 13 [doi: 10.1038/nm.3052]).

Images courtesy Wellman Center for Photomedicine, Massachusetts General Hospital

"This system gives us a convenient way to screen for Barrett?s [esophagus] that doesn?t require patient sedation, a specialized setting and equipment, or a physician who has been trained in endoscopy. By showing the three-dimensional, microscopic structure of the esophageal lining, it reveals much more detail than can be seen with even high-resolution endoscopy. The images produced have been some of the best we have seen of the esophagus," investigator Dr. Guillermo Tearney, a Harvard Medical School pathology professor and the associate director of the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said in a statement.

The capsule is on a tether, which carries its fiber optic line and laser driveshaft and helps with positioning. The capsule is pulled up and out after use, and disinfected for the next patient.

In early testing, 15 cm of esophagus in seven healthy and six Barrett?s esophagus patients was imaged in a mean of 58 seconds; it took about 6 minutes to make two down- and two up-transits. The technique, dubbed tethered capsule endomicroscopy, clearly distinguished the cellular abnormalities of Barrett?s. Standard upper GI endoscopy takes about 90 minutes.

"We originally were concerned that we might miss a lot of data because of the small size of the capsule, but we were surprised to find that, once the pill has been swallowed, it is firmly grasped by the esophagus, allowing complete microscopic imaging of the entire wall," Dr. Tearney said.

There were no complications, and 12 of the 13 subjects said they preferred the capsule to previous endoscopies.

"Because the tethered endomicroscopy pill traverses the gastrointestinal tract without visual guidance, the training required to conduct the procedure is minimal. This fact, combined with the brevity and ease with which the procedure is performed, will enable internal microscopic imaging in almost any health care setting, including in the office of the primary care physician," Dr. Tearney and his colleagues wrote in their paper.

The research was supported by grants from the National Institutes of Health. The researchers said they had no disclosures.

[email protected]

A small, swallowed, laser imaging capsule provides full-thickness imaging of the upper gastro- intestinal tract without biopsy, and is quicker and less invasive than traditional endoscopy, according to the Harvard University research-ers who are developing it.

About the size of a large multivitamin pill, the transparent capsule generates a near-infrared beam that spins rapidly about its circumference during transit. Changes in the reflected light allow cross-sectional imaging of the esophagus in a few minutes. Sequential cross-sections can be compiled into three-dimensional models of the entire lumen (Nat. Med. 2013 Jan. 13 [doi: 10.1038/nm.3052]).

Images courtesy Wellman Center for Photomedicine, Massachusetts General Hospital

"This system gives us a convenient way to screen for Barrett?s [esophagus] that doesn?t require patient sedation, a specialized setting and equipment, or a physician who has been trained in endoscopy. By showing the three-dimensional, microscopic structure of the esophageal lining, it reveals much more detail than can be seen with even high-resolution endoscopy. The images produced have been some of the best we have seen of the esophagus," investigator Dr. Guillermo Tearney, a Harvard Medical School pathology professor and the associate director of the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said in a statement.

The capsule is on a tether, which carries its fiber optic line and laser driveshaft and helps with positioning. The capsule is pulled up and out after use, and disinfected for the next patient.

In early testing, 15 cm of esophagus in seven healthy and six Barrett?s esophagus patients was imaged in a mean of 58 seconds; it took about 6 minutes to make two down- and two up-transits. The technique, dubbed tethered capsule endomicroscopy, clearly distinguished the cellular abnormalities of Barrett?s. Standard upper GI endoscopy takes about 90 minutes.

"We originally were concerned that we might miss a lot of data because of the small size of the capsule, but we were surprised to find that, once the pill has been swallowed, it is firmly grasped by the esophagus, allowing complete microscopic imaging of the entire wall," Dr. Tearney said.

There were no complications, and 12 of the 13 subjects said they preferred the capsule to previous endoscopies.

"Because the tethered endomicroscopy pill traverses the gastrointestinal tract without visual guidance, the training required to conduct the procedure is minimal. This fact, combined with the brevity and ease with which the procedure is performed, will enable internal microscopic imaging in almost any health care setting, including in the office of the primary care physician," Dr. Tearney and his colleagues wrote in their paper.

The research was supported by grants from the National Institutes of Health. The researchers said they had no disclosures.

[email protected]

A small, swallowed, laser imaging capsule provides full-thickness imaging of the upper gastro- intestinal tract without biopsy, and is quicker and less invasive than traditional endoscopy, according to the Harvard University research-ers who are developing it.

About the size of a large multivitamin pill, the transparent capsule generates a near-infrared beam that spins rapidly about its circumference during transit. Changes in the reflected light allow cross-sectional imaging of the esophagus in a few minutes. Sequential cross-sections can be compiled into three-dimensional models of the entire lumen (Nat. Med. 2013 Jan. 13 [doi: 10.1038/nm.3052]).

Images courtesy Wellman Center for Photomedicine, Massachusetts General Hospital

"This system gives us a convenient way to screen for Barrett?s [esophagus] that doesn?t require patient sedation, a specialized setting and equipment, or a physician who has been trained in endoscopy. By showing the three-dimensional, microscopic structure of the esophageal lining, it reveals much more detail than can be seen with even high-resolution endoscopy. The images produced have been some of the best we have seen of the esophagus," investigator Dr. Guillermo Tearney, a Harvard Medical School pathology professor and the associate director of the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said in a statement.

The capsule is on a tether, which carries its fiber optic line and laser driveshaft and helps with positioning. The capsule is pulled up and out after use, and disinfected for the next patient.

In early testing, 15 cm of esophagus in seven healthy and six Barrett?s esophagus patients was imaged in a mean of 58 seconds; it took about 6 minutes to make two down- and two up-transits. The technique, dubbed tethered capsule endomicroscopy, clearly distinguished the cellular abnormalities of Barrett?s. Standard upper GI endoscopy takes about 90 minutes.

"We originally were concerned that we might miss a lot of data because of the small size of the capsule, but we were surprised to find that, once the pill has been swallowed, it is firmly grasped by the esophagus, allowing complete microscopic imaging of the entire wall," Dr. Tearney said.

There were no complications, and 12 of the 13 subjects said they preferred the capsule to previous endoscopies.

"Because the tethered endomicroscopy pill traverses the gastrointestinal tract without visual guidance, the training required to conduct the procedure is minimal. This fact, combined with the brevity and ease with which the procedure is performed, will enable internal microscopic imaging in almost any health care setting, including in the office of the primary care physician," Dr. Tearney and his colleagues wrote in their paper.

The research was supported by grants from the National Institutes of Health. The researchers said they had no disclosures.

[email protected]