Michele G. Sullivan

A two-round cervical cancer screening strategy based on testing for human papillomavirus DNA may detect significantly more invasive cancers than one based on cytology.

However, the benefit could come at the expense of overtreatment, especially for younger women, Dr. Guglielmo Ronco and his colleagues reported (Lancet Onc. 2010: DOI:10.1016/S1470-2045(09)70360-2). “For young women … the detection of cervical intraepithelial neoplasia was much higher … at round one, but only slightly lower at round two, suggesting that a large number of regressive CIN2 lesions were identified and treated,” wrote Dr. Ronco of the Center for Cancer Prevention, Turin, Italy, and his co-authors. “Overtreatment of regressive lesions is a problem because excisional treatment of cervical lesions is associated with increased risk of pregnancy-related morbidity.”

The New Technologies for Cervical Cancer (NTCC) screening study randomized 94,000 women to one of two two-round screening programs for cervical cancer. One program was based on cytology alone and the other on HPV testing plus cytology. Women who screened positive for HPV DNA were treated according to their age. Those aged 35–60 years were referred to colposcopy, while those aged 25–34 years were referred to colposcopy only if after a year the test remained positive, or if cytology was atypical squamous cells of undetermined significance (ASCUS) or more severe.

During phase two, women were referred for colposcopy if the HPV test was positive. The primary end point was the number of women with confirmed pre-invasive and invasive cervical cancers.

The subjects' median age at recruitment was 41 years. The median duration of follow-up was 3.5 years.

Both HPV and cytology detected a similar number of invasive cancers during the first round of screening (seven and nine). However, during the second round, no additional cancers were found in the HPV group, while nine cancers were found in the cytology group. Five (55%) of these were squamous cell carcinomas (one stage T1A and four stage T1B) and four (44%) were adenocarcinomas (two stage T1A, one stage T1B, and one TX). This represented a significant increase over the percentage of cervical cancers identified as adenocarcinomas by Italian cancer registries in 2005 (12%), the investigators noted.

Women aged 35–60 years reaped most of the benefit. In the first round, HPV screening detected six invasive cancers and cytology detected eight. In the second round, there were no additional cancers detected in the HPV group, and seven more identified in the cytology group.

For these women, HPV testing detected significantly more CIN2 lesions than cytology (108 vs. 54) during round 1, but significantly fewer during round 2 (8 vs. 15). For CIN3 or adenocarcinoma in situ, HPV testing detected significantly more in round 1 (98 vs. 47) and fewer in round 2 (8 vs. 17). For women aged 25–34 years, HPV testing identified 4.5 times more CIN2 lesions than did cytology testing (126 vs. 27) in round 1. In round 2, HPV testing detected significantly fewer CIN2 lesions than cytology (8 vs. 15). This suggests that the first round of screening identified many lesions that might not have needed treatment.

Disclosures: The study was funded by the European Union and the Italian government. Dr. Ronco disclosed that he has been an adviser to Gen-Probe, which is developing an HPV DNA assay.

A two-round cervical cancer screening strategy based on testing for human papillomavirus DNA may detect significantly more invasive cancers than one based on cytology.

However, the benefit could come at the expense of overtreatment, especially for younger women, Dr. Guglielmo Ronco and his colleagues reported (Lancet Onc. 2010: DOI:10.1016/S1470-2045(09)70360-2). “For young women … the detection of cervical intraepithelial neoplasia was much higher … at round one, but only slightly lower at round two, suggesting that a large number of regressive CIN2 lesions were identified and treated,” wrote Dr. Ronco of the Center for Cancer Prevention, Turin, Italy, and his co-authors. “Overtreatment of regressive lesions is a problem because excisional treatment of cervical lesions is associated with increased risk of pregnancy-related morbidity.”

The New Technologies for Cervical Cancer (NTCC) screening study randomized 94,000 women to one of two two-round screening programs for cervical cancer. One program was based on cytology alone and the other on HPV testing plus cytology. Women who screened positive for HPV DNA were treated according to their age. Those aged 35–60 years were referred to colposcopy, while those aged 25–34 years were referred to colposcopy only if after a year the test remained positive, or if cytology was atypical squamous cells of undetermined significance (ASCUS) or more severe.

During phase two, women were referred for colposcopy if the HPV test was positive. The primary end point was the number of women with confirmed pre-invasive and invasive cervical cancers.

The subjects' median age at recruitment was 41 years. The median duration of follow-up was 3.5 years.

Both HPV and cytology detected a similar number of invasive cancers during the first round of screening (seven and nine). However, during the second round, no additional cancers were found in the HPV group, while nine cancers were found in the cytology group. Five (55%) of these were squamous cell carcinomas (one stage T1A and four stage T1B) and four (44%) were adenocarcinomas (two stage T1A, one stage T1B, and one TX). This represented a significant increase over the percentage of cervical cancers identified as adenocarcinomas by Italian cancer registries in 2005 (12%), the investigators noted.

Women aged 35–60 years reaped most of the benefit. In the first round, HPV screening detected six invasive cancers and cytology detected eight. In the second round, there were no additional cancers detected in the HPV group, and seven more identified in the cytology group.

For these women, HPV testing detected significantly more CIN2 lesions than cytology (108 vs. 54) during round 1, but significantly fewer during round 2 (8 vs. 15). For CIN3 or adenocarcinoma in situ, HPV testing detected significantly more in round 1 (98 vs. 47) and fewer in round 2 (8 vs. 17). For women aged 25–34 years, HPV testing identified 4.5 times more CIN2 lesions than did cytology testing (126 vs. 27) in round 1. In round 2, HPV testing detected significantly fewer CIN2 lesions than cytology (8 vs. 15). This suggests that the first round of screening identified many lesions that might not have needed treatment.

Disclosures: The study was funded by the European Union and the Italian government. Dr. Ronco disclosed that he has been an adviser to Gen-Probe, which is developing an HPV DNA assay.

A two-round cervical cancer screening strategy based on testing for human papillomavirus DNA may detect significantly more invasive cancers than one based on cytology.

However, the benefit could come at the expense of overtreatment, especially for younger women, Dr. Guglielmo Ronco and his colleagues reported (Lancet Onc. 2010: DOI:10.1016/S1470-2045(09)70360-2). “For young women … the detection of cervical intraepithelial neoplasia was much higher … at round one, but only slightly lower at round two, suggesting that a large number of regressive CIN2 lesions were identified and treated,” wrote Dr. Ronco of the Center for Cancer Prevention, Turin, Italy, and his co-authors. “Overtreatment of regressive lesions is a problem because excisional treatment of cervical lesions is associated with increased risk of pregnancy-related morbidity.”

The New Technologies for Cervical Cancer (NTCC) screening study randomized 94,000 women to one of two two-round screening programs for cervical cancer. One program was based on cytology alone and the other on HPV testing plus cytology. Women who screened positive for HPV DNA were treated according to their age. Those aged 35–60 years were referred to colposcopy, while those aged 25–34 years were referred to colposcopy only if after a year the test remained positive, or if cytology was atypical squamous cells of undetermined significance (ASCUS) or more severe.

During phase two, women were referred for colposcopy if the HPV test was positive. The primary end point was the number of women with confirmed pre-invasive and invasive cervical cancers.

The subjects' median age at recruitment was 41 years. The median duration of follow-up was 3.5 years.

Both HPV and cytology detected a similar number of invasive cancers during the first round of screening (seven and nine). However, during the second round, no additional cancers were found in the HPV group, while nine cancers were found in the cytology group. Five (55%) of these were squamous cell carcinomas (one stage T1A and four stage T1B) and four (44%) were adenocarcinomas (two stage T1A, one stage T1B, and one TX). This represented a significant increase over the percentage of cervical cancers identified as adenocarcinomas by Italian cancer registries in 2005 (12%), the investigators noted.

Women aged 35–60 years reaped most of the benefit. In the first round, HPV screening detected six invasive cancers and cytology detected eight. In the second round, there were no additional cancers detected in the HPV group, and seven more identified in the cytology group.

For these women, HPV testing detected significantly more CIN2 lesions than cytology (108 vs. 54) during round 1, but significantly fewer during round 2 (8 vs. 15). For CIN3 or adenocarcinoma in situ, HPV testing detected significantly more in round 1 (98 vs. 47) and fewer in round 2 (8 vs. 17). For women aged 25–34 years, HPV testing identified 4.5 times more CIN2 lesions than did cytology testing (126 vs. 27) in round 1. In round 2, HPV testing detected significantly fewer CIN2 lesions than cytology (8 vs. 15). This suggests that the first round of screening identified many lesions that might not have needed treatment.

Disclosures: The study was funded by the European Union and the Italian government. Dr. Ronco disclosed that he has been an adviser to Gen-Probe, which is developing an HPV DNA assay.

Women who need vaginal reconstruction now have another surgical option—a vascularized free jejunal graft that provides a durable, lubricated neovagina without the scarring that skin grafts can leave.

Dr. Münire E. Akar and her colleagues have reported the largest series of these operations yet—31 patients since 2005. During the mean follow-up of 19 months, the team has had a 100% graft survival rate and a 10% rate of anastomosis revision.

Dr. Akar reported on 14 of these patients at the Global Congress of Minimally Invasive Gynecology, held last November. In December, she and her colleagues published a series of 22 such cases (Microsurgery 2009 [doi:10.1002/micr.20713]), but since the article was accepted, the team has performed 9 more operations, for a total of 31. All procedures were performed at Akdeniz (Turkey) University, Antalya; Dr. Akar is currently performing research at Wake Forest University, Winston-Salem, N.C.

Although the procedure takes about 5 hours and the recovery period is long, the end result is worthwhile, Dr. Akar said in an interview. “It can be very hard for patients to go through, but usually they are fed up with their condition and so they are ready to do whatever is necessary,” she said.

The ideal vaginal reconstruction should provide a long-lasting, functional passage for sexual intercourse that does not need maintenance with dilators or lubrication for sexual activity. The jejunal flap offers these advantages over grafted skin and is less likely to cause gastrointestinal problems, compared with the more widely performed colon transfer, she said. Although she and her team have not had any graft failures, if one did occur there would be plenty of replacement material, which is not the case with a bowel transfer, she added.

The surgery is a significant contributor, but not a perfect answer, for women with vaginal agenesis or those who require reconstruction as a result of trauma or gynecologic surgery, said Dr. Ronald Silverman, chief of plastic surgery at the University of Maryland, Baltimore.

“It's definitely an excellent technique, but there are some negatives,” he said in an interview. “It's very high demand in terms of the length of operation and the technical demand on the surgeons. And since it's done through the abdomen, there is an additional scar.”

Harvesting the intestine is much more invasive than taking skin. “This would not be my first choice of technique,” said Dr. Silverman, who prefers the Singapore, or pudendal, thigh, flap. “One of the nice things about [the thigh flap] is that the medial thigh does have erogenous sensation, while the jejunal transfer is insensate,” because of the severing of its neural connections. “The whole reason for doing a vaginal reconstruction is to have a normal sex life,” so having vaginal sensation is a logical goal for such surgery, he said.

A skin-grafted neovagina, however, requires a lot of postoperative care to maintain its integrity. Unless the woman engages in frequent penetrative sex, she must make regular use of a dilator or stent to maintain vaginal depth and avoid introital constriction. In Turkey, this is an almost unthinkable task for women, Dr. Akar said.

“Women in our society are not conditioned to do this kind of thing. Our culture is very conservative, so until they are married, girls don't ever touch their genitals or even talk to their mothers about such things. It's very hard to ask them to do this—it's not really a choice for our women.”

This societal inhibition also precludes what is often the first-line treatment for vaginal agenesis: the use of graduated dilators or internal traction to create a functional vagina.

Surgical Technique

After making a 10-cm incision beside the umbilicus, the surgeon isolates a jejunal segment of about 30 cm, distal to Treitz's ligament.

The segment is removed, along with its vascular pedicle, and the ends of the remaining jejunum approximated and anastomosed.

The surgeon creates a pouch for the neovagina from the blind vaginal introitus into the abdominal cavity. The jejunal segment is transferred into this pouch vaginally, and the proximal end closed with sutures and anchored to the retropubic periosteum.

A second tunnel from the periosteum to the inguinal region accommodates the vascular pedicle. Arterial and venous anastomoses between the flap and the recipient vessels are performed through a 6- to 7-cm inguinal incision. Finally, the surgeon attaches the distal opening of the jejunal segment to the vaginal introitus, creating a vagina of about 15–17 cm in length.

The mean surgical time in the series was 5 hours, with patients discharged about 2 weeks later. They were allowed to engage in sexual intercourse after 1 month.

Results

The patients' mean age was 22.5 years (range 16–32 years). Most (27) of the patients had Müllerian agenesis; one patient needed a reconstruction because of previous oncologic surgery.

One patient had testicular feminization syndrome and had previously received a skin flap but developed postoperative stenosis. Only two patients had a normal uterus; their neovaginas were connected to the cervix, and they now experience a normal menstrual cycle with vaginal bleeding.

Three patients required reoperation because of venous compromise in the flap that occurred on postoperative days 2, 3, and 9. All flaps were salvaged. There was one mucosal prolapse, which was treated surgically. One patient developed hematomas in the abdominal and inguinal incision, which resolved with drainage. There were no surgical, urinary, or gastrointestinal infections or complications.

Follow-up ranged from 3 to 50 months. The patients were allowed to engage in sexual intercourse 1 month after surgery. Although two reported mild bleeding during intercourse early on, this did not continue. One patient developed an introital stricture that was treated with temporary dilation.

While mucosal secretion is one of the big benefits of an intestinal reconstruction—eliminating the need for artificial lubrication during sex—hypersecretion can be a problem as well, Dr. Akar said. Dr. Silverman agreed. “It's thicker than normal vaginal mucus, and sometimes, this can get to be so much of a problem that the women need to wear a pad,” he said.

Three of Dr. Akar's patients complained of this problem, but the severity lessened with time, she said. The incidence seems to be lower than what is observed after a pedicle bowel transfer, possibly because of the ischemia induced during the transfer period. In fact, Dr. Akar said, she and her colleagues are preparing to report on some adjustments they have made to cope with discharge, observing that the ischemia period seems to decrease the amount of mucus the graft secretes after transfer.

Most of the patients (29) are now able to have satisfactory sexual intercourse. Two patients are single and haven't engaged in intercourse yet. Although the investigators did not report any specific sexual outcomes data, Dr. Akar said “there were no complaints in that regard” conveyed by patients.

Follow-up will continue, and one question that remains is the possibility of conception in those patients with a normal uterus. “If there is endometrium and now a connection to the cervix, there is a chance to get pregnant, although we don't know how that will go in the future,” Dr. Akar said. Of course, any term pregnancies would have to be delivered by cesarean section, she said, since the grafted intestine would not expand enough to permit a vaginal birth.

The large abdominal incision for the reconstruction procedure is a drawback, she admitted, but the improvements may be made in the future. The team has performed one similar procedure with laparoscopic assist—a pedicled jejunal flap transfer on a woman who had most of her reproductive organs removed due to cancer when she was 3 years old.

The team used three cannula ports. The jejunal segment and vascular pedicle were divided laparoscopically. Insertion into the neovaginal pouch was completed through a Pfannenstiel incision (Microsurgery 2008;28:671-5).

Because of the length of transfer needed to reconstruct an entire vagina, the pedicle technique is a better alternative for women who have some vaginal length and need a distal extension, Dr. Akar said.

Otherwise, the transfer might put too much pressure on the vascular pedicle and endanger the graft.

Disclosures: None was reported.

Although the procedure and recovery period are long, the end result is worthwhile.

Source DR. AKAR

This image provides an immediate postoperative view of the neovaginal introitus and the jejunum flap. Results were promising for vaginal reconstruction in 31 patients.

Source Courtesy Dr. Münire E. Akar

Women who need vaginal reconstruction now have another surgical option—a vascularized free jejunal graft that provides a durable, lubricated neovagina without the scarring that skin grafts can leave.

Dr. Münire E. Akar and her colleagues have reported the largest series of these operations yet—31 patients since 2005. During the mean follow-up of 19 months, the team has had a 100% graft survival rate and a 10% rate of anastomosis revision.

Dr. Akar reported on 14 of these patients at the Global Congress of Minimally Invasive Gynecology, held last November. In December, she and her colleagues published a series of 22 such cases (Microsurgery 2009 [doi:10.1002/micr.20713]), but since the article was accepted, the team has performed 9 more operations, for a total of 31. All procedures were performed at Akdeniz (Turkey) University, Antalya; Dr. Akar is currently performing research at Wake Forest University, Winston-Salem, N.C.

Although the procedure takes about 5 hours and the recovery period is long, the end result is worthwhile, Dr. Akar said in an interview. “It can be very hard for patients to go through, but usually they are fed up with their condition and so they are ready to do whatever is necessary,” she said.

The ideal vaginal reconstruction should provide a long-lasting, functional passage for sexual intercourse that does not need maintenance with dilators or lubrication for sexual activity. The jejunal flap offers these advantages over grafted skin and is less likely to cause gastrointestinal problems, compared with the more widely performed colon transfer, she said. Although she and her team have not had any graft failures, if one did occur there would be plenty of replacement material, which is not the case with a bowel transfer, she added.

The surgery is a significant contributor, but not a perfect answer, for women with vaginal agenesis or those who require reconstruction as a result of trauma or gynecologic surgery, said Dr. Ronald Silverman, chief of plastic surgery at the University of Maryland, Baltimore.

“It's definitely an excellent technique, but there are some negatives,” he said in an interview. “It's very high demand in terms of the length of operation and the technical demand on the surgeons. And since it's done through the abdomen, there is an additional scar.”

Harvesting the intestine is much more invasive than taking skin. “This would not be my first choice of technique,” said Dr. Silverman, who prefers the Singapore, or pudendal, thigh, flap. “One of the nice things about [the thigh flap] is that the medial thigh does have erogenous sensation, while the jejunal transfer is insensate,” because of the severing of its neural connections. “The whole reason for doing a vaginal reconstruction is to have a normal sex life,” so having vaginal sensation is a logical goal for such surgery, he said.

A skin-grafted neovagina, however, requires a lot of postoperative care to maintain its integrity. Unless the woman engages in frequent penetrative sex, she must make regular use of a dilator or stent to maintain vaginal depth and avoid introital constriction. In Turkey, this is an almost unthinkable task for women, Dr. Akar said.

“Women in our society are not conditioned to do this kind of thing. Our culture is very conservative, so until they are married, girls don't ever touch their genitals or even talk to their mothers about such things. It's very hard to ask them to do this—it's not really a choice for our women.”

This societal inhibition also precludes what is often the first-line treatment for vaginal agenesis: the use of graduated dilators or internal traction to create a functional vagina.

Surgical Technique

After making a 10-cm incision beside the umbilicus, the surgeon isolates a jejunal segment of about 30 cm, distal to Treitz's ligament.

The segment is removed, along with its vascular pedicle, and the ends of the remaining jejunum approximated and anastomosed.

The surgeon creates a pouch for the neovagina from the blind vaginal introitus into the abdominal cavity. The jejunal segment is transferred into this pouch vaginally, and the proximal end closed with sutures and anchored to the retropubic periosteum.

A second tunnel from the periosteum to the inguinal region accommodates the vascular pedicle. Arterial and venous anastomoses between the flap and the recipient vessels are performed through a 6- to 7-cm inguinal incision. Finally, the surgeon attaches the distal opening of the jejunal segment to the vaginal introitus, creating a vagina of about 15–17 cm in length.

The mean surgical time in the series was 5 hours, with patients discharged about 2 weeks later. They were allowed to engage in sexual intercourse after 1 month.

Results

The patients' mean age was 22.5 years (range 16–32 years). Most (27) of the patients had Müllerian agenesis; one patient needed a reconstruction because of previous oncologic surgery.

One patient had testicular feminization syndrome and had previously received a skin flap but developed postoperative stenosis. Only two patients had a normal uterus; their neovaginas were connected to the cervix, and they now experience a normal menstrual cycle with vaginal bleeding.

Three patients required reoperation because of venous compromise in the flap that occurred on postoperative days 2, 3, and 9. All flaps were salvaged. There was one mucosal prolapse, which was treated surgically. One patient developed hematomas in the abdominal and inguinal incision, which resolved with drainage. There were no surgical, urinary, or gastrointestinal infections or complications.

Follow-up ranged from 3 to 50 months. The patients were allowed to engage in sexual intercourse 1 month after surgery. Although two reported mild bleeding during intercourse early on, this did not continue. One patient developed an introital stricture that was treated with temporary dilation.

While mucosal secretion is one of the big benefits of an intestinal reconstruction—eliminating the need for artificial lubrication during sex—hypersecretion can be a problem as well, Dr. Akar said. Dr. Silverman agreed. “It's thicker than normal vaginal mucus, and sometimes, this can get to be so much of a problem that the women need to wear a pad,” he said.

Three of Dr. Akar's patients complained of this problem, but the severity lessened with time, she said. The incidence seems to be lower than what is observed after a pedicle bowel transfer, possibly because of the ischemia induced during the transfer period. In fact, Dr. Akar said, she and her colleagues are preparing to report on some adjustments they have made to cope with discharge, observing that the ischemia period seems to decrease the amount of mucus the graft secretes after transfer.

Most of the patients (29) are now able to have satisfactory sexual intercourse. Two patients are single and haven't engaged in intercourse yet. Although the investigators did not report any specific sexual outcomes data, Dr. Akar said “there were no complaints in that regard” conveyed by patients.

Follow-up will continue, and one question that remains is the possibility of conception in those patients with a normal uterus. “If there is endometrium and now a connection to the cervix, there is a chance to get pregnant, although we don't know how that will go in the future,” Dr. Akar said. Of course, any term pregnancies would have to be delivered by cesarean section, she said, since the grafted intestine would not expand enough to permit a vaginal birth.

The large abdominal incision for the reconstruction procedure is a drawback, she admitted, but the improvements may be made in the future. The team has performed one similar procedure with laparoscopic assist—a pedicled jejunal flap transfer on a woman who had most of her reproductive organs removed due to cancer when she was 3 years old.

The team used three cannula ports. The jejunal segment and vascular pedicle were divided laparoscopically. Insertion into the neovaginal pouch was completed through a Pfannenstiel incision (Microsurgery 2008;28:671-5).

Because of the length of transfer needed to reconstruct an entire vagina, the pedicle technique is a better alternative for women who have some vaginal length and need a distal extension, Dr. Akar said.

Otherwise, the transfer might put too much pressure on the vascular pedicle and endanger the graft.

Disclosures: None was reported.

Although the procedure and recovery period are long, the end result is worthwhile.

Source DR. AKAR

This image provides an immediate postoperative view of the neovaginal introitus and the jejunum flap. Results were promising for vaginal reconstruction in 31 patients.

Source Courtesy Dr. Münire E. Akar

Women who need vaginal reconstruction now have another surgical option—a vascularized free jejunal graft that provides a durable, lubricated neovagina without the scarring that skin grafts can leave.

Dr. Münire E. Akar and her colleagues have reported the largest series of these operations yet—31 patients since 2005. During the mean follow-up of 19 months, the team has had a 100% graft survival rate and a 10% rate of anastomosis revision.

Dr. Akar reported on 14 of these patients at the Global Congress of Minimally Invasive Gynecology, held last November. In December, she and her colleagues published a series of 22 such cases (Microsurgery 2009 [doi:10.1002/micr.20713]), but since the article was accepted, the team has performed 9 more operations, for a total of 31. All procedures were performed at Akdeniz (Turkey) University, Antalya; Dr. Akar is currently performing research at Wake Forest University, Winston-Salem, N.C.

Although the procedure takes about 5 hours and the recovery period is long, the end result is worthwhile, Dr. Akar said in an interview. “It can be very hard for patients to go through, but usually they are fed up with their condition and so they are ready to do whatever is necessary,” she said.

The ideal vaginal reconstruction should provide a long-lasting, functional passage for sexual intercourse that does not need maintenance with dilators or lubrication for sexual activity. The jejunal flap offers these advantages over grafted skin and is less likely to cause gastrointestinal problems, compared with the more widely performed colon transfer, she said. Although she and her team have not had any graft failures, if one did occur there would be plenty of replacement material, which is not the case with a bowel transfer, she added.

The surgery is a significant contributor, but not a perfect answer, for women with vaginal agenesis or those who require reconstruction as a result of trauma or gynecologic surgery, said Dr. Ronald Silverman, chief of plastic surgery at the University of Maryland, Baltimore.

“It's definitely an excellent technique, but there are some negatives,” he said in an interview. “It's very high demand in terms of the length of operation and the technical demand on the surgeons. And since it's done through the abdomen, there is an additional scar.”

Harvesting the intestine is much more invasive than taking skin. “This would not be my first choice of technique,” said Dr. Silverman, who prefers the Singapore, or pudendal, thigh, flap. “One of the nice things about [the thigh flap] is that the medial thigh does have erogenous sensation, while the jejunal transfer is insensate,” because of the severing of its neural connections. “The whole reason for doing a vaginal reconstruction is to have a normal sex life,” so having vaginal sensation is a logical goal for such surgery, he said.

A skin-grafted neovagina, however, requires a lot of postoperative care to maintain its integrity. Unless the woman engages in frequent penetrative sex, she must make regular use of a dilator or stent to maintain vaginal depth and avoid introital constriction. In Turkey, this is an almost unthinkable task for women, Dr. Akar said.

“Women in our society are not conditioned to do this kind of thing. Our culture is very conservative, so until they are married, girls don't ever touch their genitals or even talk to their mothers about such things. It's very hard to ask them to do this—it's not really a choice for our women.”

This societal inhibition also precludes what is often the first-line treatment for vaginal agenesis: the use of graduated dilators or internal traction to create a functional vagina.

Surgical Technique

After making a 10-cm incision beside the umbilicus, the surgeon isolates a jejunal segment of about 30 cm, distal to Treitz's ligament.

The segment is removed, along with its vascular pedicle, and the ends of the remaining jejunum approximated and anastomosed.

The surgeon creates a pouch for the neovagina from the blind vaginal introitus into the abdominal cavity. The jejunal segment is transferred into this pouch vaginally, and the proximal end closed with sutures and anchored to the retropubic periosteum.

A second tunnel from the periosteum to the inguinal region accommodates the vascular pedicle. Arterial and venous anastomoses between the flap and the recipient vessels are performed through a 6- to 7-cm inguinal incision. Finally, the surgeon attaches the distal opening of the jejunal segment to the vaginal introitus, creating a vagina of about 15–17 cm in length.

The mean surgical time in the series was 5 hours, with patients discharged about 2 weeks later. They were allowed to engage in sexual intercourse after 1 month.

Results

The patients' mean age was 22.5 years (range 16–32 years). Most (27) of the patients had Müllerian agenesis; one patient needed a reconstruction because of previous oncologic surgery.

One patient had testicular feminization syndrome and had previously received a skin flap but developed postoperative stenosis. Only two patients had a normal uterus; their neovaginas were connected to the cervix, and they now experience a normal menstrual cycle with vaginal bleeding.

Three patients required reoperation because of venous compromise in the flap that occurred on postoperative days 2, 3, and 9. All flaps were salvaged. There was one mucosal prolapse, which was treated surgically. One patient developed hematomas in the abdominal and inguinal incision, which resolved with drainage. There were no surgical, urinary, or gastrointestinal infections or complications.

Follow-up ranged from 3 to 50 months. The patients were allowed to engage in sexual intercourse 1 month after surgery. Although two reported mild bleeding during intercourse early on, this did not continue. One patient developed an introital stricture that was treated with temporary dilation.

While mucosal secretion is one of the big benefits of an intestinal reconstruction—eliminating the need for artificial lubrication during sex—hypersecretion can be a problem as well, Dr. Akar said. Dr. Silverman agreed. “It's thicker than normal vaginal mucus, and sometimes, this can get to be so much of a problem that the women need to wear a pad,” he said.

Three of Dr. Akar's patients complained of this problem, but the severity lessened with time, she said. The incidence seems to be lower than what is observed after a pedicle bowel transfer, possibly because of the ischemia induced during the transfer period. In fact, Dr. Akar said, she and her colleagues are preparing to report on some adjustments they have made to cope with discharge, observing that the ischemia period seems to decrease the amount of mucus the graft secretes after transfer.

Most of the patients (29) are now able to have satisfactory sexual intercourse. Two patients are single and haven't engaged in intercourse yet. Although the investigators did not report any specific sexual outcomes data, Dr. Akar said “there were no complaints in that regard” conveyed by patients.

Follow-up will continue, and one question that remains is the possibility of conception in those patients with a normal uterus. “If there is endometrium and now a connection to the cervix, there is a chance to get pregnant, although we don't know how that will go in the future,” Dr. Akar said. Of course, any term pregnancies would have to be delivered by cesarean section, she said, since the grafted intestine would not expand enough to permit a vaginal birth.

The large abdominal incision for the reconstruction procedure is a drawback, she admitted, but the improvements may be made in the future. The team has performed one similar procedure with laparoscopic assist—a pedicled jejunal flap transfer on a woman who had most of her reproductive organs removed due to cancer when she was 3 years old.

The team used three cannula ports. The jejunal segment and vascular pedicle were divided laparoscopically. Insertion into the neovaginal pouch was completed through a Pfannenstiel incision (Microsurgery 2008;28:671-5).

Because of the length of transfer needed to reconstruct an entire vagina, the pedicle technique is a better alternative for women who have some vaginal length and need a distal extension, Dr. Akar said.

Otherwise, the transfer might put too much pressure on the vascular pedicle and endanger the graft.

Disclosures: None was reported.

Although the procedure and recovery period are long, the end result is worthwhile.

Source DR. AKAR

This image provides an immediate postoperative view of the neovaginal introitus and the jejunum flap. Results were promising for vaginal reconstruction in 31 patients.

Source Courtesy Dr. Münire E. Akar

Major Finding: Both newly trained and experienced physicians had at least a 97% success rate for placing the Essure 305 inserts in both fallopian tubes in one postmarketing study. The rate of adverse events due to nickel hypersensitivity was lower than expected in a second study.

Data Source: The first postmarketing study included 578 women. The second postmarketing study looked at nickel hypersensitivity.

Disclosures: Dr. Levie and Dr. Zurawin are both on the medical advisory board of Conceptus Inc. Dr. Levie also serves as a physician educator for the company.

KISSIMMEE, FLA. — The third generation of a hysteroscopic sterilization microinsert is quick and simple to deploy, with a negligible rate of adverse events due to nickel hypersensitivity reactions, two postmarketing studies have concluded.

Both newly trained and experienced physicians had at least a 97% success rate for placing the Essure 305 inserts in both fallopian tubes, Dr. Mark Levie reported at the annual meeting of the AAGL.

“The only significant difference we saw was that experienced physicians [who had done at least 25 placements] completed the procedure in 8 minutes, significantly faster than newly trained physicians,” said Dr. Levie of Montefiore Medical Center, New York.

The first postmarketing study, required by the Food and Drug Administration and sponsored by Conceptus Inc., which manufactures the implants, examined successful bilateral placement rates in 578 women. The procedures were performed by 37 physicians who were newly trained in placing the implants and 39 physicians who had placed at least 25 of them.

The study began in 2007; the FDA terminated it early in March 2009, after a preliminary analysis determined that enrolling more women would not significantly change the placement rate.

The patients' mean age was 35 years; their mean body mass index was 29 kg/m

Among the 578 women, there were 562 successful bilateral placements, 10 unilateral placements, and 6 bilateral failures, resulting in an overall success rate of 97%.

Parity, mode of delivery (cesarean section vs. vaginal), prior surgery, prior abortion, and body mass index did not significantly affect placement rate. Age was a factor; the average age of the patient with a successful placement was 35 years, significantly younger than the average age for patients with unsuccessful placement (39 years).

Novice physicians and experienced physicians had similar success rates (97% vs. 98%).

The mean placement time was 9 minutes, with experienced physicians placing the microinserts an average of 2 minutes faster than novice physicians.

“Ninety-five percent of the cases were completed in less than 20 minutes, and 71% were done in an office setting,” Dr. Levie said.

The inserts are composed of stainless steel and nitinol, both of which contain nickel, Dr. Robert Zurawin said at the meeting. Nickel hypersensitivity is a contraindication for placement in the United States; in Europe, there is a warning against placing the inserts in patients allergic to the metal.

To date, 330,000 of the devices have been implanted in women worldwide, with 23 reports of adverse events due to nickel hypersensitivity, said Dr. Zurawin of Baylor College of Medicine, Houston.

The rate is much lower than might be expected given the background rate of nickel hypersensitivity, he said. “Between 10% and 15% of the female population is allergic to nickel, and that rate is higher in younger women than it is in older women,” he said.

To investigate the events, Dr. Zurawin conducted a retrospective study of adverse events reported in Essure' s phase II clinical trial and a pivotal trial that included 518 women. He also included reports of nickel-related adverse events in the FDA's MAUDE database and Conceptus's adverse event reporting system.

No nickel-attributed adverse events were reported in the phase II trial or the pivotal trial, Dr. Zurawin said. Symptoms of the postmarketing events included rash, hives, pain, cyanotic extremities, cramping, dizziness, nausea, fatigue, confusion, and headaches.

Only one patient had a confirmed nickel allergy, and three had positive nickel hypersensitivity skin tests. The patient with a confirmed nickel allergy was asymptomatic.

Of those with a positive skin test, one complained of a rash on her thighs where she had been washed with an iodine-containing antiseptic. One complained of postprocedural nausea, shivering, and discomfort; the inserts were removed 8 months later with nothing remarkable observed at that time. One patient went to the hospital with pain, rash, and hives after the procedure; the inserts were removed, and pathology noted white blood cells and eosinophils around them.

“This is one case where nickel allergy is a reasonable assumption,” Dr. Zurawin said.

Major Finding: Both newly trained and experienced physicians had at least a 97% success rate for placing the Essure 305 inserts in both fallopian tubes in one postmarketing study. The rate of adverse events due to nickel hypersensitivity was lower than expected in a second study.

Data Source: The first postmarketing study included 578 women. The second postmarketing study looked at nickel hypersensitivity.

Disclosures: Dr. Levie and Dr. Zurawin are both on the medical advisory board of Conceptus Inc. Dr. Levie also serves as a physician educator for the company.

KISSIMMEE, FLA. — The third generation of a hysteroscopic sterilization microinsert is quick and simple to deploy, with a negligible rate of adverse events due to nickel hypersensitivity reactions, two postmarketing studies have concluded.

Both newly trained and experienced physicians had at least a 97% success rate for placing the Essure 305 inserts in both fallopian tubes, Dr. Mark Levie reported at the annual meeting of the AAGL.

“The only significant difference we saw was that experienced physicians [who had done at least 25 placements] completed the procedure in 8 minutes, significantly faster than newly trained physicians,” said Dr. Levie of Montefiore Medical Center, New York.

The first postmarketing study, required by the Food and Drug Administration and sponsored by Conceptus Inc., which manufactures the implants, examined successful bilateral placement rates in 578 women. The procedures were performed by 37 physicians who were newly trained in placing the implants and 39 physicians who had placed at least 25 of them.

The study began in 2007; the FDA terminated it early in March 2009, after a preliminary analysis determined that enrolling more women would not significantly change the placement rate.

The patients' mean age was 35 years; their mean body mass index was 29 kg/m

Among the 578 women, there were 562 successful bilateral placements, 10 unilateral placements, and 6 bilateral failures, resulting in an overall success rate of 97%.

Parity, mode of delivery (cesarean section vs. vaginal), prior surgery, prior abortion, and body mass index did not significantly affect placement rate. Age was a factor; the average age of the patient with a successful placement was 35 years, significantly younger than the average age for patients with unsuccessful placement (39 years).

Novice physicians and experienced physicians had similar success rates (97% vs. 98%).

The mean placement time was 9 minutes, with experienced physicians placing the microinserts an average of 2 minutes faster than novice physicians.

“Ninety-five percent of the cases were completed in less than 20 minutes, and 71% were done in an office setting,” Dr. Levie said.

The inserts are composed of stainless steel and nitinol, both of which contain nickel, Dr. Robert Zurawin said at the meeting. Nickel hypersensitivity is a contraindication for placement in the United States; in Europe, there is a warning against placing the inserts in patients allergic to the metal.

To date, 330,000 of the devices have been implanted in women worldwide, with 23 reports of adverse events due to nickel hypersensitivity, said Dr. Zurawin of Baylor College of Medicine, Houston.

The rate is much lower than might be expected given the background rate of nickel hypersensitivity, he said. “Between 10% and 15% of the female population is allergic to nickel, and that rate is higher in younger women than it is in older women,” he said.

To investigate the events, Dr. Zurawin conducted a retrospective study of adverse events reported in Essure' s phase II clinical trial and a pivotal trial that included 518 women. He also included reports of nickel-related adverse events in the FDA's MAUDE database and Conceptus's adverse event reporting system.

No nickel-attributed adverse events were reported in the phase II trial or the pivotal trial, Dr. Zurawin said. Symptoms of the postmarketing events included rash, hives, pain, cyanotic extremities, cramping, dizziness, nausea, fatigue, confusion, and headaches.

Only one patient had a confirmed nickel allergy, and three had positive nickel hypersensitivity skin tests. The patient with a confirmed nickel allergy was asymptomatic.

Of those with a positive skin test, one complained of a rash on her thighs where she had been washed with an iodine-containing antiseptic. One complained of postprocedural nausea, shivering, and discomfort; the inserts were removed 8 months later with nothing remarkable observed at that time. One patient went to the hospital with pain, rash, and hives after the procedure; the inserts were removed, and pathology noted white blood cells and eosinophils around them.

“This is one case where nickel allergy is a reasonable assumption,” Dr. Zurawin said.

Major Finding: Both newly trained and experienced physicians had at least a 97% success rate for placing the Essure 305 inserts in both fallopian tubes in one postmarketing study. The rate of adverse events due to nickel hypersensitivity was lower than expected in a second study.

Data Source: The first postmarketing study included 578 women. The second postmarketing study looked at nickel hypersensitivity.

Disclosures: Dr. Levie and Dr. Zurawin are both on the medical advisory board of Conceptus Inc. Dr. Levie also serves as a physician educator for the company.

KISSIMMEE, FLA. — The third generation of a hysteroscopic sterilization microinsert is quick and simple to deploy, with a negligible rate of adverse events due to nickel hypersensitivity reactions, two postmarketing studies have concluded.

Both newly trained and experienced physicians had at least a 97% success rate for placing the Essure 305 inserts in both fallopian tubes, Dr. Mark Levie reported at the annual meeting of the AAGL.

“The only significant difference we saw was that experienced physicians [who had done at least 25 placements] completed the procedure in 8 minutes, significantly faster than newly trained physicians,” said Dr. Levie of Montefiore Medical Center, New York.

The first postmarketing study, required by the Food and Drug Administration and sponsored by Conceptus Inc., which manufactures the implants, examined successful bilateral placement rates in 578 women. The procedures were performed by 37 physicians who were newly trained in placing the implants and 39 physicians who had placed at least 25 of them.

The study began in 2007; the FDA terminated it early in March 2009, after a preliminary analysis determined that enrolling more women would not significantly change the placement rate.

The patients' mean age was 35 years; their mean body mass index was 29 kg/m

Among the 578 women, there were 562 successful bilateral placements, 10 unilateral placements, and 6 bilateral failures, resulting in an overall success rate of 97%.

Parity, mode of delivery (cesarean section vs. vaginal), prior surgery, prior abortion, and body mass index did not significantly affect placement rate. Age was a factor; the average age of the patient with a successful placement was 35 years, significantly younger than the average age for patients with unsuccessful placement (39 years).

Novice physicians and experienced physicians had similar success rates (97% vs. 98%).

The mean placement time was 9 minutes, with experienced physicians placing the microinserts an average of 2 minutes faster than novice physicians.

“Ninety-five percent of the cases were completed in less than 20 minutes, and 71% were done in an office setting,” Dr. Levie said.

The inserts are composed of stainless steel and nitinol, both of which contain nickel, Dr. Robert Zurawin said at the meeting. Nickel hypersensitivity is a contraindication for placement in the United States; in Europe, there is a warning against placing the inserts in patients allergic to the metal.

To date, 330,000 of the devices have been implanted in women worldwide, with 23 reports of adverse events due to nickel hypersensitivity, said Dr. Zurawin of Baylor College of Medicine, Houston.

The rate is much lower than might be expected given the background rate of nickel hypersensitivity, he said. “Between 10% and 15% of the female population is allergic to nickel, and that rate is higher in younger women than it is in older women,” he said.

To investigate the events, Dr. Zurawin conducted a retrospective study of adverse events reported in Essure' s phase II clinical trial and a pivotal trial that included 518 women. He also included reports of nickel-related adverse events in the FDA's MAUDE database and Conceptus's adverse event reporting system.

No nickel-attributed adverse events were reported in the phase II trial or the pivotal trial, Dr. Zurawin said. Symptoms of the postmarketing events included rash, hives, pain, cyanotic extremities, cramping, dizziness, nausea, fatigue, confusion, and headaches.

Only one patient had a confirmed nickel allergy, and three had positive nickel hypersensitivity skin tests. The patient with a confirmed nickel allergy was asymptomatic.

Of those with a positive skin test, one complained of a rash on her thighs where she had been washed with an iodine-containing antiseptic. One complained of postprocedural nausea, shivering, and discomfort; the inserts were removed 8 months later with nothing remarkable observed at that time. One patient went to the hospital with pain, rash, and hives after the procedure; the inserts were removed, and pathology noted white blood cells and eosinophils around them.

“This is one case where nickel allergy is a reasonable assumption,” Dr. Zurawin said.

KISSIMMEE, FLA. — Women who present with vaginal bleeding—with or without abdominal pain—in the first trimester of pregnancy should undergo an ultrasound scan to rule out an ectopic pregnancy in the cervix, according to Dr. Valerie Shavell.

Because cervical pregnancy is so rare—about 1 in 9,000 pregnancies—it may not be on the diagnostic radar when a woman arrives in the emergency department with such common symptoms. Thus, a cervical pregnancy can easily be misdiagnosed as a threatened spontaneous abortion, she said at the annual meeting of the AAGL.

If the patient is then discharged under watchful waiting, rupture may occur with a potentially fatal bleed. Hemorrhage is also possible if she undergoes a dilation and curettage for a suspected threatened abortion. Either way, the outcome may be a hysterectomy, said Dr. Shavell of Wayne State University, Detroit.

Ultrasound can identify more than 80% of cervical pregnancies in time for medical or minimally invasive therapy, which can prevent hysterectomy and preserve fertility, said Dr. Shavell and her colleague, Dr. Mark Zakaria.

Dr. Shavell discussed symptoms and ultrasound findings in a case series of 14 women (mean age 32 years) who were treated for cervical pregnancy at the Detroit Medical Center over a 10-year period. Most of the patients (eight) presented directly to the hospital's emergency department. Four were transferred from other hospitals, and two were admitted from the resident clinic. Their mean gravidity was 5, and their mean parity was 2.

Consistent with the area's demographics, 71% were black. Eleven of the women had a risk factor for cervical pregnancy: prior termination of pregnancy (9), cesarean section (4), or cervical cone biopsy (2). The gestational age at presentation ranged from 5 to 11 weeks.

All patients presented with vaginal bleeding, which was mild in seven, moderate in four, and heavy with clots in three. Six patients also reported some abdominal pain or cramping.

“In all cases, ultrasound identified a gestational sac and yolk sac consistent with the gestational age as measured by the last menstrual period,” Dr. Shavell said. “We also saw prominent vascularity surrounding the gestational sac in every case.”

Fetal heart activity was present in 64%. The distance between the external cervical os and the leading edge of the gestational sac ranged from 7 to 25 mm.

Dr. Zakaria reported treatment outcomes for all 14 of the patients, plus 1 additional patient. All received the first-line therapy of methotrexate and leucovorin (used to protect healthy cells from methotrexate); this was sufficient to terminate the pregnancy in five. Six women received additional therapy and also underwent a uterine artery embolization. In four patients, the methotrexate combination was delivered in conjunction with a fetal intraembryonic potassium chloride injection, followed by uterine artery embolization.

It's important to carefully assess both the patient and the services available to her while making treatment decisions, Dr. Zakaria said. “Methotrexate is a reasonable first-line therapy. It's easy to administer and can be given in any hospital. The other treatments require an interventional radiologist, who might not always be available at a community hospital. If the patient comes to the emergency department and the physician suspects a cervical pregnancy, that physician should consider whether the hospital is equipped to do these interventions, or whether a transfer might be necessary.”

“Generally, those who had lower human chorionic gonadotropin levels required less intervention, although it's hard to say what that means,” he said in an interview. “It could have been that these women were in an earlier stage of pregnancy, or we could have also caught them at a later stage, when the pregnancy was already failing and the hormones were already on the way down.”

Ultrasound can identify more than 80% of cases in time for therapy.

Source Courtesy Dr. Valerie Shavell

KISSIMMEE, FLA. — Women who present with vaginal bleeding—with or without abdominal pain—in the first trimester of pregnancy should undergo an ultrasound scan to rule out an ectopic pregnancy in the cervix, according to Dr. Valerie Shavell.

Because cervical pregnancy is so rare—about 1 in 9,000 pregnancies—it may not be on the diagnostic radar when a woman arrives in the emergency department with such common symptoms. Thus, a cervical pregnancy can easily be misdiagnosed as a threatened spontaneous abortion, she said at the annual meeting of the AAGL.

If the patient is then discharged under watchful waiting, rupture may occur with a potentially fatal bleed. Hemorrhage is also possible if she undergoes a dilation and curettage for a suspected threatened abortion. Either way, the outcome may be a hysterectomy, said Dr. Shavell of Wayne State University, Detroit.

Ultrasound can identify more than 80% of cervical pregnancies in time for medical or minimally invasive therapy, which can prevent hysterectomy and preserve fertility, said Dr. Shavell and her colleague, Dr. Mark Zakaria.

Dr. Shavell discussed symptoms and ultrasound findings in a case series of 14 women (mean age 32 years) who were treated for cervical pregnancy at the Detroit Medical Center over a 10-year period. Most of the patients (eight) presented directly to the hospital's emergency department. Four were transferred from other hospitals, and two were admitted from the resident clinic. Their mean gravidity was 5, and their mean parity was 2.

Consistent with the area's demographics, 71% were black. Eleven of the women had a risk factor for cervical pregnancy: prior termination of pregnancy (9), cesarean section (4), or cervical cone biopsy (2). The gestational age at presentation ranged from 5 to 11 weeks.

All patients presented with vaginal bleeding, which was mild in seven, moderate in four, and heavy with clots in three. Six patients also reported some abdominal pain or cramping.

“In all cases, ultrasound identified a gestational sac and yolk sac consistent with the gestational age as measured by the last menstrual period,” Dr. Shavell said. “We also saw prominent vascularity surrounding the gestational sac in every case.”

Fetal heart activity was present in 64%. The distance between the external cervical os and the leading edge of the gestational sac ranged from 7 to 25 mm.

Dr. Zakaria reported treatment outcomes for all 14 of the patients, plus 1 additional patient. All received the first-line therapy of methotrexate and leucovorin (used to protect healthy cells from methotrexate); this was sufficient to terminate the pregnancy in five. Six women received additional therapy and also underwent a uterine artery embolization. In four patients, the methotrexate combination was delivered in conjunction with a fetal intraembryonic potassium chloride injection, followed by uterine artery embolization.

It's important to carefully assess both the patient and the services available to her while making treatment decisions, Dr. Zakaria said. “Methotrexate is a reasonable first-line therapy. It's easy to administer and can be given in any hospital. The other treatments require an interventional radiologist, who might not always be available at a community hospital. If the patient comes to the emergency department and the physician suspects a cervical pregnancy, that physician should consider whether the hospital is equipped to do these interventions, or whether a transfer might be necessary.”

“Generally, those who had lower human chorionic gonadotropin levels required less intervention, although it's hard to say what that means,” he said in an interview. “It could have been that these women were in an earlier stage of pregnancy, or we could have also caught them at a later stage, when the pregnancy was already failing and the hormones were already on the way down.”

Ultrasound can identify more than 80% of cases in time for therapy.

Source Courtesy Dr. Valerie Shavell

KISSIMMEE, FLA. — Women who present with vaginal bleeding—with or without abdominal pain—in the first trimester of pregnancy should undergo an ultrasound scan to rule out an ectopic pregnancy in the cervix, according to Dr. Valerie Shavell.

Because cervical pregnancy is so rare—about 1 in 9,000 pregnancies—it may not be on the diagnostic radar when a woman arrives in the emergency department with such common symptoms. Thus, a cervical pregnancy can easily be misdiagnosed as a threatened spontaneous abortion, she said at the annual meeting of the AAGL.

If the patient is then discharged under watchful waiting, rupture may occur with a potentially fatal bleed. Hemorrhage is also possible if she undergoes a dilation and curettage for a suspected threatened abortion. Either way, the outcome may be a hysterectomy, said Dr. Shavell of Wayne State University, Detroit.

Ultrasound can identify more than 80% of cervical pregnancies in time for medical or minimally invasive therapy, which can prevent hysterectomy and preserve fertility, said Dr. Shavell and her colleague, Dr. Mark Zakaria.

Dr. Shavell discussed symptoms and ultrasound findings in a case series of 14 women (mean age 32 years) who were treated for cervical pregnancy at the Detroit Medical Center over a 10-year period. Most of the patients (eight) presented directly to the hospital's emergency department. Four were transferred from other hospitals, and two were admitted from the resident clinic. Their mean gravidity was 5, and their mean parity was 2.

Consistent with the area's demographics, 71% were black. Eleven of the women had a risk factor for cervical pregnancy: prior termination of pregnancy (9), cesarean section (4), or cervical cone biopsy (2). The gestational age at presentation ranged from 5 to 11 weeks.

All patients presented with vaginal bleeding, which was mild in seven, moderate in four, and heavy with clots in three. Six patients also reported some abdominal pain or cramping.

“In all cases, ultrasound identified a gestational sac and yolk sac consistent with the gestational age as measured by the last menstrual period,” Dr. Shavell said. “We also saw prominent vascularity surrounding the gestational sac in every case.”

Fetal heart activity was present in 64%. The distance between the external cervical os and the leading edge of the gestational sac ranged from 7 to 25 mm.

Dr. Zakaria reported treatment outcomes for all 14 of the patients, plus 1 additional patient. All received the first-line therapy of methotrexate and leucovorin (used to protect healthy cells from methotrexate); this was sufficient to terminate the pregnancy in five. Six women received additional therapy and also underwent a uterine artery embolization. In four patients, the methotrexate combination was delivered in conjunction with a fetal intraembryonic potassium chloride injection, followed by uterine artery embolization.

It's important to carefully assess both the patient and the services available to her while making treatment decisions, Dr. Zakaria said. “Methotrexate is a reasonable first-line therapy. It's easy to administer and can be given in any hospital. The other treatments require an interventional radiologist, who might not always be available at a community hospital. If the patient comes to the emergency department and the physician suspects a cervical pregnancy, that physician should consider whether the hospital is equipped to do these interventions, or whether a transfer might be necessary.”

“Generally, those who had lower human chorionic gonadotropin levels required less intervention, although it's hard to say what that means,” he said in an interview. “It could have been that these women were in an earlier stage of pregnancy, or we could have also caught them at a later stage, when the pregnancy was already failing and the hormones were already on the way down.”

Ultrasound can identify more than 80% of cases in time for therapy.

Source Courtesy Dr. Valerie Shavell

PHILADELPHIA – The monoamine oxidase inhibitor isocarboxazid may be an effective migraine preventive as well, Dr. Bruce Corser reported in a poster presented at the International Headache Congress.

Although the open-label trial was small, with just 14 patients, all of those who completed it showed a significant decrease in migraine frequency over 20 weeks, said Dr. Corser, the medical director of Community Research, Cincinnati.

Isocarboxazid is approved for the treatment of depression. “The efficacy of antidepressants and other serotonin-modulating drugs in the treatment of migraine has suggested that monoaminergic pathways are involved in the etiology of migraine,” Dr. Corser wrote. “In addition, a recent study has identified an association between genetic polymorphisms of MAO-A and migraine.”

Dr. Corser and his colleagues included 14 patients (mean age 44 years) who had a diagnosis of migraine and a history of 3-12 migraine headaches per month for the 3 months preceding recruitment. The patients were not allowed concomitant use of antidepressants or other common anti-migraine drugs.

Isocarboxazid was started at 20 mg/day and increased as needed and tolerated to a maximum of 60 mg/day. Most of the patients tolerated a maximum dose of 20-40 mg/day.

However, adverse effects were common and caused five patients to discontinue the trial–one each for insomnia, irritability/anxiety, mood swings/fatigue, anorgasmia, and fatigue. Three other patients reported adverse events as well (fatigue, insomnia, and nosebleed), but they completed the trial.

A total of seven patients completed the final follow-up.

At baseline, patients reported an average of five migraines a month. By week 8, there was a significant reduction in frequency. By week 20, the average frequency per month was less than one.

All of the patients who completed the trial were considered responders by week 16–that is, they experienced at least a 50% decrease in migraine frequency, Dr. Corser and his colleagues reported at the meeting, which was sponsored by the International Headache Society and the American Headache Society.

“In this trial, isocarboxazid showed very robust clinical efficacy in the prophylactic treatment of migraine attack,” Dr. Corser wrote.

In addition to affecting monoaminergic neurotransmission, the drug's effect on blood pressure and vascular tone might add to its benefit in migraine, he added.

The trial was funded by Validus Pharmaceuticals of Parsippany, N.J., and Oxford Pharmaceutical Services of West Totowa, N.J.

PHILADELPHIA – The monoamine oxidase inhibitor isocarboxazid may be an effective migraine preventive as well, Dr. Bruce Corser reported in a poster presented at the International Headache Congress.

Although the open-label trial was small, with just 14 patients, all of those who completed it showed a significant decrease in migraine frequency over 20 weeks, said Dr. Corser, the medical director of Community Research, Cincinnati.

Isocarboxazid is approved for the treatment of depression. “The efficacy of antidepressants and other serotonin-modulating drugs in the treatment of migraine has suggested that monoaminergic pathways are involved in the etiology of migraine,” Dr. Corser wrote. “In addition, a recent study has identified an association between genetic polymorphisms of MAO-A and migraine.”

Dr. Corser and his colleagues included 14 patients (mean age 44 years) who had a diagnosis of migraine and a history of 3-12 migraine headaches per month for the 3 months preceding recruitment. The patients were not allowed concomitant use of antidepressants or other common anti-migraine drugs.

Isocarboxazid was started at 20 mg/day and increased as needed and tolerated to a maximum of 60 mg/day. Most of the patients tolerated a maximum dose of 20-40 mg/day.

However, adverse effects were common and caused five patients to discontinue the trial–one each for insomnia, irritability/anxiety, mood swings/fatigue, anorgasmia, and fatigue. Three other patients reported adverse events as well (fatigue, insomnia, and nosebleed), but they completed the trial.

A total of seven patients completed the final follow-up.

At baseline, patients reported an average of five migraines a month. By week 8, there was a significant reduction in frequency. By week 20, the average frequency per month was less than one.

All of the patients who completed the trial were considered responders by week 16–that is, they experienced at least a 50% decrease in migraine frequency, Dr. Corser and his colleagues reported at the meeting, which was sponsored by the International Headache Society and the American Headache Society.

“In this trial, isocarboxazid showed very robust clinical efficacy in the prophylactic treatment of migraine attack,” Dr. Corser wrote.

In addition to affecting monoaminergic neurotransmission, the drug's effect on blood pressure and vascular tone might add to its benefit in migraine, he added.

The trial was funded by Validus Pharmaceuticals of Parsippany, N.J., and Oxford Pharmaceutical Services of West Totowa, N.J.

PHILADELPHIA – The monoamine oxidase inhibitor isocarboxazid may be an effective migraine preventive as well, Dr. Bruce Corser reported in a poster presented at the International Headache Congress.

Although the open-label trial was small, with just 14 patients, all of those who completed it showed a significant decrease in migraine frequency over 20 weeks, said Dr. Corser, the medical director of Community Research, Cincinnati.

Isocarboxazid is approved for the treatment of depression. “The efficacy of antidepressants and other serotonin-modulating drugs in the treatment of migraine has suggested that monoaminergic pathways are involved in the etiology of migraine,” Dr. Corser wrote. “In addition, a recent study has identified an association between genetic polymorphisms of MAO-A and migraine.”

Dr. Corser and his colleagues included 14 patients (mean age 44 years) who had a diagnosis of migraine and a history of 3-12 migraine headaches per month for the 3 months preceding recruitment. The patients were not allowed concomitant use of antidepressants or other common anti-migraine drugs.

Isocarboxazid was started at 20 mg/day and increased as needed and tolerated to a maximum of 60 mg/day. Most of the patients tolerated a maximum dose of 20-40 mg/day.

However, adverse effects were common and caused five patients to discontinue the trial–one each for insomnia, irritability/anxiety, mood swings/fatigue, anorgasmia, and fatigue. Three other patients reported adverse events as well (fatigue, insomnia, and nosebleed), but they completed the trial.

A total of seven patients completed the final follow-up.

At baseline, patients reported an average of five migraines a month. By week 8, there was a significant reduction in frequency. By week 20, the average frequency per month was less than one.

All of the patients who completed the trial were considered responders by week 16–that is, they experienced at least a 50% decrease in migraine frequency, Dr. Corser and his colleagues reported at the meeting, which was sponsored by the International Headache Society and the American Headache Society.

“In this trial, isocarboxazid showed very robust clinical efficacy in the prophylactic treatment of migraine attack,” Dr. Corser wrote.

In addition to affecting monoaminergic neurotransmission, the drug's effect on blood pressure and vascular tone might add to its benefit in migraine, he added.

The trial was funded by Validus Pharmaceuticals of Parsippany, N.J., and Oxford Pharmaceutical Services of West Totowa, N.J.

Pregnant women consumed just as much alcohol in 2005 as they did in 1991, with 12% drinking at least once during pregnancy and 2% reporting binge drinking.

The findings illustrate the small effect of national educational programs that have been aimed at decreasing this dangerous behavior, according to the primary author, Clark Denny, Ph.D.

In Healthy People 2010, the national health agenda that was published in 2000, Dr. David Satcher, the U.S. Surgeon General at that time, set abstinence targets of 95% for alcohol and 100% for binge drinking among pregnant women.

“The prevalence of both types of drinking behavior among pregnant women remains higher than the Healthy People 2010 targets and greater progress will be needed to reach them,” Dr. Denny wrote (MMWR 2009;58:529-32).

The 15-year study found that women aged 35 to 44 years had the highest incidence of drinking during pregnancy (18%), wrote Dr. Denny, an epidemiologist from the Centers for Disease Control and Prevention. Rates were also higher in college-educated women, employed women, and unmarried women.

The study was based on data collected from 1991 to 2005 through the Behavioral Risk Factor Surveillance System surveys. These annual surveys randomly poll community-dwelling U.S. adults about behavioral health issues. The CDC study included data collected from women aged 18 to 44 years, who were asked about alcohol use (at least one drink in the last 30 days) and binge drinking (at least five drinks on any one occasion in the last 30 days).

During the 15-year period, 533,500 women were surveyed; 22,000 (4%) reported being pregnant at the time of the survey. The average annual percentage of any alcohol use among the pregnant women was 12% and did not change from 1991 to 2005. The average annual percentage of pregnant women who said they binged was 2%; again, that percentage was stable over the survey period.

From 2001 to 2005, the study also examined the relationship between drinking during pregnancy and demographic factors. Age was associated with both any drinking and binge drinking. The oldest women (35 to 44 years) had the highest drinking rate (18%), while the youngest women (18 to 24 years) had the lowest rate (9%). Age was not highly associated with binge drinking.

Education, employment, and marital status were also associated with drinking during pregnancy. Any drinking was higher in employed women than unemployed (14% vs. 8%), and in unmarried women than married women (13% vs. 10%). Binge drinking was also more common in employed than unemployed women (2% vs. 1%), and unmarried women than married women (4% vs. 1%).

The reasons for these associations are unclear, Dr. Denny wrote. “Some possible reasons include that older women might be more likely to be alcohol dependent and have more difficult abstaining while pregnant; more educated and employed women might have more discretionary money for the purchase of alcohol; and unmarried women might attend more social occasions where alcohol is served.”

The rates of drinking and binge drinking were higher among nonpregnant women (54% and 12%, respectively). Prepregnancy alcohol use is a strong predictor of use during pregnancy, and many women who drink continue to do so before realizing that they are pregnant, Dr. Denny noted. “Approximately 40% of women realize they are pregnant at 4 weeks of gestation, a critical period for fetal organ development.”

The findings confirm the need for alcohol use screening and counseling among all women, he wrote in a press statement. “By screening and advising women about the risks of drinking while pregnant, health care providers can play a key role in reducing rates of fetal alcohol syndrome. This study revealed that there is still a great need for health care professionals to routinely ask all women who are pregnant or at risk of being pregnant about their alcohol consumption.”

Pregnant women consumed just as much alcohol in 2005 as they did in 1991, with 12% drinking at least once during pregnancy and 2% reporting binge drinking.

The findings illustrate the small effect of national educational programs that have been aimed at decreasing this dangerous behavior, according to the primary author, Clark Denny, Ph.D.

In Healthy People 2010, the national health agenda that was published in 2000, Dr. David Satcher, the U.S. Surgeon General at that time, set abstinence targets of 95% for alcohol and 100% for binge drinking among pregnant women.

“The prevalence of both types of drinking behavior among pregnant women remains higher than the Healthy People 2010 targets and greater progress will be needed to reach them,” Dr. Denny wrote (MMWR 2009;58:529-32).

The 15-year study found that women aged 35 to 44 years had the highest incidence of drinking during pregnancy (18%), wrote Dr. Denny, an epidemiologist from the Centers for Disease Control and Prevention. Rates were also higher in college-educated women, employed women, and unmarried women.

The study was based on data collected from 1991 to 2005 through the Behavioral Risk Factor Surveillance System surveys. These annual surveys randomly poll community-dwelling U.S. adults about behavioral health issues. The CDC study included data collected from women aged 18 to 44 years, who were asked about alcohol use (at least one drink in the last 30 days) and binge drinking (at least five drinks on any one occasion in the last 30 days).

During the 15-year period, 533,500 women were surveyed; 22,000 (4%) reported being pregnant at the time of the survey. The average annual percentage of any alcohol use among the pregnant women was 12% and did not change from 1991 to 2005. The average annual percentage of pregnant women who said they binged was 2%; again, that percentage was stable over the survey period.

From 2001 to 2005, the study also examined the relationship between drinking during pregnancy and demographic factors. Age was associated with both any drinking and binge drinking. The oldest women (35 to 44 years) had the highest drinking rate (18%), while the youngest women (18 to 24 years) had the lowest rate (9%). Age was not highly associated with binge drinking.

Education, employment, and marital status were also associated with drinking during pregnancy. Any drinking was higher in employed women than unemployed (14% vs. 8%), and in unmarried women than married women (13% vs. 10%). Binge drinking was also more common in employed than unemployed women (2% vs. 1%), and unmarried women than married women (4% vs. 1%).

The reasons for these associations are unclear, Dr. Denny wrote. “Some possible reasons include that older women might be more likely to be alcohol dependent and have more difficult abstaining while pregnant; more educated and employed women might have more discretionary money for the purchase of alcohol; and unmarried women might attend more social occasions where alcohol is served.”

The rates of drinking and binge drinking were higher among nonpregnant women (54% and 12%, respectively). Prepregnancy alcohol use is a strong predictor of use during pregnancy, and many women who drink continue to do so before realizing that they are pregnant, Dr. Denny noted. “Approximately 40% of women realize they are pregnant at 4 weeks of gestation, a critical period for fetal organ development.”

The findings confirm the need for alcohol use screening and counseling among all women, he wrote in a press statement. “By screening and advising women about the risks of drinking while pregnant, health care providers can play a key role in reducing rates of fetal alcohol syndrome. This study revealed that there is still a great need for health care professionals to routinely ask all women who are pregnant or at risk of being pregnant about their alcohol consumption.”

Pregnant women consumed just as much alcohol in 2005 as they did in 1991, with 12% drinking at least once during pregnancy and 2% reporting binge drinking.

The findings illustrate the small effect of national educational programs that have been aimed at decreasing this dangerous behavior, according to the primary author, Clark Denny, Ph.D.

In Healthy People 2010, the national health agenda that was published in 2000, Dr. David Satcher, the U.S. Surgeon General at that time, set abstinence targets of 95% for alcohol and 100% for binge drinking among pregnant women.

“The prevalence of both types of drinking behavior among pregnant women remains higher than the Healthy People 2010 targets and greater progress will be needed to reach them,” Dr. Denny wrote (MMWR 2009;58:529-32).

The 15-year study found that women aged 35 to 44 years had the highest incidence of drinking during pregnancy (18%), wrote Dr. Denny, an epidemiologist from the Centers for Disease Control and Prevention. Rates were also higher in college-educated women, employed women, and unmarried women.

The study was based on data collected from 1991 to 2005 through the Behavioral Risk Factor Surveillance System surveys. These annual surveys randomly poll community-dwelling U.S. adults about behavioral health issues. The CDC study included data collected from women aged 18 to 44 years, who were asked about alcohol use (at least one drink in the last 30 days) and binge drinking (at least five drinks on any one occasion in the last 30 days).

During the 15-year period, 533,500 women were surveyed; 22,000 (4%) reported being pregnant at the time of the survey. The average annual percentage of any alcohol use among the pregnant women was 12% and did not change from 1991 to 2005. The average annual percentage of pregnant women who said they binged was 2%; again, that percentage was stable over the survey period.

From 2001 to 2005, the study also examined the relationship between drinking during pregnancy and demographic factors. Age was associated with both any drinking and binge drinking. The oldest women (35 to 44 years) had the highest drinking rate (18%), while the youngest women (18 to 24 years) had the lowest rate (9%). Age was not highly associated with binge drinking.

Education, employment, and marital status were also associated with drinking during pregnancy. Any drinking was higher in employed women than unemployed (14% vs. 8%), and in unmarried women than married women (13% vs. 10%). Binge drinking was also more common in employed than unemployed women (2% vs. 1%), and unmarried women than married women (4% vs. 1%).

The reasons for these associations are unclear, Dr. Denny wrote. “Some possible reasons include that older women might be more likely to be alcohol dependent and have more difficult abstaining while pregnant; more educated and employed women might have more discretionary money for the purchase of alcohol; and unmarried women might attend more social occasions where alcohol is served.”

The rates of drinking and binge drinking were higher among nonpregnant women (54% and 12%, respectively). Prepregnancy alcohol use is a strong predictor of use during pregnancy, and many women who drink continue to do so before realizing that they are pregnant, Dr. Denny noted. “Approximately 40% of women realize they are pregnant at 4 weeks of gestation, a critical period for fetal organ development.”

The findings confirm the need for alcohol use screening and counseling among all women, he wrote in a press statement. “By screening and advising women about the risks of drinking while pregnant, health care providers can play a key role in reducing rates of fetal alcohol syndrome. This study revealed that there is still a great need for health care professionals to routinely ask all women who are pregnant or at risk of being pregnant about their alcohol consumption.”

VIENNA – Docosahexaenoic acid might improve memory in elderly subjects with mild memory complaints, but the nutritional supplement has no beneficial effect in those with Alzheimer's disease, two randomized, placebo-controlled trials have determined.

Although docosahexaenoic acid (DHA) did slow cognitive decline in a subset of Alzheimer's patients who carried the ApoE4 gene, the nonsignificant finding is not enough to recommend the supplement as a possible therapy, Dr. Joseph F. Quinn said at the International Conference on Alzheimer's Disease. “This is an intriguing exploratory result,” said Dr. Quinn, primary investigator of the National Institute on Aging–supported trial. “However, it must be treated with appropriate caution.” Overall, he said, “these results do not support the routine use of DHA for patients with Alzheimer's.”

The second study, which examined DHA's effect on memory performance in normal subjects with mild, age-related memory difficulties, concluded that the supplement did significantly improve performance on a memory test. This finding suggests that DHA may offer some benefit very early in the disease process, said Dr. Marwan Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz.

“The data suggest that DHA may serve to reduce risk by perhaps facilitating neuronal health,” Dr. Sabbagh said in an interview. “However, it appears that once symptomatic Alzheimer's is present, the critical mass of pathology may be too much for even DHA to offset.”

Dr. Samuel Gandy, the Mount Sinai Professor of Alzheimer's Disease Research at the Mount Sinai School of Medicine, New York, agreed. “I would conclude that there is no consensus indicating any obvious meaningful benefit,” for DHA treatment in Alzheimer's, he said in an interview.

The federally sponsored DHA trial in Alzheimer's patients was part of the national Alzheimer's Disease Cooperative Study. Dr. Quinn, of the Oregon Health & Science University, Portland, and his colleagues conducted a randomized, placebo-controlled trial that comprised 402 patients with mild to moderate Alzheimer's; they were randomized to either placebo or 2 g DHA per day for 18 months.

The patients' mean age was 76 years; their mean score on the Mini-Mental State Exam (MMSE) was 21. Almost 60% were positive for the ApoE4 gene. Primary outcomes were changes in the MMSE, the Alzheimer's disease Assessment Scale-cognitive domain (ADAS-cog), the Clinical Dementia Rating (CDR), and the Nurse Psychiatric Inventory (NPI).

“Although DHA had a modest benefit on the ADAS-cog score compared to placebo at 12 months, there was no significant difference between the two by the end of the study,” Dr. Quinn said. “If you compared the scores at 12 months, they were statistically significantly different, but that was not a planned finding so it's nothing we can hang our hats on.”

Both the CDR and ADAS-cog scores showed sharp, linear declines that were virtually identical in both groups. There were no significant differences in either the MMSE or NPI scores at the end of the trial.

When the group was stratified by ApoE4 status, the researchers did identify a trend toward a slower rate of decline on both the MMSE and ADAS-cog among ApoE4-negative patients taking DHA. “It appears that there was some effect in the treatment group,” Dr. Quinn said. “However, we have to remember that this analysis is a preliminary finding, and we don't think it's likely to hold up after adjustment” for possible confounding factors.

The second trial was sponsored by Martek Biosciences Corp. of Columbia, Md. Karin Yurko-Mauro, Ph.D., and her colleagues randomized 485 healthy older people with mild memory complaint to either placebo or 900 mg/day DHA. The primary outcome measure was a change from baseline on the CANTAB Paired Associate Learning (PAL), a visuo spatial episodic memory test.

At baseline, the subjects' mean age was 70 years; they had a mean of 15 years of education. Most (84%) were white. The mean baseline MMSE was 28.

After 18 months of therapy, subjects taking DHA performed significantly better on the PAL than those taking placebo. The DHA group made an average of four fewer errors on the PAL than they did at baseline, while those taking placebo made an average of two fewer errors on the subsequent test–a significant difference. “The benefit is roughly equivalent to having the learning and memory skills of someone 3 years younger,” Dr. Yurko-Mauro said.

Patients taking DHA also experienced a significant decrease in heart rate from baseline of three fewer beats per minute, while those taking placebo experienced a decrease of just one beat per minute. Blood pressure and body weight were unchanged in both groups. There were no treatment-related adverse events.

Dr. Yurko-Mauro is the associate director of clinical studies at Martek Biosciences, which sponsored the study; Dr. Quinn reported no potential conflict of interest.

The meeting was sponsored by the Alzheimer's Association.

VIENNA – Docosahexaenoic acid might improve memory in elderly subjects with mild memory complaints, but the nutritional supplement has no beneficial effect in those with Alzheimer's disease, two randomized, placebo-controlled trials have determined.

Although docosahexaenoic acid (DHA) did slow cognitive decline in a subset of Alzheimer's patients who carried the ApoE4 gene, the nonsignificant finding is not enough to recommend the supplement as a possible therapy, Dr. Joseph F. Quinn said at the International Conference on Alzheimer's Disease. “This is an intriguing exploratory result,” said Dr. Quinn, primary investigator of the National Institute on Aging–supported trial. “However, it must be treated with appropriate caution.” Overall, he said, “these results do not support the routine use of DHA for patients with Alzheimer's.”

The second study, which examined DHA's effect on memory performance in normal subjects with mild, age-related memory difficulties, concluded that the supplement did significantly improve performance on a memory test. This finding suggests that DHA may offer some benefit very early in the disease process, said Dr. Marwan Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz.

“The data suggest that DHA may serve to reduce risk by perhaps facilitating neuronal health,” Dr. Sabbagh said in an interview. “However, it appears that once symptomatic Alzheimer's is present, the critical mass of pathology may be too much for even DHA to offset.”

Dr. Samuel Gandy, the Mount Sinai Professor of Alzheimer's Disease Research at the Mount Sinai School of Medicine, New York, agreed. “I would conclude that there is no consensus indicating any obvious meaningful benefit,” for DHA treatment in Alzheimer's, he said in an interview.

The federally sponsored DHA trial in Alzheimer's patients was part of the national Alzheimer's Disease Cooperative Study. Dr. Quinn, of the Oregon Health & Science University, Portland, and his colleagues conducted a randomized, placebo-controlled trial that comprised 402 patients with mild to moderate Alzheimer's; they were randomized to either placebo or 2 g DHA per day for 18 months.

The patients' mean age was 76 years; their mean score on the Mini-Mental State Exam (MMSE) was 21. Almost 60% were positive for the ApoE4 gene. Primary outcomes were changes in the MMSE, the Alzheimer's disease Assessment Scale-cognitive domain (ADAS-cog), the Clinical Dementia Rating (CDR), and the Nurse Psychiatric Inventory (NPI).

“Although DHA had a modest benefit on the ADAS-cog score compared to placebo at 12 months, there was no significant difference between the two by the end of the study,” Dr. Quinn said. “If you compared the scores at 12 months, they were statistically significantly different, but that was not a planned finding so it's nothing we can hang our hats on.”

Both the CDR and ADAS-cog scores showed sharp, linear declines that were virtually identical in both groups. There were no significant differences in either the MMSE or NPI scores at the end of the trial.

When the group was stratified by ApoE4 status, the researchers did identify a trend toward a slower rate of decline on both the MMSE and ADAS-cog among ApoE4-negative patients taking DHA. “It appears that there was some effect in the treatment group,” Dr. Quinn said. “However, we have to remember that this analysis is a preliminary finding, and we don't think it's likely to hold up after adjustment” for possible confounding factors.

The second trial was sponsored by Martek Biosciences Corp. of Columbia, Md. Karin Yurko-Mauro, Ph.D., and her colleagues randomized 485 healthy older people with mild memory complaint to either placebo or 900 mg/day DHA. The primary outcome measure was a change from baseline on the CANTAB Paired Associate Learning (PAL), a visuo spatial episodic memory test.

At baseline, the subjects' mean age was 70 years; they had a mean of 15 years of education. Most (84%) were white. The mean baseline MMSE was 28.

After 18 months of therapy, subjects taking DHA performed significantly better on the PAL than those taking placebo. The DHA group made an average of four fewer errors on the PAL than they did at baseline, while those taking placebo made an average of two fewer errors on the subsequent test–a significant difference. “The benefit is roughly equivalent to having the learning and memory skills of someone 3 years younger,” Dr. Yurko-Mauro said.

Patients taking DHA also experienced a significant decrease in heart rate from baseline of three fewer beats per minute, while those taking placebo experienced a decrease of just one beat per minute. Blood pressure and body weight were unchanged in both groups. There were no treatment-related adverse events.

Dr. Yurko-Mauro is the associate director of clinical studies at Martek Biosciences, which sponsored the study; Dr. Quinn reported no potential conflict of interest.

The meeting was sponsored by the Alzheimer's Association.

VIENNA – Docosahexaenoic acid might improve memory in elderly subjects with mild memory complaints, but the nutritional supplement has no beneficial effect in those with Alzheimer's disease, two randomized, placebo-controlled trials have determined.

Although docosahexaenoic acid (DHA) did slow cognitive decline in a subset of Alzheimer's patients who carried the ApoE4 gene, the nonsignificant finding is not enough to recommend the supplement as a possible therapy, Dr. Joseph F. Quinn said at the International Conference on Alzheimer's Disease. “This is an intriguing exploratory result,” said Dr. Quinn, primary investigator of the National Institute on Aging–supported trial. “However, it must be treated with appropriate caution.” Overall, he said, “these results do not support the routine use of DHA for patients with Alzheimer's.”

The second study, which examined DHA's effect on memory performance in normal subjects with mild, age-related memory difficulties, concluded that the supplement did significantly improve performance on a memory test. This finding suggests that DHA may offer some benefit very early in the disease process, said Dr. Marwan Sabbagh, director of clinical research at the Sun Health Research Institute, Sun City, Ariz.

“The data suggest that DHA may serve to reduce risk by perhaps facilitating neuronal health,” Dr. Sabbagh said in an interview. “However, it appears that once symptomatic Alzheimer's is present, the critical mass of pathology may be too much for even DHA to offset.”

Dr. Samuel Gandy, the Mount Sinai Professor of Alzheimer's Disease Research at the Mount Sinai School of Medicine, New York, agreed. “I would conclude that there is no consensus indicating any obvious meaningful benefit,” for DHA treatment in Alzheimer's, he said in an interview.

The federally sponsored DHA trial in Alzheimer's patients was part of the national Alzheimer's Disease Cooperative Study. Dr. Quinn, of the Oregon Health & Science University, Portland, and his colleagues conducted a randomized, placebo-controlled trial that comprised 402 patients with mild to moderate Alzheimer's; they were randomized to either placebo or 2 g DHA per day for 18 months.

The patients' mean age was 76 years; their mean score on the Mini-Mental State Exam (MMSE) was 21. Almost 60% were positive for the ApoE4 gene. Primary outcomes were changes in the MMSE, the Alzheimer's disease Assessment Scale-cognitive domain (ADAS-cog), the Clinical Dementia Rating (CDR), and the Nurse Psychiatric Inventory (NPI).

“Although DHA had a modest benefit on the ADAS-cog score compared to placebo at 12 months, there was no significant difference between the two by the end of the study,” Dr. Quinn said. “If you compared the scores at 12 months, they were statistically significantly different, but that was not a planned finding so it's nothing we can hang our hats on.”

Both the CDR and ADAS-cog scores showed sharp, linear declines that were virtually identical in both groups. There were no significant differences in either the MMSE or NPI scores at the end of the trial.

When the group was stratified by ApoE4 status, the researchers did identify a trend toward a slower rate of decline on both the MMSE and ADAS-cog among ApoE4-negative patients taking DHA. “It appears that there was some effect in the treatment group,” Dr. Quinn said. “However, we have to remember that this analysis is a preliminary finding, and we don't think it's likely to hold up after adjustment” for possible confounding factors.

The second trial was sponsored by Martek Biosciences Corp. of Columbia, Md. Karin Yurko-Mauro, Ph.D., and her colleagues randomized 485 healthy older people with mild memory complaint to either placebo or 900 mg/day DHA. The primary outcome measure was a change from baseline on the CANTAB Paired Associate Learning (PAL), a visuo spatial episodic memory test.

At baseline, the subjects' mean age was 70 years; they had a mean of 15 years of education. Most (84%) were white. The mean baseline MMSE was 28.

After 18 months of therapy, subjects taking DHA performed significantly better on the PAL than those taking placebo. The DHA group made an average of four fewer errors on the PAL than they did at baseline, while those taking placebo made an average of two fewer errors on the subsequent test–a significant difference. “The benefit is roughly equivalent to having the learning and memory skills of someone 3 years younger,” Dr. Yurko-Mauro said.

Patients taking DHA also experienced a significant decrease in heart rate from baseline of three fewer beats per minute, while those taking placebo experienced a decrease of just one beat per minute. Blood pressure and body weight were unchanged in both groups. There were no treatment-related adverse events.

Dr. Yurko-Mauro is the associate director of clinical studies at Martek Biosciences, which sponsored the study; Dr. Quinn reported no potential conflict of interest.

The meeting was sponsored by the Alzheimer's Association.

HOT SPRINGS, VA. — Delaying gallbladder surgery in elderly patients with acute cholecystitis might save money in the short run, but it racks up a bigger bill later in health outcomes and cash outlay, judging by a Medicare claims database study.

Early surgery significantly reduced cholecystitis recurrence and emergency gallstone-related readmissions, saving Medicare $7,000 for each avoided readmission, Dr. Taylor S. Riall said at the annual meeting of the Southern Surgical Association.

“Our study will be relevant to policy issues such as episode of care reimbursement and determination of quality of care at the patient, physician, and hospital level,” said Dr. Riall of the University of Texas Medical Branch at Galveston. “Locally, we have already used these data to implement a pathway to maximize cholecystectomy rates during initial emergency admission.”

Dr. Riall and her colleagues tracked Medicare claims data for almost 30,000 elderly patients (mean age 78 years) who were admitted for acute cholecystitis from 1996 to 2005. They examined cost and health outcomes for 24 months after the admission.

Most patients (89%) were white. More than half of the admissions (64%) were emergent; 36% were urgent.

The majority of the patients (75%) underwent cholecystectomy during their initial hospitalization, and 71% of the procedures were laparoscopic. The median length of stay was 5 days, and the median Medicare payment was $7,362. There was a 2% in-hospital mortality rate.

For the 25% of patients who did not undergo surgery during their initial hospitalization, the median hospital length of stay was 4 days and the median Medicare payment was $4,251. However, Dr. Riall said, surgical patients had significantly fewer rehospitalizations over the 24-month follow-up period than did nonsurgical patients. Of the 21,907 who had the surgery and were discharged alive, 1.6% (352 patients) were rehospitalized for gallstone-related problems and 2.5% (556 patients) for surgical complications. The overall Kaplan-Meier readmission rate in this group was 4.4%, with all readmissions occurring in the first 60 days postoperatively; the median Medicare payment for each readmission was $5,000.

These measures were all significantly different among patients who initially did not undergo cholecystectomy. Among the 7,250 who were discharged alive, 1,980 (27%) were later rehospitalized for gallbladder problems and 1,604 (22%) died in the 2 years following initial hospitalization. The Kaplan-Meier 2-year readmission rate was 38%, after adjustment for patient deaths. Of the patients readmitted for gallstone-related problems, 1,372 (19% of the discharged group) underwent a cholecystectomy and 608 (8%) did not. The median Medicare payment for readmission was $7,000. Another 694 patients (9.6%) had a later cholecystectomy on an outpatient basis.

Mortality rates during the next 24 months also were significantly different between the groups: 15% for those who had surgery during initial hospitalization vs. 29% for those who did not. “The survival difference was significant even after controlling for patient comorbidities; patients who did not undergo cholecystectomy were 56% more likely to die,” Dr. Riall said.

Although the survival difference was significant, Dr. Riall warned against making too many assumptions about mortality. “It's almost certain that most patients who did not undergo cholecystectomy were sicker and had a higher 2-year mortality without cholecystitis,” she said.

Several factors significantly influenced whether surgery was performed during the initial hospitalization. Every 5 years of advancing age decreased by 17% the chance that a patient would have surgery. Black patients were 32% less likely to have the operation than were white patients, and women were 6% less likely than men. Patients admitted by a gastroenterologist were 48% less likely to have surgery than those admitted by a surgeon.

Disclosures: Dr. Riall did not have any relevant financial disclosures.

HOT SPRINGS, VA. — Delaying gallbladder surgery in elderly patients with acute cholecystitis might save money in the short run, but it racks up a bigger bill later in health outcomes and cash outlay, judging by a Medicare claims database study.

Early surgery significantly reduced cholecystitis recurrence and emergency gallstone-related readmissions, saving Medicare $7,000 for each avoided readmission, Dr. Taylor S. Riall said at the annual meeting of the Southern Surgical Association.

“Our study will be relevant to policy issues such as episode of care reimbursement and determination of quality of care at the patient, physician, and hospital level,” said Dr. Riall of the University of Texas Medical Branch at Galveston. “Locally, we have already used these data to implement a pathway to maximize cholecystectomy rates during initial emergency admission.”

Dr. Riall and her colleagues tracked Medicare claims data for almost 30,000 elderly patients (mean age 78 years) who were admitted for acute cholecystitis from 1996 to 2005. They examined cost and health outcomes for 24 months after the admission.

Most patients (89%) were white. More than half of the admissions (64%) were emergent; 36% were urgent.

The majority of the patients (75%) underwent cholecystectomy during their initial hospitalization, and 71% of the procedures were laparoscopic. The median length of stay was 5 days, and the median Medicare payment was $7,362. There was a 2% in-hospital mortality rate.

For the 25% of patients who did not undergo surgery during their initial hospitalization, the median hospital length of stay was 4 days and the median Medicare payment was $4,251. However, Dr. Riall said, surgical patients had significantly fewer rehospitalizations over the 24-month follow-up period than did nonsurgical patients. Of the 21,907 who had the surgery and were discharged alive, 1.6% (352 patients) were rehospitalized for gallstone-related problems and 2.5% (556 patients) for surgical complications. The overall Kaplan-Meier readmission rate in this group was 4.4%, with all readmissions occurring in the first 60 days postoperatively; the median Medicare payment for each readmission was $5,000.

These measures were all significantly different among patients who initially did not undergo cholecystectomy. Among the 7,250 who were discharged alive, 1,980 (27%) were later rehospitalized for gallbladder problems and 1,604 (22%) died in the 2 years following initial hospitalization. The Kaplan-Meier 2-year readmission rate was 38%, after adjustment for patient deaths. Of the patients readmitted for gallstone-related problems, 1,372 (19% of the discharged group) underwent a cholecystectomy and 608 (8%) did not. The median Medicare payment for readmission was $7,000. Another 694 patients (9.6%) had a later cholecystectomy on an outpatient basis.

Mortality rates during the next 24 months also were significantly different between the groups: 15% for those who had surgery during initial hospitalization vs. 29% for those who did not. “The survival difference was significant even after controlling for patient comorbidities; patients who did not undergo cholecystectomy were 56% more likely to die,” Dr. Riall said.

Although the survival difference was significant, Dr. Riall warned against making too many assumptions about mortality. “It's almost certain that most patients who did not undergo cholecystectomy were sicker and had a higher 2-year mortality without cholecystitis,” she said.

Several factors significantly influenced whether surgery was performed during the initial hospitalization. Every 5 years of advancing age decreased by 17% the chance that a patient would have surgery. Black patients were 32% less likely to have the operation than were white patients, and women were 6% less likely than men. Patients admitted by a gastroenterologist were 48% less likely to have surgery than those admitted by a surgeon.

Disclosures: Dr. Riall did not have any relevant financial disclosures.

HOT SPRINGS, VA. — Delaying gallbladder surgery in elderly patients with acute cholecystitis might save money in the short run, but it racks up a bigger bill later in health outcomes and cash outlay, judging by a Medicare claims database study.

Early surgery significantly reduced cholecystitis recurrence and emergency gallstone-related readmissions, saving Medicare $7,000 for each avoided readmission, Dr. Taylor S. Riall said at the annual meeting of the Southern Surgical Association.

“Our study will be relevant to policy issues such as episode of care reimbursement and determination of quality of care at the patient, physician, and hospital level,” said Dr. Riall of the University of Texas Medical Branch at Galveston. “Locally, we have already used these data to implement a pathway to maximize cholecystectomy rates during initial emergency admission.”

Dr. Riall and her colleagues tracked Medicare claims data for almost 30,000 elderly patients (mean age 78 years) who were admitted for acute cholecystitis from 1996 to 2005. They examined cost and health outcomes for 24 months after the admission.

Most patients (89%) were white. More than half of the admissions (64%) were emergent; 36% were urgent.

The majority of the patients (75%) underwent cholecystectomy during their initial hospitalization, and 71% of the procedures were laparoscopic. The median length of stay was 5 days, and the median Medicare payment was $7,362. There was a 2% in-hospital mortality rate.

For the 25% of patients who did not undergo surgery during their initial hospitalization, the median hospital length of stay was 4 days and the median Medicare payment was $4,251. However, Dr. Riall said, surgical patients had significantly fewer rehospitalizations over the 24-month follow-up period than did nonsurgical patients. Of the 21,907 who had the surgery and were discharged alive, 1.6% (352 patients) were rehospitalized for gallstone-related problems and 2.5% (556 patients) for surgical complications. The overall Kaplan-Meier readmission rate in this group was 4.4%, with all readmissions occurring in the first 60 days postoperatively; the median Medicare payment for each readmission was $5,000.

These measures were all significantly different among patients who initially did not undergo cholecystectomy. Among the 7,250 who were discharged alive, 1,980 (27%) were later rehospitalized for gallbladder problems and 1,604 (22%) died in the 2 years following initial hospitalization. The Kaplan-Meier 2-year readmission rate was 38%, after adjustment for patient deaths. Of the patients readmitted for gallstone-related problems, 1,372 (19% of the discharged group) underwent a cholecystectomy and 608 (8%) did not. The median Medicare payment for readmission was $7,000. Another 694 patients (9.6%) had a later cholecystectomy on an outpatient basis.

Mortality rates during the next 24 months also were significantly different between the groups: 15% for those who had surgery during initial hospitalization vs. 29% for those who did not. “The survival difference was significant even after controlling for patient comorbidities; patients who did not undergo cholecystectomy were 56% more likely to die,” Dr. Riall said.

Although the survival difference was significant, Dr. Riall warned against making too many assumptions about mortality. “It's almost certain that most patients who did not undergo cholecystectomy were sicker and had a higher 2-year mortality without cholecystitis,” she said.

Several factors significantly influenced whether surgery was performed during the initial hospitalization. Every 5 years of advancing age decreased by 17% the chance that a patient would have surgery. Black patients were 32% less likely to have the operation than were white patients, and women were 6% less likely than men. Patients admitted by a gastroenterologist were 48% less likely to have surgery than those admitted by a surgeon.

Disclosures: Dr. Riall did not have any relevant financial disclosures.

BANGKOK, THAILAND — Many cases of encephalitis lack pathologic evidence for a specific etiology even though methods for detecting infectious agents have improved, suggesting that new infectious agents could be the source of some cases, according to the results of two studies.

Julia Granerod reviewed the etiology of encephalitis in 45 studies and concluded that the cause of up to 65% of cases remains a mystery. Because methodologic differences among the studies did not account for the unknown cases, other causes must be considered.

“It's important to consider the incidence in a global context, because with the threat of newly emerging infectious agents, increasing international travel, and global warming, there may be shifts in incidence over time,” Ms. Granerod said at the World Congress of Neurology.

Her colleague, Dr. Nicholas Davies, a fellow in neurology at St. Vincent's Hospital, Sydney, came to a similar conclusion in his prospective study of encephalitis etiology. In the largest proportion of cases (38%), no infectious or inflammatory cause for the disease could be determined.

In her review, Ms. Granerod, the national scientific coordinator of the U.K. Health Protection Agency Centre for Infections, included studies from Asia, Africa, Europe, and North America. Encephalitis incidence ranged from 0.07 to 12.6/100,000 per year. She also found that the incidence significantly decreased over time, due to the introduction of vaccines for some encephalitis vectors, such as Japanese encephalitis, yellow fever, and tick-borne encephalitis.

Etiology varied by geography. The most common etiology in Asia was Japanese encephalitis, whereas in Europe most cases were caused by herpes simplex viruses (HSV) and varicella zoster virus (VZV). Mycoplasma pneumoniae also caused a significant amount of encephalitis in Europe. In North America, insect vectors (ticks and mosquitoes) contributed the greatest number of identifiable cases.

The etiology was unknown in 65% of the North American cases, 43% of the European cases, and 59% of the Asian cases. “The most striking thing was that in 63% of the studies, more than 50% of the cases had an unknown etiology,” Ms. Granerod said. “That is a very significant finding.”

To determine the effect of methodologic differences between the studies, she conducted a multivariate regression analysis. “We considered year—the more sensitive diagnostic methods, such as polymerase chain reaction, were started in the mid-90s, so studies conducted after that should have had a lower proportion of unknown etiology. We also considered age, continent, subsyndrome, the number of agents tested for, whether the study was retrospective or prospective, and the case definition.”

Only year, continent, and subsyndrome remained significantly associated with etiology. “These findings support an emerging unknown etiology of encephalitis,” she said.

The review's findings may be more fully explained by a soon-to-be-published U.K. trial. The Etiology of Encephalitis in England study, sponsored by the country's Health Protection Agency, included patients recruited over a 4-year period from 18 hospitals and neurology centers in the U.K. Preliminary observations suggest that many of the cases with unknown etiology may be immune-mediated, most notably by antibodies associated with the N-methyl D-aspartate receptors, Ms. Granerod said.

While he was a research fellow at Guy's & St. Thomas' Hospital, London, Dr. Davies and his colleagues prospectively studied 61 adult patients with encephalitis treated at any of three London hospitals. In addition to describing the disease etiology, the researchers obtained clinical outcomes and quality of life data on the patients after discharge.

Of the 61 patients, 46% were female; the mean age was 40 years. The researchers analyzed 91 cerebrospinal fluid samples, including 52 that were obtained in the first 14 days and 39 that were obtained after 2 weeks.

An identifiable infectious etiology was found in 21 (34%) patients. Those were HSV (15), VZV (2), a combination of HSV and VZV (1), and Toxoplasma gondii (1) and bacterial infections (2). A noninfectious, inflammatory etiology was noted in 14 patients (23%). These included acute disseminated encephalomyelitis (6), fulminant multiple sclerosis (3), antiphospholipid syndrome (2), antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (2) and a paraneoplastic encephalitis (1). Three (5%) patients had other identifiable etiologies.

The etiology was unknown in 23 (38%) patients. Three of these patients had Epstein-Barr virus in their blood, but the viral load was less than 50 copies/million leukocytes, which was too low to cause symptoms. Two patients had herpesvirus 7, but there was no evidence of a primary infection.

The subgroups were similar in terms of clinical findings, with the exception of fever. Patients with an infectious etiology had higher temperatures at admission than did those with inflammatory, unknown, or other causes.

Overall mortality was 21%, and was highest among those with inflammatory causes (43%). Mortality rates were 14% in those with infections and 9% in those with an unknown etiology.

After a mean follow-up of 20 months, morbidity was significantly better in the unknown etiology group than in the infectious and inflammatory groups. The Glasgow Outcomes Score was less than 4 in 67% of patients in the infectious group, 57% of the inflammatory group, and 24% of the unknown group.

Disclosures: Ms. Granerod reported no relevant disclosures; her review was funded by the Health Protection Agency. Dr. Davies reported no relevant disclosures; his study was funded by the Charitable Foundation of Guy's and St. Thomas' Hospital.

BANGKOK, THAILAND — Many cases of encephalitis lack pathologic evidence for a specific etiology even though methods for detecting infectious agents have improved, suggesting that new infectious agents could be the source of some cases, according to the results of two studies.

Julia Granerod reviewed the etiology of encephalitis in 45 studies and concluded that the cause of up to 65% of cases remains a mystery. Because methodologic differences among the studies did not account for the unknown cases, other causes must be considered.

“It's important to consider the incidence in a global context, because with the threat of newly emerging infectious agents, increasing international travel, and global warming, there may be shifts in incidence over time,” Ms. Granerod said at the World Congress of Neurology.

Her colleague, Dr. Nicholas Davies, a fellow in neurology at St. Vincent's Hospital, Sydney, came to a similar conclusion in his prospective study of encephalitis etiology. In the largest proportion of cases (38%), no infectious or inflammatory cause for the disease could be determined.

In her review, Ms. Granerod, the national scientific coordinator of the U.K. Health Protection Agency Centre for Infections, included studies from Asia, Africa, Europe, and North America. Encephalitis incidence ranged from 0.07 to 12.6/100,000 per year. She also found that the incidence significantly decreased over time, due to the introduction of vaccines for some encephalitis vectors, such as Japanese encephalitis, yellow fever, and tick-borne encephalitis.

Etiology varied by geography. The most common etiology in Asia was Japanese encephalitis, whereas in Europe most cases were caused by herpes simplex viruses (HSV) and varicella zoster virus (VZV). Mycoplasma pneumoniae also caused a significant amount of encephalitis in Europe. In North America, insect vectors (ticks and mosquitoes) contributed the greatest number of identifiable cases.

The etiology was unknown in 65% of the North American cases, 43% of the European cases, and 59% of the Asian cases. “The most striking thing was that in 63% of the studies, more than 50% of the cases had an unknown etiology,” Ms. Granerod said. “That is a very significant finding.”

To determine the effect of methodologic differences between the studies, she conducted a multivariate regression analysis. “We considered year—the more sensitive diagnostic methods, such as polymerase chain reaction, were started in the mid-90s, so studies conducted after that should have had a lower proportion of unknown etiology. We also considered age, continent, subsyndrome, the number of agents tested for, whether the study was retrospective or prospective, and the case definition.”

Only year, continent, and subsyndrome remained significantly associated with etiology. “These findings support an emerging unknown etiology of encephalitis,” she said.

The review's findings may be more fully explained by a soon-to-be-published U.K. trial. The Etiology of Encephalitis in England study, sponsored by the country's Health Protection Agency, included patients recruited over a 4-year period from 18 hospitals and neurology centers in the U.K. Preliminary observations suggest that many of the cases with unknown etiology may be immune-mediated, most notably by antibodies associated with the N-methyl D-aspartate receptors, Ms. Granerod said.

While he was a research fellow at Guy's & St. Thomas' Hospital, London, Dr. Davies and his colleagues prospectively studied 61 adult patients with encephalitis treated at any of three London hospitals. In addition to describing the disease etiology, the researchers obtained clinical outcomes and quality of life data on the patients after discharge.

Of the 61 patients, 46% were female; the mean age was 40 years. The researchers analyzed 91 cerebrospinal fluid samples, including 52 that were obtained in the first 14 days and 39 that were obtained after 2 weeks.

An identifiable infectious etiology was found in 21 (34%) patients. Those were HSV (15), VZV (2), a combination of HSV and VZV (1), and Toxoplasma gondii (1) and bacterial infections (2). A noninfectious, inflammatory etiology was noted in 14 patients (23%). These included acute disseminated encephalomyelitis (6), fulminant multiple sclerosis (3), antiphospholipid syndrome (2), antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (2) and a paraneoplastic encephalitis (1). Three (5%) patients had other identifiable etiologies.

The etiology was unknown in 23 (38%) patients. Three of these patients had Epstein-Barr virus in their blood, but the viral load was less than 50 copies/million leukocytes, which was too low to cause symptoms. Two patients had herpesvirus 7, but there was no evidence of a primary infection.

The subgroups were similar in terms of clinical findings, with the exception of fever. Patients with an infectious etiology had higher temperatures at admission than did those with inflammatory, unknown, or other causes.

Overall mortality was 21%, and was highest among those with inflammatory causes (43%). Mortality rates were 14% in those with infections and 9% in those with an unknown etiology.

After a mean follow-up of 20 months, morbidity was significantly better in the unknown etiology group than in the infectious and inflammatory groups. The Glasgow Outcomes Score was less than 4 in 67% of patients in the infectious group, 57% of the inflammatory group, and 24% of the unknown group.

Disclosures: Ms. Granerod reported no relevant disclosures; her review was funded by the Health Protection Agency. Dr. Davies reported no relevant disclosures; his study was funded by the Charitable Foundation of Guy's and St. Thomas' Hospital.

BANGKOK, THAILAND — Many cases of encephalitis lack pathologic evidence for a specific etiology even though methods for detecting infectious agents have improved, suggesting that new infectious agents could be the source of some cases, according to the results of two studies.

Julia Granerod reviewed the etiology of encephalitis in 45 studies and concluded that the cause of up to 65% of cases remains a mystery. Because methodologic differences among the studies did not account for the unknown cases, other causes must be considered.

“It's important to consider the incidence in a global context, because with the threat of newly emerging infectious agents, increasing international travel, and global warming, there may be shifts in incidence over time,” Ms. Granerod said at the World Congress of Neurology.

Her colleague, Dr. Nicholas Davies, a fellow in neurology at St. Vincent's Hospital, Sydney, came to a similar conclusion in his prospective study of encephalitis etiology. In the largest proportion of cases (38%), no infectious or inflammatory cause for the disease could be determined.

In her review, Ms. Granerod, the national scientific coordinator of the U.K. Health Protection Agency Centre for Infections, included studies from Asia, Africa, Europe, and North America. Encephalitis incidence ranged from 0.07 to 12.6/100,000 per year. She also found that the incidence significantly decreased over time, due to the introduction of vaccines for some encephalitis vectors, such as Japanese encephalitis, yellow fever, and tick-borne encephalitis.

Etiology varied by geography. The most common etiology in Asia was Japanese encephalitis, whereas in Europe most cases were caused by herpes simplex viruses (HSV) and varicella zoster virus (VZV). Mycoplasma pneumoniae also caused a significant amount of encephalitis in Europe. In North America, insect vectors (ticks and mosquitoes) contributed the greatest number of identifiable cases.

The etiology was unknown in 65% of the North American cases, 43% of the European cases, and 59% of the Asian cases. “The most striking thing was that in 63% of the studies, more than 50% of the cases had an unknown etiology,” Ms. Granerod said. “That is a very significant finding.”

To determine the effect of methodologic differences between the studies, she conducted a multivariate regression analysis. “We considered year—the more sensitive diagnostic methods, such as polymerase chain reaction, were started in the mid-90s, so studies conducted after that should have had a lower proportion of unknown etiology. We also considered age, continent, subsyndrome, the number of agents tested for, whether the study was retrospective or prospective, and the case definition.”

Only year, continent, and subsyndrome remained significantly associated with etiology. “These findings support an emerging unknown etiology of encephalitis,” she said.

The review's findings may be more fully explained by a soon-to-be-published U.K. trial. The Etiology of Encephalitis in England study, sponsored by the country's Health Protection Agency, included patients recruited over a 4-year period from 18 hospitals and neurology centers in the U.K. Preliminary observations suggest that many of the cases with unknown etiology may be immune-mediated, most notably by antibodies associated with the N-methyl D-aspartate receptors, Ms. Granerod said.

While he was a research fellow at Guy's & St. Thomas' Hospital, London, Dr. Davies and his colleagues prospectively studied 61 adult patients with encephalitis treated at any of three London hospitals. In addition to describing the disease etiology, the researchers obtained clinical outcomes and quality of life data on the patients after discharge.

Of the 61 patients, 46% were female; the mean age was 40 years. The researchers analyzed 91 cerebrospinal fluid samples, including 52 that were obtained in the first 14 days and 39 that were obtained after 2 weeks.

An identifiable infectious etiology was found in 21 (34%) patients. Those were HSV (15), VZV (2), a combination of HSV and VZV (1), and Toxoplasma gondii (1) and bacterial infections (2). A noninfectious, inflammatory etiology was noted in 14 patients (23%). These included acute disseminated encephalomyelitis (6), fulminant multiple sclerosis (3), antiphospholipid syndrome (2), antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (2) and a paraneoplastic encephalitis (1). Three (5%) patients had other identifiable etiologies.

The etiology was unknown in 23 (38%) patients. Three of these patients had Epstein-Barr virus in their blood, but the viral load was less than 50 copies/million leukocytes, which was too low to cause symptoms. Two patients had herpesvirus 7, but there was no evidence of a primary infection.

The subgroups were similar in terms of clinical findings, with the exception of fever. Patients with an infectious etiology had higher temperatures at admission than did those with inflammatory, unknown, or other causes.

Overall mortality was 21%, and was highest among those with inflammatory causes (43%). Mortality rates were 14% in those with infections and 9% in those with an unknown etiology.

After a mean follow-up of 20 months, morbidity was significantly better in the unknown etiology group than in the infectious and inflammatory groups. The Glasgow Outcomes Score was less than 4 in 67% of patients in the infectious group, 57% of the inflammatory group, and 24% of the unknown group.

Disclosures: Ms. Granerod reported no relevant disclosures; her review was funded by the Health Protection Agency. Dr. Davies reported no relevant disclosures; his study was funded by the Charitable Foundation of Guy's and St. Thomas' Hospital.

Up to a quarter of patients with diabetic retinopathy may also have unrecognized stenotic coronary artery disease, putting them at risk for heart attack or sudden cardiovascular death.

Since many of these patients are already receiving outpatient care for their eye disorders, a clinic that proactively targets them for cardiac screening could improve their health and long-term survival, reported Dr. Takayuki Ohno and colleagues at the University of Tokyo.

The investigators found that 12% of patients attending a retinocoronary clinic had undiagnosed coronary artery disease. Diabetic retinopathy (DR) is present in 3 million Japanese citizens, they said; therefore, 363,000 of these people could have unsuspected heart disease. “These estimates suggest that a large number of patients with DR … would remain without diagnoses until a fatal coronary event,” they wrote. “We think that this specialized clinic might become the new model of an institution for identifying occult [coronary artery disease] in patients with DR requiring [coronary artery bypass grafting].”

To test this hypothesis, the researchers opened a diabetic retinocoronary clinic in 2007. Patients with type 2 diabetes and DR who were getting outpatient ophthalmologic care were randomly referred to the clinic. There they were asked to undergo a cardiac screening. Patients who tested positive were asked to undergo exercise thallium scintigraphy or a coronary CT scan. Those with abnormal results in this second tier of screening were approached for coronary angiography for further diagnosis.

Over an 18-month period, 286 patients were referred to the clinic; 214 were included in the study. Of these, 59 had nonproliferative DR and 155 had proliferative DR. Most (82%) were asymptomatic for cardiac problems; 12% had previously reported atypical chest discomfort (J. Thorac. Cardiovasc. Surg. 2010;139:92-7).

A total of 172 underwent an exercise tolerance test. The results were positive in 50 (29%) and nondiagnostic in 15 (9%). A total of 33 patients underwent exercise thallium scintigraphy, with abnormal results in eight (24%). A coronary CT was performed in 24 patients, with seven (29%) showing atherosclerotic coronary artery disease.

A total of 65 patients had a coronary angiography; 55 of these (26% of the entire cohort of 214) had angiographically confirmed stenotic coronary artery disease (CAD). Compared with patients without confirmed CAD, these patients were older (62 vs. 58 years) and more likely to have Q-wave or ST-T changes on resting ECG (47% vs. 21%, respectively).

CABG was recommended for 17 patients, percutaneous coronary intervention for 25, and aggressive medical therapy alone for 13. So far, 12 have undergone CABG (including 3 for whom PCI was recommended) and 27 have undergone PCI. Three refused to have any type of coronary revascularization.

During 288 days of follow-up, all patients have remained alive with no myocardial infarction. But eight (four in each intervention group), all of whom had proliferative DR, experienced vision-threatening vitreous hemorrhage.

Up to a quarter of patients with diabetic retinopathy may also have unrecognized stenotic coronary artery disease, putting them at risk for heart attack or sudden cardiovascular death.

Since many of these patients are already receiving outpatient care for their eye disorders, a clinic that proactively targets them for cardiac screening could improve their health and long-term survival, reported Dr. Takayuki Ohno and colleagues at the University of Tokyo.

The investigators found that 12% of patients attending a retinocoronary clinic had undiagnosed coronary artery disease. Diabetic retinopathy (DR) is present in 3 million Japanese citizens, they said; therefore, 363,000 of these people could have unsuspected heart disease. “These estimates suggest that a large number of patients with DR … would remain without diagnoses until a fatal coronary event,” they wrote. “We think that this specialized clinic might become the new model of an institution for identifying occult [coronary artery disease] in patients with DR requiring [coronary artery bypass grafting].”

To test this hypothesis, the researchers opened a diabetic retinocoronary clinic in 2007. Patients with type 2 diabetes and DR who were getting outpatient ophthalmologic care were randomly referred to the clinic. There they were asked to undergo a cardiac screening. Patients who tested positive were asked to undergo exercise thallium scintigraphy or a coronary CT scan. Those with abnormal results in this second tier of screening were approached for coronary angiography for further diagnosis.

Over an 18-month period, 286 patients were referred to the clinic; 214 were included in the study. Of these, 59 had nonproliferative DR and 155 had proliferative DR. Most (82%) were asymptomatic for cardiac problems; 12% had previously reported atypical chest discomfort (J. Thorac. Cardiovasc. Surg. 2010;139:92-7).

A total of 172 underwent an exercise tolerance test. The results were positive in 50 (29%) and nondiagnostic in 15 (9%). A total of 33 patients underwent exercise thallium scintigraphy, with abnormal results in eight (24%). A coronary CT was performed in 24 patients, with seven (29%) showing atherosclerotic coronary artery disease.

A total of 65 patients had a coronary angiography; 55 of these (26% of the entire cohort of 214) had angiographically confirmed stenotic coronary artery disease (CAD). Compared with patients without confirmed CAD, these patients were older (62 vs. 58 years) and more likely to have Q-wave or ST-T changes on resting ECG (47% vs. 21%, respectively).

CABG was recommended for 17 patients, percutaneous coronary intervention for 25, and aggressive medical therapy alone for 13. So far, 12 have undergone CABG (including 3 for whom PCI was recommended) and 27 have undergone PCI. Three refused to have any type of coronary revascularization.

During 288 days of follow-up, all patients have remained alive with no myocardial infarction. But eight (four in each intervention group), all of whom had proliferative DR, experienced vision-threatening vitreous hemorrhage.

Up to a quarter of patients with diabetic retinopathy may also have unrecognized stenotic coronary artery disease, putting them at risk for heart attack or sudden cardiovascular death.

Since many of these patients are already receiving outpatient care for their eye disorders, a clinic that proactively targets them for cardiac screening could improve their health and long-term survival, reported Dr. Takayuki Ohno and colleagues at the University of Tokyo.

The investigators found that 12% of patients attending a retinocoronary clinic had undiagnosed coronary artery disease. Diabetic retinopathy (DR) is present in 3 million Japanese citizens, they said; therefore, 363,000 of these people could have unsuspected heart disease. “These estimates suggest that a large number of patients with DR … would remain without diagnoses until a fatal coronary event,” they wrote. “We think that this specialized clinic might become the new model of an institution for identifying occult [coronary artery disease] in patients with DR requiring [coronary artery bypass grafting].”

To test this hypothesis, the researchers opened a diabetic retinocoronary clinic in 2007. Patients with type 2 diabetes and DR who were getting outpatient ophthalmologic care were randomly referred to the clinic. There they were asked to undergo a cardiac screening. Patients who tested positive were asked to undergo exercise thallium scintigraphy or a coronary CT scan. Those with abnormal results in this second tier of screening were approached for coronary angiography for further diagnosis.

Over an 18-month period, 286 patients were referred to the clinic; 214 were included in the study. Of these, 59 had nonproliferative DR and 155 had proliferative DR. Most (82%) were asymptomatic for cardiac problems; 12% had previously reported atypical chest discomfort (J. Thorac. Cardiovasc. Surg. 2010;139:92-7).

A total of 172 underwent an exercise tolerance test. The results were positive in 50 (29%) and nondiagnostic in 15 (9%). A total of 33 patients underwent exercise thallium scintigraphy, with abnormal results in eight (24%). A coronary CT was performed in 24 patients, with seven (29%) showing atherosclerotic coronary artery disease.

A total of 65 patients had a coronary angiography; 55 of these (26% of the entire cohort of 214) had angiographically confirmed stenotic coronary artery disease (CAD). Compared with patients without confirmed CAD, these patients were older (62 vs. 58 years) and more likely to have Q-wave or ST-T changes on resting ECG (47% vs. 21%, respectively).

CABG was recommended for 17 patients, percutaneous coronary intervention for 25, and aggressive medical therapy alone for 13. So far, 12 have undergone CABG (including 3 for whom PCI was recommended) and 27 have undergone PCI. Three refused to have any type of coronary revascularization.

During 288 days of follow-up, all patients have remained alive with no myocardial infarction. But eight (four in each intervention group), all of whom had proliferative DR, experienced vision-threatening vitreous hemorrhage.