Sharon Worcester

ST. LOUIS – Mesh kits aren't a one-size-fits-all option when it comes to the treatment of anterior compartment prolapse.

A number of kits are available, and unlike many other aspects of surgery in which one product or tool might be relatively equivalent to another, that's not the case when it comes to mesh kits, Dr. Peter M. Lotze said at the conference.

Although the kits all have a shared goal of creating a tension-free environment, they are anchored at different points. The right choice – and the right training – is important for a good outcome.

Dr. Lotze of the department of obstetrics and gynecology at the University of Texas, Houston, who is a practicing urogynecologist, described some of the most frequently used kits in the United States.

The Perigee Prolapse Repair System (American Medical Systems), the Gynecare Prolift Total, Anterior and Posterior Pelvic Floor Repair System (Ethicon), and the Avaulta Plus Biosynthetic Support System – Anterior (Bard Urological) all use a transobturator approach and use the ileococcygeus muscle and the internal obturator muscles as their anchor points, he said. These kits are designed to hold up a cystocele.

The Pinnacle Pelvic Floor Repair Kit and Uphold Vaginal Support System (both from Boston Scientific) and the Elevate Apical and Posterior Prolapse Repair System (American Medical Systems) use an anterior compartment approach, and use the sacrospinous ligament as their principal anchor of support, he said. These kits provide apical support in addition to correcting a cystocele.

The Gynecare Prosima Pelvic Floor Repair System (Ethicon) is the newest kit on the market, and via anterior compartment dissection to the ischial spines, it is placed up against the arcus tendineus fascia pelvis rather than anchoring into it. This kit is marketed for use in stage 1 prolapse, Dr. Lotze said.

Although a prospective observational study that he and his colleagues have submitted for publication suggests that fixation at the sacrospinous ligament is best for patients with a cystocele as well as apical prolapse – because it provides better apical support (see sidebar) – data are generally limited in regard to outcomes with these kits. This is true particularly because most reported cases involved combined repairs, making the findings difficult to interpret. However, existing data do suggest some benefit, and the kits do offer a minimally invasive vaginal approach that can be performed in an outpatient setting, Dr. Lotze said, noting that durability and patient satisfaction need further evaluation in future studies.

In the meantime, one important way to avoid complications is to pay careful attention to mesh tensioning. While the kits are technically considered “tension-free,” there is no such thing when a woman is standing up. The bladder, bowel, and vagina all rest on the mesh, creating tension. If you think it's too loose – you probably did it right, Dr. Lotze said.

Conversely, if you think it's a perfect result, your patient will likely be back to have the mesh cut out, because it will contract and cause pain, he said.

Know the anatomy, understand the success of classical surgery, know when to augment, and get training, training, and more training, he advised.

“You've got to be trained on your mesh kits,” he said, adding that a “weekend warrior” training course may not be sufficient.

Too often, physicians spoiled by quick and easy sling training sessions insist on pared-down weekend mesh kit training sessions to accommodate their social schedules – or vendors offer such limited training to entice participation. This is the biggest mistake physicians and vendors make, and that cycle needs to be broken, Dr. Lotze said.

In fact, even a full Saturday course may be insufficient, he said, noting that it's unrealistic to think you'll be proficient without additional training. There's nothing to lose by coming back to the next cadaver course.

“Go as many times as it takes. Vendors are happy to send you back – they know you're a long-term investment, so invest in your patients and go back if you need to,” he said.

Dr. Lotze disclosed that he is a speaker and researcher for Boston Scientific.

Use Sacrospinous Ligament Fixation

Apical support is best achieved by using sacrospinous ligament fixation rather than prespinous fixation when using mesh for the treatment of prolapse.

In a prospective observational study of 100 patients, Dr. Lotze and his colleagues found that on average, vaginal length was between 9.0 and 9.3 cm, and length from the introitus to the level of the ischial spine was about 7.5 cm – a difference of about 1 finger breadth.

Fixation of mesh at the sacrospinous ligament will provide support for about 80% of the total vaginal length; fixation at a level 1 finger breadth below that will provide support for only 58% of the total vaginal length, Dr. Lotze said.

Therefore, using prespinous fixation means that about a third of the apex will not be supported, and in patients with both cystocele and apical prolapse, this approach is more likely to fail.

Testing this in a cadaver lab to see how high they could get with the mesh kits in total vaginal length, Dr. Lotze and his colleagues found that with sacrospinous kits they were able to get to 100% of the total vaginal length, compared with only 60% of total vaginal length using prespinous kits, in most cases.

“So again, this emphasizes that the prespinous kits may not cut it if you have apical prolapse,” he said.

ST. LOUIS – Mesh kits aren't a one-size-fits-all option when it comes to the treatment of anterior compartment prolapse.

A number of kits are available, and unlike many other aspects of surgery in which one product or tool might be relatively equivalent to another, that's not the case when it comes to mesh kits, Dr. Peter M. Lotze said at the conference.

Although the kits all have a shared goal of creating a tension-free environment, they are anchored at different points. The right choice – and the right training – is important for a good outcome.

Dr. Lotze of the department of obstetrics and gynecology at the University of Texas, Houston, who is a practicing urogynecologist, described some of the most frequently used kits in the United States.

The Perigee Prolapse Repair System (American Medical Systems), the Gynecare Prolift Total, Anterior and Posterior Pelvic Floor Repair System (Ethicon), and the Avaulta Plus Biosynthetic Support System – Anterior (Bard Urological) all use a transobturator approach and use the ileococcygeus muscle and the internal obturator muscles as their anchor points, he said. These kits are designed to hold up a cystocele.

The Pinnacle Pelvic Floor Repair Kit and Uphold Vaginal Support System (both from Boston Scientific) and the Elevate Apical and Posterior Prolapse Repair System (American Medical Systems) use an anterior compartment approach, and use the sacrospinous ligament as their principal anchor of support, he said. These kits provide apical support in addition to correcting a cystocele.

The Gynecare Prosima Pelvic Floor Repair System (Ethicon) is the newest kit on the market, and via anterior compartment dissection to the ischial spines, it is placed up against the arcus tendineus fascia pelvis rather than anchoring into it. This kit is marketed for use in stage 1 prolapse, Dr. Lotze said.

Although a prospective observational study that he and his colleagues have submitted for publication suggests that fixation at the sacrospinous ligament is best for patients with a cystocele as well as apical prolapse – because it provides better apical support (see sidebar) – data are generally limited in regard to outcomes with these kits. This is true particularly because most reported cases involved combined repairs, making the findings difficult to interpret. However, existing data do suggest some benefit, and the kits do offer a minimally invasive vaginal approach that can be performed in an outpatient setting, Dr. Lotze said, noting that durability and patient satisfaction need further evaluation in future studies.

In the meantime, one important way to avoid complications is to pay careful attention to mesh tensioning. While the kits are technically considered “tension-free,” there is no such thing when a woman is standing up. The bladder, bowel, and vagina all rest on the mesh, creating tension. If you think it's too loose – you probably did it right, Dr. Lotze said.

Conversely, if you think it's a perfect result, your patient will likely be back to have the mesh cut out, because it will contract and cause pain, he said.

Know the anatomy, understand the success of classical surgery, know when to augment, and get training, training, and more training, he advised.

“You've got to be trained on your mesh kits,” he said, adding that a “weekend warrior” training course may not be sufficient.

Too often, physicians spoiled by quick and easy sling training sessions insist on pared-down weekend mesh kit training sessions to accommodate their social schedules – or vendors offer such limited training to entice participation. This is the biggest mistake physicians and vendors make, and that cycle needs to be broken, Dr. Lotze said.

In fact, even a full Saturday course may be insufficient, he said, noting that it's unrealistic to think you'll be proficient without additional training. There's nothing to lose by coming back to the next cadaver course.

“Go as many times as it takes. Vendors are happy to send you back – they know you're a long-term investment, so invest in your patients and go back if you need to,” he said.

Dr. Lotze disclosed that he is a speaker and researcher for Boston Scientific.

Use Sacrospinous Ligament Fixation

Apical support is best achieved by using sacrospinous ligament fixation rather than prespinous fixation when using mesh for the treatment of prolapse.

In a prospective observational study of 100 patients, Dr. Lotze and his colleagues found that on average, vaginal length was between 9.0 and 9.3 cm, and length from the introitus to the level of the ischial spine was about 7.5 cm – a difference of about 1 finger breadth.

Fixation of mesh at the sacrospinous ligament will provide support for about 80% of the total vaginal length; fixation at a level 1 finger breadth below that will provide support for only 58% of the total vaginal length, Dr. Lotze said.

Therefore, using prespinous fixation means that about a third of the apex will not be supported, and in patients with both cystocele and apical prolapse, this approach is more likely to fail.

Testing this in a cadaver lab to see how high they could get with the mesh kits in total vaginal length, Dr. Lotze and his colleagues found that with sacrospinous kits they were able to get to 100% of the total vaginal length, compared with only 60% of total vaginal length using prespinous kits, in most cases.

“So again, this emphasizes that the prespinous kits may not cut it if you have apical prolapse,” he said.

ST. LOUIS – Mesh kits aren't a one-size-fits-all option when it comes to the treatment of anterior compartment prolapse.

A number of kits are available, and unlike many other aspects of surgery in which one product or tool might be relatively equivalent to another, that's not the case when it comes to mesh kits, Dr. Peter M. Lotze said at the conference.

Although the kits all have a shared goal of creating a tension-free environment, they are anchored at different points. The right choice – and the right training – is important for a good outcome.

Dr. Lotze of the department of obstetrics and gynecology at the University of Texas, Houston, who is a practicing urogynecologist, described some of the most frequently used kits in the United States.

The Perigee Prolapse Repair System (American Medical Systems), the Gynecare Prolift Total, Anterior and Posterior Pelvic Floor Repair System (Ethicon), and the Avaulta Plus Biosynthetic Support System – Anterior (Bard Urological) all use a transobturator approach and use the ileococcygeus muscle and the internal obturator muscles as their anchor points, he said. These kits are designed to hold up a cystocele.

The Pinnacle Pelvic Floor Repair Kit and Uphold Vaginal Support System (both from Boston Scientific) and the Elevate Apical and Posterior Prolapse Repair System (American Medical Systems) use an anterior compartment approach, and use the sacrospinous ligament as their principal anchor of support, he said. These kits provide apical support in addition to correcting a cystocele.

The Gynecare Prosima Pelvic Floor Repair System (Ethicon) is the newest kit on the market, and via anterior compartment dissection to the ischial spines, it is placed up against the arcus tendineus fascia pelvis rather than anchoring into it. This kit is marketed for use in stage 1 prolapse, Dr. Lotze said.

Although a prospective observational study that he and his colleagues have submitted for publication suggests that fixation at the sacrospinous ligament is best for patients with a cystocele as well as apical prolapse – because it provides better apical support (see sidebar) – data are generally limited in regard to outcomes with these kits. This is true particularly because most reported cases involved combined repairs, making the findings difficult to interpret. However, existing data do suggest some benefit, and the kits do offer a minimally invasive vaginal approach that can be performed in an outpatient setting, Dr. Lotze said, noting that durability and patient satisfaction need further evaluation in future studies.

In the meantime, one important way to avoid complications is to pay careful attention to mesh tensioning. While the kits are technically considered “tension-free,” there is no such thing when a woman is standing up. The bladder, bowel, and vagina all rest on the mesh, creating tension. If you think it's too loose – you probably did it right, Dr. Lotze said.

Conversely, if you think it's a perfect result, your patient will likely be back to have the mesh cut out, because it will contract and cause pain, he said.

Know the anatomy, understand the success of classical surgery, know when to augment, and get training, training, and more training, he advised.

“You've got to be trained on your mesh kits,” he said, adding that a “weekend warrior” training course may not be sufficient.

Too often, physicians spoiled by quick and easy sling training sessions insist on pared-down weekend mesh kit training sessions to accommodate their social schedules – or vendors offer such limited training to entice participation. This is the biggest mistake physicians and vendors make, and that cycle needs to be broken, Dr. Lotze said.

In fact, even a full Saturday course may be insufficient, he said, noting that it's unrealistic to think you'll be proficient without additional training. There's nothing to lose by coming back to the next cadaver course.

“Go as many times as it takes. Vendors are happy to send you back – they know you're a long-term investment, so invest in your patients and go back if you need to,” he said.

Dr. Lotze disclosed that he is a speaker and researcher for Boston Scientific.

Use Sacrospinous Ligament Fixation

Apical support is best achieved by using sacrospinous ligament fixation rather than prespinous fixation when using mesh for the treatment of prolapse.

In a prospective observational study of 100 patients, Dr. Lotze and his colleagues found that on average, vaginal length was between 9.0 and 9.3 cm, and length from the introitus to the level of the ischial spine was about 7.5 cm – a difference of about 1 finger breadth.

Fixation of mesh at the sacrospinous ligament will provide support for about 80% of the total vaginal length; fixation at a level 1 finger breadth below that will provide support for only 58% of the total vaginal length, Dr. Lotze said.

Therefore, using prespinous fixation means that about a third of the apex will not be supported, and in patients with both cystocele and apical prolapse, this approach is more likely to fail.

Testing this in a cadaver lab to see how high they could get with the mesh kits in total vaginal length, Dr. Lotze and his colleagues found that with sacrospinous kits they were able to get to 100% of the total vaginal length, compared with only 60% of total vaginal length using prespinous kits, in most cases.

“So again, this emphasizes that the prespinous kits may not cut it if you have apical prolapse,” he said.

ST. LOUIS – Performance of routine cystoscopy in vaginal surgery and surgery for incontinence is useful to detect sutures and mesh going into the bladder, and to facilitate their removal, thus preventing morbidity from vesicovaginal fistulas, as well as ensuring that the ureters aren't injured.

This was the message delivered by Dr. Peter M. Lotze of the University of Texas and Baylor College of Medicine, Houston.

He showed an example of a Burch suture that was left in the bladder during urethropexy. Had the suture been identified perioperatively, it could have been easily removed, but because it was identified at a later time, operative cystoscopy was required for removal of the stitch, he explained.

During a video demonstration of cystoscopy at the conference, which was sponsored by the Society of Pelvic Reconstructive Surgeons, Dr. Lotze provided a number of tips and techniques for improving surgery outcomes using cystoscopy and cystourethroscopy.

For example, examination of the bladder is best accomplished using either a 30-degree or 70-degree rigid cystoscope, both of which offer the angles necessary to examine the bladder in its entirety, the urogynecologist said.

A 0- or 15-degree cystoscope is best for examining the circumferential nature of the urethra. Switching between scopes with different angles may be necessary to examine both the bladder and urethra, he noted. A small sheath, such as a 17 French (17 Fr), should be considered to allow easier passage through the urethra and into the bladder; larger sheaths may be difficult to pass and could traumatize the urethra, Dr. Lotze said.

For office cystoscopy during which the patient is awake, consider the use of a flexible cystoscope to enhance patient comfort.

If the view of the bladder wall is obscured, excess sediment, blood, or intravenous dye could be the cause; filling, emptying, and refilling the bladder as needed will allow a clearer view of the urothelium. The administration of IV dye such as indigo carmine dye should be used only after the surgical procedure is complete to provide clearer confirmation that the ureters are patent, compared with when it is given before or during the procedure.

Changing out the light cords regularly is imperative, as these are frequently damaged, causing impaired visualization.

For the cystoscopic procedure, Dr. Lotze suggested using a methodological approach each time to ensure that a consistent, reliable, reproducible bladder survey is done.

In his demonstration of a cystoscopic bladder survey, he recommended beginning at the base of the bladder, moving along the mid-hemitrigone and then up to the bladder dome, paying careful attention to stay within a few centimeters of the surface of the bladder to allow for adequate assessment of the bladder surface. Next, move from the 6 o'clock position to the 12 o'clock position, pass the scope from the 2 o'clock to the 7 o'clock position, then divert the scope to the 4 o'clock position, and proceed to the 10 o'clock position.

After a viewing of these multiple angles, the bladder survey is completed by beginning at the 3 o'clock position and moving to the 9 o'clock position. The trigone should then be examined. It is at this point that ureteral patency can be evaluated if indicated.

The procedure is completed with an examination of the proximal, middle, and distal thirds of the urethra to rule out evidence of pathology within the structure.

Common findings on cystoscopy include:

▸ Normal urothelium. This is characterized by a somewhat pale appearance, with fine arterial and venous blood vessels.

▸ Hypervascularity. In stark contrast to normal urothelium, this involves an increase in both the arterial and venous blood vessels within the bladder. Consider a bladder biopsy if the cause of this pathology is unknown.

▸ A lesion growing from the wall of the bladder. This should be biopsied, as it likely represents a carcinoma.

▸ A lesion with a grape-like cluster of cells. This typically represents a transitional cell carcinoma and should be biopsied and treated.

▸ Squamous metaplasia. This benign overgrowth of cells that make up the trigone may include clear cysts, known as cystitis cystica. Floating particles in the cystoscopy field, which are referred to as exudate, are the result of a squamous metaplasia detaching from the trigone.

▸ Lesions on the hemitrigone and bladder dome areas. These may include plaques (typically associated with bladder infection) or opaque cysts, known as cystitis glandularis (which may be associated with recurrent bladder infections). If the cause of these cysts is unknown, a biopsy is warranted.

▸ A hypertrophied detrusor muscle within the bladder. This finding, known as a trabeculation, is common in patients with overactive bladder and also can be seen in patients with outlet obstruction.

▸ An inflammatory reaction in the bladder neck or proximal urethra. These “pseudo-polyps” or “fronds” are an inflammatory response to a recent bladder infection, and represent a benign condition.

▸ Sluggish flow of urine on ureteral examination. This could be normal, but could be a sign of partial obstruction from the current surgery or a past surgery, a kidney stone, or a possible stricture in the ureter. Postoperative swelling neighboring the ureter could cause obstruction, and a work-up is warranted if this is suspected.

Dr. Lotze disclosed that he is a speaker for Boston Scientific, and has conducted research for the company.

ST. LOUIS – Performance of routine cystoscopy in vaginal surgery and surgery for incontinence is useful to detect sutures and mesh going into the bladder, and to facilitate their removal, thus preventing morbidity from vesicovaginal fistulas, as well as ensuring that the ureters aren't injured.

This was the message delivered by Dr. Peter M. Lotze of the University of Texas and Baylor College of Medicine, Houston.

He showed an example of a Burch suture that was left in the bladder during urethropexy. Had the suture been identified perioperatively, it could have been easily removed, but because it was identified at a later time, operative cystoscopy was required for removal of the stitch, he explained.

During a video demonstration of cystoscopy at the conference, which was sponsored by the Society of Pelvic Reconstructive Surgeons, Dr. Lotze provided a number of tips and techniques for improving surgery outcomes using cystoscopy and cystourethroscopy.

For example, examination of the bladder is best accomplished using either a 30-degree or 70-degree rigid cystoscope, both of which offer the angles necessary to examine the bladder in its entirety, the urogynecologist said.

A 0- or 15-degree cystoscope is best for examining the circumferential nature of the urethra. Switching between scopes with different angles may be necessary to examine both the bladder and urethra, he noted. A small sheath, such as a 17 French (17 Fr), should be considered to allow easier passage through the urethra and into the bladder; larger sheaths may be difficult to pass and could traumatize the urethra, Dr. Lotze said.

For office cystoscopy during which the patient is awake, consider the use of a flexible cystoscope to enhance patient comfort.

If the view of the bladder wall is obscured, excess sediment, blood, or intravenous dye could be the cause; filling, emptying, and refilling the bladder as needed will allow a clearer view of the urothelium. The administration of IV dye such as indigo carmine dye should be used only after the surgical procedure is complete to provide clearer confirmation that the ureters are patent, compared with when it is given before or during the procedure.

Changing out the light cords regularly is imperative, as these are frequently damaged, causing impaired visualization.

For the cystoscopic procedure, Dr. Lotze suggested using a methodological approach each time to ensure that a consistent, reliable, reproducible bladder survey is done.

In his demonstration of a cystoscopic bladder survey, he recommended beginning at the base of the bladder, moving along the mid-hemitrigone and then up to the bladder dome, paying careful attention to stay within a few centimeters of the surface of the bladder to allow for adequate assessment of the bladder surface. Next, move from the 6 o'clock position to the 12 o'clock position, pass the scope from the 2 o'clock to the 7 o'clock position, then divert the scope to the 4 o'clock position, and proceed to the 10 o'clock position.

After a viewing of these multiple angles, the bladder survey is completed by beginning at the 3 o'clock position and moving to the 9 o'clock position. The trigone should then be examined. It is at this point that ureteral patency can be evaluated if indicated.

The procedure is completed with an examination of the proximal, middle, and distal thirds of the urethra to rule out evidence of pathology within the structure.

Common findings on cystoscopy include:

▸ Normal urothelium. This is characterized by a somewhat pale appearance, with fine arterial and venous blood vessels.

▸ Hypervascularity. In stark contrast to normal urothelium, this involves an increase in both the arterial and venous blood vessels within the bladder. Consider a bladder biopsy if the cause of this pathology is unknown.

▸ A lesion growing from the wall of the bladder. This should be biopsied, as it likely represents a carcinoma.

▸ A lesion with a grape-like cluster of cells. This typically represents a transitional cell carcinoma and should be biopsied and treated.

▸ Squamous metaplasia. This benign overgrowth of cells that make up the trigone may include clear cysts, known as cystitis cystica. Floating particles in the cystoscopy field, which are referred to as exudate, are the result of a squamous metaplasia detaching from the trigone.

▸ Lesions on the hemitrigone and bladder dome areas. These may include plaques (typically associated with bladder infection) or opaque cysts, known as cystitis glandularis (which may be associated with recurrent bladder infections). If the cause of these cysts is unknown, a biopsy is warranted.

▸ A hypertrophied detrusor muscle within the bladder. This finding, known as a trabeculation, is common in patients with overactive bladder and also can be seen in patients with outlet obstruction.

▸ An inflammatory reaction in the bladder neck or proximal urethra. These “pseudo-polyps” or “fronds” are an inflammatory response to a recent bladder infection, and represent a benign condition.

▸ Sluggish flow of urine on ureteral examination. This could be normal, but could be a sign of partial obstruction from the current surgery or a past surgery, a kidney stone, or a possible stricture in the ureter. Postoperative swelling neighboring the ureter could cause obstruction, and a work-up is warranted if this is suspected.

Dr. Lotze disclosed that he is a speaker for Boston Scientific, and has conducted research for the company.

ST. LOUIS – Performance of routine cystoscopy in vaginal surgery and surgery for incontinence is useful to detect sutures and mesh going into the bladder, and to facilitate their removal, thus preventing morbidity from vesicovaginal fistulas, as well as ensuring that the ureters aren't injured.

This was the message delivered by Dr. Peter M. Lotze of the University of Texas and Baylor College of Medicine, Houston.

He showed an example of a Burch suture that was left in the bladder during urethropexy. Had the suture been identified perioperatively, it could have been easily removed, but because it was identified at a later time, operative cystoscopy was required for removal of the stitch, he explained.

During a video demonstration of cystoscopy at the conference, which was sponsored by the Society of Pelvic Reconstructive Surgeons, Dr. Lotze provided a number of tips and techniques for improving surgery outcomes using cystoscopy and cystourethroscopy.

For example, examination of the bladder is best accomplished using either a 30-degree or 70-degree rigid cystoscope, both of which offer the angles necessary to examine the bladder in its entirety, the urogynecologist said.

A 0- or 15-degree cystoscope is best for examining the circumferential nature of the urethra. Switching between scopes with different angles may be necessary to examine both the bladder and urethra, he noted. A small sheath, such as a 17 French (17 Fr), should be considered to allow easier passage through the urethra and into the bladder; larger sheaths may be difficult to pass and could traumatize the urethra, Dr. Lotze said.

For office cystoscopy during which the patient is awake, consider the use of a flexible cystoscope to enhance patient comfort.

If the view of the bladder wall is obscured, excess sediment, blood, or intravenous dye could be the cause; filling, emptying, and refilling the bladder as needed will allow a clearer view of the urothelium. The administration of IV dye such as indigo carmine dye should be used only after the surgical procedure is complete to provide clearer confirmation that the ureters are patent, compared with when it is given before or during the procedure.

Changing out the light cords regularly is imperative, as these are frequently damaged, causing impaired visualization.

For the cystoscopic procedure, Dr. Lotze suggested using a methodological approach each time to ensure that a consistent, reliable, reproducible bladder survey is done.

In his demonstration of a cystoscopic bladder survey, he recommended beginning at the base of the bladder, moving along the mid-hemitrigone and then up to the bladder dome, paying careful attention to stay within a few centimeters of the surface of the bladder to allow for adequate assessment of the bladder surface. Next, move from the 6 o'clock position to the 12 o'clock position, pass the scope from the 2 o'clock to the 7 o'clock position, then divert the scope to the 4 o'clock position, and proceed to the 10 o'clock position.

After a viewing of these multiple angles, the bladder survey is completed by beginning at the 3 o'clock position and moving to the 9 o'clock position. The trigone should then be examined. It is at this point that ureteral patency can be evaluated if indicated.

The procedure is completed with an examination of the proximal, middle, and distal thirds of the urethra to rule out evidence of pathology within the structure.

Common findings on cystoscopy include:

▸ Normal urothelium. This is characterized by a somewhat pale appearance, with fine arterial and venous blood vessels.

▸ Hypervascularity. In stark contrast to normal urothelium, this involves an increase in both the arterial and venous blood vessels within the bladder. Consider a bladder biopsy if the cause of this pathology is unknown.

▸ A lesion growing from the wall of the bladder. This should be biopsied, as it likely represents a carcinoma.

▸ A lesion with a grape-like cluster of cells. This typically represents a transitional cell carcinoma and should be biopsied and treated.

▸ Squamous metaplasia. This benign overgrowth of cells that make up the trigone may include clear cysts, known as cystitis cystica. Floating particles in the cystoscopy field, which are referred to as exudate, are the result of a squamous metaplasia detaching from the trigone.

▸ Lesions on the hemitrigone and bladder dome areas. These may include plaques (typically associated with bladder infection) or opaque cysts, known as cystitis glandularis (which may be associated with recurrent bladder infections). If the cause of these cysts is unknown, a biopsy is warranted.

▸ A hypertrophied detrusor muscle within the bladder. This finding, known as a trabeculation, is common in patients with overactive bladder and also can be seen in patients with outlet obstruction.

▸ An inflammatory reaction in the bladder neck or proximal urethra. These “pseudo-polyps” or “fronds” are an inflammatory response to a recent bladder infection, and represent a benign condition.

▸ Sluggish flow of urine on ureteral examination. This could be normal, but could be a sign of partial obstruction from the current surgery or a past surgery, a kidney stone, or a possible stricture in the ureter. Postoperative swelling neighboring the ureter could cause obstruction, and a work-up is warranted if this is suspected.

Dr. Lotze disclosed that he is a speaker for Boston Scientific, and has conducted research for the company.

Major Finding: At the end of the 12-month study, 17 of 24 patients randomized to receive placebo and prednisone experienced a relapse, compared with 15 of 46 patients randomized to methotrexate and prednisone.

Data Source: A randomized, double-blind, placebo-controlled trial of 70 children with juvenile localized scleroderma.

Disclosures: Dr. Zulian said he had no relevant financial disclosures.

ATLANTA — Methotrexate was an effective, well-tolerated treatment for juvenile localized scleroderma in a randomized, double-blind, placebo-controlled trial of 70 patients with active disease.

At the end of the 12-month study, 31 of 46 patients randomized to receive methotrexate had responded to treatment and were flare-free, compared with 7 of 24 patients given placebo, Dr. Francesco Zulian reported.

Participants were aged 6–17 years, and had active localized scleroderma of linear, generalized, or deep subtypes with onset before age 16.

Methotrexate patients received an oral dose of 15 mg/m

Patients' lesions were evaluated using a computerized scoring system, and changes were quantified using a skin score rate. Active lesions were monitored by clinical exam and serial thermography. Mean skin score rates fell significantly from 1.0 at baseline to 0.79 in the patients on methotrexate, but did not decrease in the placebo patients. The mean target lesion temperature on thermography decreased by 44% in the methotrexate group and by 12% in the placebo group, a significant difference, he said.

Adverse events occurred in 26 of 46 patients on methotrexate, and in 11 of 24 on placebo. In the methotrexate group, adverse events included alopecia, nausea, headache, fatigue, hepatotoxicity, weight gain, and striae rubra. The only adverse events in the placebo group were weight gain and striae rubra.

Interestingly, weight gain of more than 5% of body weight occurred in 11% of the methotrexate patients and 42% of the placebo patients, Dr. Zulian said, noting that this may suggest there is a “biological or pathophysiological link” between prednisone and methotrexate that tempers this steroid-related side effect.

None of the side effects was severe enough to stop treatment, but both groups had a high drop-out rate due to relapse or lack of response: 31 of 46 patients on methotrexate, and 7 of 24 in the placebo group, completed the study.

Mean skin score fell from 1.0 at baseline to 0.79 in the methotrexate group, but did not fall in the placebo group.

Source DR. ZULIAN

Major Finding: At the end of the 12-month study, 17 of 24 patients randomized to receive placebo and prednisone experienced a relapse, compared with 15 of 46 patients randomized to methotrexate and prednisone.

Data Source: A randomized, double-blind, placebo-controlled trial of 70 children with juvenile localized scleroderma.

Disclosures: Dr. Zulian said he had no relevant financial disclosures.

ATLANTA — Methotrexate was an effective, well-tolerated treatment for juvenile localized scleroderma in a randomized, double-blind, placebo-controlled trial of 70 patients with active disease.

At the end of the 12-month study, 31 of 46 patients randomized to receive methotrexate had responded to treatment and were flare-free, compared with 7 of 24 patients given placebo, Dr. Francesco Zulian reported.

Participants were aged 6–17 years, and had active localized scleroderma of linear, generalized, or deep subtypes with onset before age 16.

Methotrexate patients received an oral dose of 15 mg/m

Patients' lesions were evaluated using a computerized scoring system, and changes were quantified using a skin score rate. Active lesions were monitored by clinical exam and serial thermography. Mean skin score rates fell significantly from 1.0 at baseline to 0.79 in the patients on methotrexate, but did not decrease in the placebo patients. The mean target lesion temperature on thermography decreased by 44% in the methotrexate group and by 12% in the placebo group, a significant difference, he said.

Adverse events occurred in 26 of 46 patients on methotrexate, and in 11 of 24 on placebo. In the methotrexate group, adverse events included alopecia, nausea, headache, fatigue, hepatotoxicity, weight gain, and striae rubra. The only adverse events in the placebo group were weight gain and striae rubra.

Interestingly, weight gain of more than 5% of body weight occurred in 11% of the methotrexate patients and 42% of the placebo patients, Dr. Zulian said, noting that this may suggest there is a “biological or pathophysiological link” between prednisone and methotrexate that tempers this steroid-related side effect.

None of the side effects was severe enough to stop treatment, but both groups had a high drop-out rate due to relapse or lack of response: 31 of 46 patients on methotrexate, and 7 of 24 in the placebo group, completed the study.

Mean skin score fell from 1.0 at baseline to 0.79 in the methotrexate group, but did not fall in the placebo group.

Source DR. ZULIAN

Major Finding: At the end of the 12-month study, 17 of 24 patients randomized to receive placebo and prednisone experienced a relapse, compared with 15 of 46 patients randomized to methotrexate and prednisone.

Data Source: A randomized, double-blind, placebo-controlled trial of 70 children with juvenile localized scleroderma.

Disclosures: Dr. Zulian said he had no relevant financial disclosures.

ATLANTA — Methotrexate was an effective, well-tolerated treatment for juvenile localized scleroderma in a randomized, double-blind, placebo-controlled trial of 70 patients with active disease.

At the end of the 12-month study, 31 of 46 patients randomized to receive methotrexate had responded to treatment and were flare-free, compared with 7 of 24 patients given placebo, Dr. Francesco Zulian reported.

Participants were aged 6–17 years, and had active localized scleroderma of linear, generalized, or deep subtypes with onset before age 16.

Methotrexate patients received an oral dose of 15 mg/m

Patients' lesions were evaluated using a computerized scoring system, and changes were quantified using a skin score rate. Active lesions were monitored by clinical exam and serial thermography. Mean skin score rates fell significantly from 1.0 at baseline to 0.79 in the patients on methotrexate, but did not decrease in the placebo patients. The mean target lesion temperature on thermography decreased by 44% in the methotrexate group and by 12% in the placebo group, a significant difference, he said.

Adverse events occurred in 26 of 46 patients on methotrexate, and in 11 of 24 on placebo. In the methotrexate group, adverse events included alopecia, nausea, headache, fatigue, hepatotoxicity, weight gain, and striae rubra. The only adverse events in the placebo group were weight gain and striae rubra.

Interestingly, weight gain of more than 5% of body weight occurred in 11% of the methotrexate patients and 42% of the placebo patients, Dr. Zulian said, noting that this may suggest there is a “biological or pathophysiological link” between prednisone and methotrexate that tempers this steroid-related side effect.

None of the side effects was severe enough to stop treatment, but both groups had a high drop-out rate due to relapse or lack of response: 31 of 46 patients on methotrexate, and 7 of 24 in the placebo group, completed the study.

Mean skin score fell from 1.0 at baseline to 0.79 in the methotrexate group, but did not fall in the placebo group.

Source DR. ZULIAN

Major Finding: Of 38 canakinumab-naive patients, 68% achieved a complete response based on physician global assessment of disease activity and skin assessment, and normalization of C-reactive protein and serum amyloid A. More than 80% of the canakinumab-naive patients were relapse-free after a median of 290 days of exposure to treatment, and normal levels were also maintained throughout the study period in the rollover patients.

Data Source: From an open-label, single treatment arm, phase III extension study of canakinumab for CAPS.

Disclosures: Dr. Kuemmerle-Deschner disclosed that she has received research grants and consulting fees from Novartis Pharmaceuticals, the maker of canakinumab (Ilaris).

ATLANTA — Canakinumab was safe, well tolerated, and highly effective in the long-term treatment of cryopyrin-associated periodic syndromes in pediatric patients in an open-label phase III extension study.

Treatment of cryopyrin-associated periodic syndromes (CAPS) in 47 patients, aged 3–17 years, was associated with a rapid and sustained clinical and biochemical remission across varying disease severity phenotypes.

Five patients had familial cold autoinflammatory syndrome (FCAS), 23 had Muckle-Wells syndrome (MWS), and 18 had chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease (CINCA/NOMID). One child was found to not have a CAPS disease phenotype, said Dr. Jasmin B. Kuemmerle-Deschner.

Of the 47 patients, 38 had not previously been treated with the human interleukin-1 beta monoclonal antibody, and 9 were “rolled over” from earlier phase II or III studies. Of the 38 canakinumab-naive patients, 68% achieved a complete response based on physician global assessment of disease activity and skin assessment, plus normalization of C-reactive protein (CRP) and lowering of serum amyloid A (SAA) to less than 10 mg/L for both measures. More than 80% of the canakinumab-naive patients were relapse-free after a median of 290 days of exposure to treatment, and normal CRP and SAA levels were also maintained throughout the study period in the rollover patients, said Dr. Kuemmerle-Deschner, a pediatric rheumatologist at Universitaetsklinikum Tuebingen (Germany).

The response in the treatment-naive patients was rapid, with CRP and SAA falling within 7 days from 14.8 to 2.5 mg/L, and from 40.6 to 7.4 mg/L, respectively. In addition, 8 of the 11 patients who had an incomplete response within 7 days developed a complete response by 14 days, and the remaining patients al a partial response, she said.

All patients were treated with 150 mg (or 2 mg/kg for those weighing 40 kg or less) of subcutaneous canakinumab once every 8 weeks. In cases of incomplete response more frequent dosing or anindditional dose of 300 mg (or 4 mg/kg for thoients weighing 40 kg or less) was allowed, orsesadjus requiradjusted in 17 patients, she said.

Major Finding: Of 38 canakinumab-naive patients, 68% achieved a complete response based on physician global assessment of disease activity and skin assessment, and normalization of C-reactive protein and serum amyloid A. More than 80% of the canakinumab-naive patients were relapse-free after a median of 290 days of exposure to treatment, and normal levels were also maintained throughout the study period in the rollover patients.

Data Source: From an open-label, single treatment arm, phase III extension study of canakinumab for CAPS.

Disclosures: Dr. Kuemmerle-Deschner disclosed that she has received research grants and consulting fees from Novartis Pharmaceuticals, the maker of canakinumab (Ilaris).

ATLANTA — Canakinumab was safe, well tolerated, and highly effective in the long-term treatment of cryopyrin-associated periodic syndromes in pediatric patients in an open-label phase III extension study.

Treatment of cryopyrin-associated periodic syndromes (CAPS) in 47 patients, aged 3–17 years, was associated with a rapid and sustained clinical and biochemical remission across varying disease severity phenotypes.

Five patients had familial cold autoinflammatory syndrome (FCAS), 23 had Muckle-Wells syndrome (MWS), and 18 had chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease (CINCA/NOMID). One child was found to not have a CAPS disease phenotype, said Dr. Jasmin B. Kuemmerle-Deschner.

Of the 47 patients, 38 had not previously been treated with the human interleukin-1 beta monoclonal antibody, and 9 were “rolled over” from earlier phase II or III studies. Of the 38 canakinumab-naive patients, 68% achieved a complete response based on physician global assessment of disease activity and skin assessment, plus normalization of C-reactive protein (CRP) and lowering of serum amyloid A (SAA) to less than 10 mg/L for both measures. More than 80% of the canakinumab-naive patients were relapse-free after a median of 290 days of exposure to treatment, and normal CRP and SAA levels were also maintained throughout the study period in the rollover patients, said Dr. Kuemmerle-Deschner, a pediatric rheumatologist at Universitaetsklinikum Tuebingen (Germany).

The response in the treatment-naive patients was rapid, with CRP and SAA falling within 7 days from 14.8 to 2.5 mg/L, and from 40.6 to 7.4 mg/L, respectively. In addition, 8 of the 11 patients who had an incomplete response within 7 days developed a complete response by 14 days, and the remaining patients al a partial response, she said.

All patients were treated with 150 mg (or 2 mg/kg for those weighing 40 kg or less) of subcutaneous canakinumab once every 8 weeks. In cases of incomplete response more frequent dosing or anindditional dose of 300 mg (or 4 mg/kg for thoients weighing 40 kg or less) was allowed, orsesadjus requiradjusted in 17 patients, she said.

Major Finding: Of 38 canakinumab-naive patients, 68% achieved a complete response based on physician global assessment of disease activity and skin assessment, and normalization of C-reactive protein and serum amyloid A. More than 80% of the canakinumab-naive patients were relapse-free after a median of 290 days of exposure to treatment, and normal levels were also maintained throughout the study period in the rollover patients.

Data Source: From an open-label, single treatment arm, phase III extension study of canakinumab for CAPS.

Disclosures: Dr. Kuemmerle-Deschner disclosed that she has received research grants and consulting fees from Novartis Pharmaceuticals, the maker of canakinumab (Ilaris).

ATLANTA — Canakinumab was safe, well tolerated, and highly effective in the long-term treatment of cryopyrin-associated periodic syndromes in pediatric patients in an open-label phase III extension study.

Treatment of cryopyrin-associated periodic syndromes (CAPS) in 47 patients, aged 3–17 years, was associated with a rapid and sustained clinical and biochemical remission across varying disease severity phenotypes.

Five patients had familial cold autoinflammatory syndrome (FCAS), 23 had Muckle-Wells syndrome (MWS), and 18 had chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease (CINCA/NOMID). One child was found to not have a CAPS disease phenotype, said Dr. Jasmin B. Kuemmerle-Deschner.

Of the 47 patients, 38 had not previously been treated with the human interleukin-1 beta monoclonal antibody, and 9 were “rolled over” from earlier phase II or III studies. Of the 38 canakinumab-naive patients, 68% achieved a complete response based on physician global assessment of disease activity and skin assessment, plus normalization of C-reactive protein (CRP) and lowering of serum amyloid A (SAA) to less than 10 mg/L for both measures. More than 80% of the canakinumab-naive patients were relapse-free after a median of 290 days of exposure to treatment, and normal CRP and SAA levels were also maintained throughout the study period in the rollover patients, said Dr. Kuemmerle-Deschner, a pediatric rheumatologist at Universitaetsklinikum Tuebingen (Germany).

The response in the treatment-naive patients was rapid, with CRP and SAA falling within 7 days from 14.8 to 2.5 mg/L, and from 40.6 to 7.4 mg/L, respectively. In addition, 8 of the 11 patients who had an incomplete response within 7 days developed a complete response by 14 days, and the remaining patients al a partial response, she said.

All patients were treated with 150 mg (or 2 mg/kg for those weighing 40 kg or less) of subcutaneous canakinumab once every 8 weeks. In cases of incomplete response more frequent dosing or anindditional dose of 300 mg (or 4 mg/kg for thoients weighing 40 kg or less) was allowed, orsesadjus requiradjusted in 17 patients, she said.

Major Finding: At a median follow-up of 33 months, 9 of 19 children studied had a good neurologic outcome based on the PSOM after treatment with steroid- and cyclophosphamide-based induction therapy, followed by maintenance therapy with azathioprine or mycophenolate mofetil.

Data Source: A single-center, open-label cohort study of 19 children with small-vessel childhood primary angiitis of the CNS.

Disclosures: The study authors had no disclosures to report.

An immunosuppressive treatment regimen was effective for reversing neurological deficits and controlling severe neurologic manifestations of small-vessel childhood primary angiitis of the central nervous system in a relatively large cohort study of the rare inflammatory brain disease.

At a median follow-up of 33 months in the single-center, open-label study, 9 of 19 children studied had a good neurologic outcome based on the pediatric stroke outcome measure (PSOM) after treatment with steroid- and cyclophosphamide-based induction therapy, followed by maintenance therapy with azathioprine or mycophenolate mofetil.

Four of the children remained in remission after as long as 57 months off treatment, reported Dr. Clare Hutchinson and her colleagues at the Hospital for Sick Children, Toronto.

This cohort is the largest to date to prospectively follow children with this recently recognized disease, and it is the first to demonstrate the potential efficacy of immunosuppressive treatment, they wrote (Lancet 2010 Oct. 4 [doi:10.1016/S1474-4422(10)70243-X]).

To date, a variety of treatments have been tried, but no standardized protocol or documentation of neurologic outcomes have been described.

The 6-month induction phase used in the current study included seven pulses of 500–750 mg/m

The 18-month maintenance phase included 800–1,200 mg/m

The regimen was well tolerated; two infections requiring hospitalization occurred, including one during induction, and one during maintenance, but there were no deaths. However, a high proportion of patients experienced a flare of neurologic symptoms or significant adverse events such as lymphopenia, pancytopenia, and infection while on azathioprine. All of these events resolved after the patients were switched to mycophenolate mofetil, prompting the investigators to recommend that mycophenolate mofetil be used during the maintenance phase of this protocol rather than azathioprine.

This immunosuppressive therapy regimen has the potential for improving long-term neurologic outcomes. “We therefore recommend this protocol for treatment of patients with small-vessel childhood primary angiitis of the CNS,” they wrote.

Children in the study were aged 5–17 years, with a median age of 9.8 years. Patients were assessed using clinical, neurologic, and quality of life measures, and laboratory markers were done at baseline, and at 3, 6, 9, 12, 18, and 24 months, and then yearly for the duration of follow-up. Brain imaging was done at baseline and then every 6 months for 24 months.

The number of patients in the study was small largely because of the requirement of a brain biopsy to confirm the diagnosis, the investigators said.

Another limitation is that the PSOM, although a useful measure of neurologic deficits on the basis of clinical findings, does not measure quality of life or account for other neurologic sequelae such as academic impairments, psychiatric manifestations, and ongoing seizure disorder.

View on The News

A Useful Framework

These promising findings are “a crucial and necessary first step in identifying the optimum treatment for children with small-vessel childhood primary angiitis of the CNS and will provide a useful reference for future studies of similar or alternative treatment options,” according to Dr. Neil. R. Friedman.

In fact, the study will undoubtedly serve as the basis for ongoing and future studies of this disease, he added, noting that although the small sample size precludes the recommended treatment regimen from being considered the standard of care in patients with small-vessel primary angiitis of the CNS, the study does provide a useful framework for managing and treating childhood stroke.

Questions that remain unanswered about the disease, according to Dr. Friedman, include whether it is homogenous, which potential risk factors at presentation affect disease course and outcome, and whether thrombosis contributes to stroke risk because of vascular inflammation.

DR. FRIEDMAN is with the Center for Pediatric Neurology at the Cleveland Clinic. His comments are derived from an accompanying editorial (Lancet 2010 Oct. 4 [doi:10.1016/S1474-4422(10)70244-1]). He has served as a speaker for Genzyme.

Major Finding: At a median follow-up of 33 months, 9 of 19 children studied had a good neurologic outcome based on the PSOM after treatment with steroid- and cyclophosphamide-based induction therapy, followed by maintenance therapy with azathioprine or mycophenolate mofetil.

Data Source: A single-center, open-label cohort study of 19 children with small-vessel childhood primary angiitis of the CNS.

Disclosures: The study authors had no disclosures to report.

An immunosuppressive treatment regimen was effective for reversing neurological deficits and controlling severe neurologic manifestations of small-vessel childhood primary angiitis of the central nervous system in a relatively large cohort study of the rare inflammatory brain disease.

At a median follow-up of 33 months in the single-center, open-label study, 9 of 19 children studied had a good neurologic outcome based on the pediatric stroke outcome measure (PSOM) after treatment with steroid- and cyclophosphamide-based induction therapy, followed by maintenance therapy with azathioprine or mycophenolate mofetil.

Four of the children remained in remission after as long as 57 months off treatment, reported Dr. Clare Hutchinson and her colleagues at the Hospital for Sick Children, Toronto.

This cohort is the largest to date to prospectively follow children with this recently recognized disease, and it is the first to demonstrate the potential efficacy of immunosuppressive treatment, they wrote (Lancet 2010 Oct. 4 [doi:10.1016/S1474-4422(10)70243-X]).

To date, a variety of treatments have been tried, but no standardized protocol or documentation of neurologic outcomes have been described.

The 6-month induction phase used in the current study included seven pulses of 500–750 mg/m

The 18-month maintenance phase included 800–1,200 mg/m

The regimen was well tolerated; two infections requiring hospitalization occurred, including one during induction, and one during maintenance, but there were no deaths. However, a high proportion of patients experienced a flare of neurologic symptoms or significant adverse events such as lymphopenia, pancytopenia, and infection while on azathioprine. All of these events resolved after the patients were switched to mycophenolate mofetil, prompting the investigators to recommend that mycophenolate mofetil be used during the maintenance phase of this protocol rather than azathioprine.

This immunosuppressive therapy regimen has the potential for improving long-term neurologic outcomes. “We therefore recommend this protocol for treatment of patients with small-vessel childhood primary angiitis of the CNS,” they wrote.

Children in the study were aged 5–17 years, with a median age of 9.8 years. Patients were assessed using clinical, neurologic, and quality of life measures, and laboratory markers were done at baseline, and at 3, 6, 9, 12, 18, and 24 months, and then yearly for the duration of follow-up. Brain imaging was done at baseline and then every 6 months for 24 months.

The number of patients in the study was small largely because of the requirement of a brain biopsy to confirm the diagnosis, the investigators said.

Another limitation is that the PSOM, although a useful measure of neurologic deficits on the basis of clinical findings, does not measure quality of life or account for other neurologic sequelae such as academic impairments, psychiatric manifestations, and ongoing seizure disorder.

View on The News

A Useful Framework

These promising findings are “a crucial and necessary first step in identifying the optimum treatment for children with small-vessel childhood primary angiitis of the CNS and will provide a useful reference for future studies of similar or alternative treatment options,” according to Dr. Neil. R. Friedman.

In fact, the study will undoubtedly serve as the basis for ongoing and future studies of this disease, he added, noting that although the small sample size precludes the recommended treatment regimen from being considered the standard of care in patients with small-vessel primary angiitis of the CNS, the study does provide a useful framework for managing and treating childhood stroke.

Questions that remain unanswered about the disease, according to Dr. Friedman, include whether it is homogenous, which potential risk factors at presentation affect disease course and outcome, and whether thrombosis contributes to stroke risk because of vascular inflammation.

DR. FRIEDMAN is with the Center for Pediatric Neurology at the Cleveland Clinic. His comments are derived from an accompanying editorial (Lancet 2010 Oct. 4 [doi:10.1016/S1474-4422(10)70244-1]). He has served as a speaker for Genzyme.

Major Finding: At a median follow-up of 33 months, 9 of 19 children studied had a good neurologic outcome based on the PSOM after treatment with steroid- and cyclophosphamide-based induction therapy, followed by maintenance therapy with azathioprine or mycophenolate mofetil.

Data Source: A single-center, open-label cohort study of 19 children with small-vessel childhood primary angiitis of the CNS.

Disclosures: The study authors had no disclosures to report.

An immunosuppressive treatment regimen was effective for reversing neurological deficits and controlling severe neurologic manifestations of small-vessel childhood primary angiitis of the central nervous system in a relatively large cohort study of the rare inflammatory brain disease.

At a median follow-up of 33 months in the single-center, open-label study, 9 of 19 children studied had a good neurologic outcome based on the pediatric stroke outcome measure (PSOM) after treatment with steroid- and cyclophosphamide-based induction therapy, followed by maintenance therapy with azathioprine or mycophenolate mofetil.

Four of the children remained in remission after as long as 57 months off treatment, reported Dr. Clare Hutchinson and her colleagues at the Hospital for Sick Children, Toronto.

This cohort is the largest to date to prospectively follow children with this recently recognized disease, and it is the first to demonstrate the potential efficacy of immunosuppressive treatment, they wrote (Lancet 2010 Oct. 4 [doi:10.1016/S1474-4422(10)70243-X]).

To date, a variety of treatments have been tried, but no standardized protocol or documentation of neurologic outcomes have been described.

The 6-month induction phase used in the current study included seven pulses of 500–750 mg/m

The 18-month maintenance phase included 800–1,200 mg/m

The regimen was well tolerated; two infections requiring hospitalization occurred, including one during induction, and one during maintenance, but there were no deaths. However, a high proportion of patients experienced a flare of neurologic symptoms or significant adverse events such as lymphopenia, pancytopenia, and infection while on azathioprine. All of these events resolved after the patients were switched to mycophenolate mofetil, prompting the investigators to recommend that mycophenolate mofetil be used during the maintenance phase of this protocol rather than azathioprine.

This immunosuppressive therapy regimen has the potential for improving long-term neurologic outcomes. “We therefore recommend this protocol for treatment of patients with small-vessel childhood primary angiitis of the CNS,” they wrote.

Children in the study were aged 5–17 years, with a median age of 9.8 years. Patients were assessed using clinical, neurologic, and quality of life measures, and laboratory markers were done at baseline, and at 3, 6, 9, 12, 18, and 24 months, and then yearly for the duration of follow-up. Brain imaging was done at baseline and then every 6 months for 24 months.

The number of patients in the study was small largely because of the requirement of a brain biopsy to confirm the diagnosis, the investigators said.

Another limitation is that the PSOM, although a useful measure of neurologic deficits on the basis of clinical findings, does not measure quality of life or account for other neurologic sequelae such as academic impairments, psychiatric manifestations, and ongoing seizure disorder.

View on The News

A Useful Framework

These promising findings are “a crucial and necessary first step in identifying the optimum treatment for children with small-vessel childhood primary angiitis of the CNS and will provide a useful reference for future studies of similar or alternative treatment options,” according to Dr. Neil. R. Friedman.

In fact, the study will undoubtedly serve as the basis for ongoing and future studies of this disease, he added, noting that although the small sample size precludes the recommended treatment regimen from being considered the standard of care in patients with small-vessel primary angiitis of the CNS, the study does provide a useful framework for managing and treating childhood stroke.

Questions that remain unanswered about the disease, according to Dr. Friedman, include whether it is homogenous, which potential risk factors at presentation affect disease course and outcome, and whether thrombosis contributes to stroke risk because of vascular inflammation.

DR. FRIEDMAN is with the Center for Pediatric Neurology at the Cleveland Clinic. His comments are derived from an accompanying editorial (Lancet 2010 Oct. 4 [doi:10.1016/S1474-4422(10)70244-1]). He has served as a speaker for Genzyme.

The incidence of group B streptococcal disease in infants has declined sharply since guidelines for prevention were implemented nearly 15 years ago, but GBS nonetheless remains the leading infectious cause of morbidity and mortality among infants in the United States, according to the Centers for Disease Control and Prevention, which recently updated the guidelines to further promote prevention efforts.

Since the guidelines were first published by the CDC in 1996 – then updated and republished in 2002 – the number of cases per 1,000 live births has declined from 1.7 to 0.34-0.37. Universal screening at 35–37 weeks' gestation and the use of intrapartum antibiotic prophylaxis as recommended in the original and updated guidelines is credited for this improvement, but the rates of maternal colonization, and therefore the risk of early-onset disease in the absence of intrapartum antibiotic prophylaxis, has remained unchanged since the 1970s.

“The continued burden of disease and newly available data relevant to early-onset GBS disease prevention from the fields of epidemiology, obstetrics, neonatology, microbiology, molecular biology, and pharmacology prompted revision of the guidelines for early-onset GBS disease prevention,” according to the CDC's report introducing the most recently revised guidelines (MMWR 2010;59[RR-10]:1–32).

A technical working group, which was formed to review and update the guidelines, identified a subset of topics for review, then revised the guidelines based on available evidence and expert opinion. Changes were made regarding both secondary prevention in newborns and maternal prophylaxis.

In large part, the revised guidelines are reaffirmation of the earlier guidelines, according to Dr. Carol Baker, professor of pediatrics, molecular virology, and microbiology at the Baylor College of Medicine, Houston, and a member of the technical working group charged with updating the guidelines.

“All women who are pregnant should be screened with cultures at 35–37 weeks. That's the main strategy to prevent early-onset disease in babies, and it hasn't changed one bit,” she said in an interview.

There was, however, some “tweaking” of the existing guidelines to simplify and clarify processes, add some new information about alternative laboratory methods for testing, and provide for alternative treatments – for example, for women allergic to penicillin, she said.

As for secondary prevention in neonates, a management algorithm for secondary GBS prevention, which is designed to detect potential cases as early as possible, remained mostly the same, except it was streamlined and now applies to all newborns.

Although the changes in the guidelines are generally small when it comes to secondary prevention in infants, they are important, and taken together, the changes for both mothers and babies are expected to provide some incremental improvements in outcome, Dr. Baker said.

The good news is there is 80% less early-onset GBS disease than there was before the culture screening recommendations came out in 1996, and that's real progress, she said, adding that there is room for improvement – particularly in late-onset disease, which hasn't changed much.

“We can probably do a little better with these [updated guidelines],” she said.

However, until the pharmaceutical industry moves forward with the available vaccine science and develops a GBS vaccine, it is doubtful much progress will be made in regard to late-onset disease, Dr. Baker said, noting that she believes the industry has failed to act on that science out of fear of the litigation so commonplace in obstetrics and maternal-fetal medicine.

Still, progress is being made, and good compliance with the guidelines is expected, particularly since the updated guidelines have been endorsed by the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American College of Nurse-Midwives, the American Academy of Family Physicians, and the American Society for Microbiology. All have had a hand in developing the guidelines, and thus have a stake in the outcomes, she noted.

“I'm very optimistic that there will be high compliance both on the baby side and the mother's side. It's a matter of education – hopefully the news will get out,” Dr. Baker said.

Indeed, the guidelines call for local and state public health agencies, in conjunction with hospitals, to establish surveillance for early-onset GBS, and to “take other steps to promote perinatal GBS disease prevention and education to reduce the incidence of early onset GBS disease in their states.”

The algorithm calls for a full diagnostic evaluation in all newborns with signs of sepsis, as well as provision of antibiotics active against GBS and other organisms that might cause sepsis pending the results of the evaluation. The evaluation should include “a blood culture; a CBC including white blood cell differential and platelet count; a chest radiograph if any abnormal respiratory signs are present; and a lumbar puncture if the newborn is stable enough to tolerate the procedure and sepsis is suspected,” according to the guidelines.

Also, well-appearing newborns whose mothers had suspected chorioamnionitis should undergo a limited evaluation (blood culture and CBC as above, but no chest x-ray or lumbar puncture is necessary) and should receive antibiotic treatment pending culture results. Well-appearing infants whose mothers had no chorioamnionitis and no indication for GBS prophylaxis should be managed according to routine clinical care.

Other key components of the algorithm call for the following:

▸ Observation for at least 48 hours – but no routine diagnostic testing – in well-appearing infants of any gestational age whose mother received adequate intrapartum GBS prophylaxis (clarified in the newly revised guidelines to be at least 4 hours of intravenous penicillin, ampicillin, or cefazolin before delivery). Observation now is also recommended in well-appearing infants born to mothers who had an indication for GBS prophylaxis but received no or inadequate prophylaxis, as long as the infant is at least 37 weeks' gestational age, and the duration of membrane rupture before delivery was less than 18 hours.

▸ Limited evaluation and observation for at least 48 hours in well-appearing infants born to mothers with an indication for prophylaxis, but who received no or inadequate prophylaxis, when the infant is less than 37 weeks' gestation or duration of membrane rupture before delivery was 18 hours or more.

Well-appearing infants with a gestational age of 35–36 weeks whose mothers received adequate intrapartum antibiotic prophylaxis do not routinely require diagnostic evaluations.

In addition to these steps, research aimed at better understanding the racial and ethnic differences that still persist in GBS disease incidence is needed, according to the CDC report. Research is needed on strategies for preventing early-onset disease among preterm infants, the role of bacteriuria as a risk factor, effectiveness of the recommended intrapartum antibiotic prophylaxis agents for penicillin-allergic women at high risk for anaphylaxis, the impact and effectiveness of recommendations for secondary prevention of early-onset disease among neonates, and factors contributing to the higher than anticipated proportion of early-onset GBS disease cases occurring among infants born to women with negative prenatal GBS screens. Such ongoing research is important because, in the absence of a licensed GBS vaccine, universal screening and intrapartum antibiotic prophylaxis continue to be the cornerstones of prevention, the report states.

“I'm very optimistic that there will be high compliance both on the baby side and the mother's side,” Dr. Carol Baker said.

Source Courtesy Marcia A. Rench

The incidence of group B streptococcal disease in infants has declined sharply since guidelines for prevention were implemented nearly 15 years ago, but GBS nonetheless remains the leading infectious cause of morbidity and mortality among infants in the United States, according to the Centers for Disease Control and Prevention, which recently updated the guidelines to further promote prevention efforts.

Since the guidelines were first published by the CDC in 1996 – then updated and republished in 2002 – the number of cases per 1,000 live births has declined from 1.7 to 0.34-0.37. Universal screening at 35–37 weeks' gestation and the use of intrapartum antibiotic prophylaxis as recommended in the original and updated guidelines is credited for this improvement, but the rates of maternal colonization, and therefore the risk of early-onset disease in the absence of intrapartum antibiotic prophylaxis, has remained unchanged since the 1970s.

“The continued burden of disease and newly available data relevant to early-onset GBS disease prevention from the fields of epidemiology, obstetrics, neonatology, microbiology, molecular biology, and pharmacology prompted revision of the guidelines for early-onset GBS disease prevention,” according to the CDC's report introducing the most recently revised guidelines (MMWR 2010;59[RR-10]:1–32).

A technical working group, which was formed to review and update the guidelines, identified a subset of topics for review, then revised the guidelines based on available evidence and expert opinion. Changes were made regarding both secondary prevention in newborns and maternal prophylaxis.

In large part, the revised guidelines are reaffirmation of the earlier guidelines, according to Dr. Carol Baker, professor of pediatrics, molecular virology, and microbiology at the Baylor College of Medicine, Houston, and a member of the technical working group charged with updating the guidelines.

“All women who are pregnant should be screened with cultures at 35–37 weeks. That's the main strategy to prevent early-onset disease in babies, and it hasn't changed one bit,” she said in an interview.

There was, however, some “tweaking” of the existing guidelines to simplify and clarify processes, add some new information about alternative laboratory methods for testing, and provide for alternative treatments – for example, for women allergic to penicillin, she said.

As for secondary prevention in neonates, a management algorithm for secondary GBS prevention, which is designed to detect potential cases as early as possible, remained mostly the same, except it was streamlined and now applies to all newborns.

Although the changes in the guidelines are generally small when it comes to secondary prevention in infants, they are important, and taken together, the changes for both mothers and babies are expected to provide some incremental improvements in outcome, Dr. Baker said.

The good news is there is 80% less early-onset GBS disease than there was before the culture screening recommendations came out in 1996, and that's real progress, she said, adding that there is room for improvement – particularly in late-onset disease, which hasn't changed much.

“We can probably do a little better with these [updated guidelines],” she said.

However, until the pharmaceutical industry moves forward with the available vaccine science and develops a GBS vaccine, it is doubtful much progress will be made in regard to late-onset disease, Dr. Baker said, noting that she believes the industry has failed to act on that science out of fear of the litigation so commonplace in obstetrics and maternal-fetal medicine.

Still, progress is being made, and good compliance with the guidelines is expected, particularly since the updated guidelines have been endorsed by the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American College of Nurse-Midwives, the American Academy of Family Physicians, and the American Society for Microbiology. All have had a hand in developing the guidelines, and thus have a stake in the outcomes, she noted.

“I'm very optimistic that there will be high compliance both on the baby side and the mother's side. It's a matter of education – hopefully the news will get out,” Dr. Baker said.

Indeed, the guidelines call for local and state public health agencies, in conjunction with hospitals, to establish surveillance for early-onset GBS, and to “take other steps to promote perinatal GBS disease prevention and education to reduce the incidence of early onset GBS disease in their states.”

The algorithm calls for a full diagnostic evaluation in all newborns with signs of sepsis, as well as provision of antibiotics active against GBS and other organisms that might cause sepsis pending the results of the evaluation. The evaluation should include “a blood culture; a CBC including white blood cell differential and platelet count; a chest radiograph if any abnormal respiratory signs are present; and a lumbar puncture if the newborn is stable enough to tolerate the procedure and sepsis is suspected,” according to the guidelines.

Also, well-appearing newborns whose mothers had suspected chorioamnionitis should undergo a limited evaluation (blood culture and CBC as above, but no chest x-ray or lumbar puncture is necessary) and should receive antibiotic treatment pending culture results. Well-appearing infants whose mothers had no chorioamnionitis and no indication for GBS prophylaxis should be managed according to routine clinical care.

Other key components of the algorithm call for the following:

▸ Observation for at least 48 hours – but no routine diagnostic testing – in well-appearing infants of any gestational age whose mother received adequate intrapartum GBS prophylaxis (clarified in the newly revised guidelines to be at least 4 hours of intravenous penicillin, ampicillin, or cefazolin before delivery). Observation now is also recommended in well-appearing infants born to mothers who had an indication for GBS prophylaxis but received no or inadequate prophylaxis, as long as the infant is at least 37 weeks' gestational age, and the duration of membrane rupture before delivery was less than 18 hours.

▸ Limited evaluation and observation for at least 48 hours in well-appearing infants born to mothers with an indication for prophylaxis, but who received no or inadequate prophylaxis, when the infant is less than 37 weeks' gestation or duration of membrane rupture before delivery was 18 hours or more.

Well-appearing infants with a gestational age of 35–36 weeks whose mothers received adequate intrapartum antibiotic prophylaxis do not routinely require diagnostic evaluations.

In addition to these steps, research aimed at better understanding the racial and ethnic differences that still persist in GBS disease incidence is needed, according to the CDC report. Research is needed on strategies for preventing early-onset disease among preterm infants, the role of bacteriuria as a risk factor, effectiveness of the recommended intrapartum antibiotic prophylaxis agents for penicillin-allergic women at high risk for anaphylaxis, the impact and effectiveness of recommendations for secondary prevention of early-onset disease among neonates, and factors contributing to the higher than anticipated proportion of early-onset GBS disease cases occurring among infants born to women with negative prenatal GBS screens. Such ongoing research is important because, in the absence of a licensed GBS vaccine, universal screening and intrapartum antibiotic prophylaxis continue to be the cornerstones of prevention, the report states.

“I'm very optimistic that there will be high compliance both on the baby side and the mother's side,” Dr. Carol Baker said.

Source Courtesy Marcia A. Rench

The incidence of group B streptococcal disease in infants has declined sharply since guidelines for prevention were implemented nearly 15 years ago, but GBS nonetheless remains the leading infectious cause of morbidity and mortality among infants in the United States, according to the Centers for Disease Control and Prevention, which recently updated the guidelines to further promote prevention efforts.

Since the guidelines were first published by the CDC in 1996 – then updated and republished in 2002 – the number of cases per 1,000 live births has declined from 1.7 to 0.34-0.37. Universal screening at 35–37 weeks' gestation and the use of intrapartum antibiotic prophylaxis as recommended in the original and updated guidelines is credited for this improvement, but the rates of maternal colonization, and therefore the risk of early-onset disease in the absence of intrapartum antibiotic prophylaxis, has remained unchanged since the 1970s.

“The continued burden of disease and newly available data relevant to early-onset GBS disease prevention from the fields of epidemiology, obstetrics, neonatology, microbiology, molecular biology, and pharmacology prompted revision of the guidelines for early-onset GBS disease prevention,” according to the CDC's report introducing the most recently revised guidelines (MMWR 2010;59[RR-10]:1–32).

A technical working group, which was formed to review and update the guidelines, identified a subset of topics for review, then revised the guidelines based on available evidence and expert opinion. Changes were made regarding both secondary prevention in newborns and maternal prophylaxis.

In large part, the revised guidelines are reaffirmation of the earlier guidelines, according to Dr. Carol Baker, professor of pediatrics, molecular virology, and microbiology at the Baylor College of Medicine, Houston, and a member of the technical working group charged with updating the guidelines.

“All women who are pregnant should be screened with cultures at 35–37 weeks. That's the main strategy to prevent early-onset disease in babies, and it hasn't changed one bit,” she said in an interview.

There was, however, some “tweaking” of the existing guidelines to simplify and clarify processes, add some new information about alternative laboratory methods for testing, and provide for alternative treatments – for example, for women allergic to penicillin, she said.

As for secondary prevention in neonates, a management algorithm for secondary GBS prevention, which is designed to detect potential cases as early as possible, remained mostly the same, except it was streamlined and now applies to all newborns.

Although the changes in the guidelines are generally small when it comes to secondary prevention in infants, they are important, and taken together, the changes for both mothers and babies are expected to provide some incremental improvements in outcome, Dr. Baker said.

The good news is there is 80% less early-onset GBS disease than there was before the culture screening recommendations came out in 1996, and that's real progress, she said, adding that there is room for improvement – particularly in late-onset disease, which hasn't changed much.

“We can probably do a little better with these [updated guidelines],” she said.

However, until the pharmaceutical industry moves forward with the available vaccine science and develops a GBS vaccine, it is doubtful much progress will be made in regard to late-onset disease, Dr. Baker said, noting that she believes the industry has failed to act on that science out of fear of the litigation so commonplace in obstetrics and maternal-fetal medicine.

Still, progress is being made, and good compliance with the guidelines is expected, particularly since the updated guidelines have been endorsed by the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American College of Nurse-Midwives, the American Academy of Family Physicians, and the American Society for Microbiology. All have had a hand in developing the guidelines, and thus have a stake in the outcomes, she noted.

“I'm very optimistic that there will be high compliance both on the baby side and the mother's side. It's a matter of education – hopefully the news will get out,” Dr. Baker said.

Indeed, the guidelines call for local and state public health agencies, in conjunction with hospitals, to establish surveillance for early-onset GBS, and to “take other steps to promote perinatal GBS disease prevention and education to reduce the incidence of early onset GBS disease in their states.”

The algorithm calls for a full diagnostic evaluation in all newborns with signs of sepsis, as well as provision of antibiotics active against GBS and other organisms that might cause sepsis pending the results of the evaluation. The evaluation should include “a blood culture; a CBC including white blood cell differential and platelet count; a chest radiograph if any abnormal respiratory signs are present; and a lumbar puncture if the newborn is stable enough to tolerate the procedure and sepsis is suspected,” according to the guidelines.

Also, well-appearing newborns whose mothers had suspected chorioamnionitis should undergo a limited evaluation (blood culture and CBC as above, but no chest x-ray or lumbar puncture is necessary) and should receive antibiotic treatment pending culture results. Well-appearing infants whose mothers had no chorioamnionitis and no indication for GBS prophylaxis should be managed according to routine clinical care.

Other key components of the algorithm call for the following:

▸ Observation for at least 48 hours – but no routine diagnostic testing – in well-appearing infants of any gestational age whose mother received adequate intrapartum GBS prophylaxis (clarified in the newly revised guidelines to be at least 4 hours of intravenous penicillin, ampicillin, or cefazolin before delivery). Observation now is also recommended in well-appearing infants born to mothers who had an indication for GBS prophylaxis but received no or inadequate prophylaxis, as long as the infant is at least 37 weeks' gestational age, and the duration of membrane rupture before delivery was less than 18 hours.

▸ Limited evaluation and observation for at least 48 hours in well-appearing infants born to mothers with an indication for prophylaxis, but who received no or inadequate prophylaxis, when the infant is less than 37 weeks' gestation or duration of membrane rupture before delivery was 18 hours or more.

Well-appearing infants with a gestational age of 35–36 weeks whose mothers received adequate intrapartum antibiotic prophylaxis do not routinely require diagnostic evaluations.

In addition to these steps, research aimed at better understanding the racial and ethnic differences that still persist in GBS disease incidence is needed, according to the CDC report. Research is needed on strategies for preventing early-onset disease among preterm infants, the role of bacteriuria as a risk factor, effectiveness of the recommended intrapartum antibiotic prophylaxis agents for penicillin-allergic women at high risk for anaphylaxis, the impact and effectiveness of recommendations for secondary prevention of early-onset disease among neonates, and factors contributing to the higher than anticipated proportion of early-onset GBS disease cases occurring among infants born to women with negative prenatal GBS screens. Such ongoing research is important because, in the absence of a licensed GBS vaccine, universal screening and intrapartum antibiotic prophylaxis continue to be the cornerstones of prevention, the report states.

“I'm very optimistic that there will be high compliance both on the baby side and the mother's side,” Dr. Carol Baker said.

Source Courtesy Marcia A. Rench

Dosing directions and measuring devices included with top-selling pediatric over-the-counter liquid medications were highly inconsistent as of November 2009, when the Food and Drug Administration issued voluntary industry guidelines in response to numerous reports of unintentional overdoses among children, according to a descriptive study of 200 such medications.

The study, conducted to provide baseline data for assessing the degree and pace of industry conformity with the new guidelines, showed that 146 of 148 medications (98.6%) that included measuring devices had one or more inconsistencies between the dosing directions and the markings on the device, Dr. H. Shonna Yin of New York University and colleagues reported.

The inconsistencies included missing markings in 24% of the products, superfluous markings in 81% of the products, and inconsistencies between the product's label and the measuring device in 89% of products.

Furthermore, 5.5% of the products used atypical units of measurement, such as cubic centimeters, drams, or fluid ounces; 71.5% used milliliters (although 97 products used a nonstandard abbreviation for milliliter); 77.5% used teaspoon units; and 18.5% used the tablespoon (JAMA 2010 Nov. 30[doi:10.1001/jama.2010.1797]).

Other potentially problematic findings included the lack of a leading zero in 12.5% of 40 products with a dose smaller than 1 presented in decimal format, the use of nonstandard fraction formats in 64.5% of 110 products that used fractions, and the lack of a statement that the measuring device should be used only with its associated product in 62% of the 148 medications that included a device.

The investigators evaluated 200 products representing 99% of the U.S. market of analgesic, cough/cold, allergy, and gastrointestinal OTC liquid products – including 58 private-label products – that contained dosing information for children under age 12 years. The medications were studied during the 52 weeks ending Oct. 30, 2009.

“Given the high prevalence of baseline inconsistencies, regulatory oversight may be helpful in accelerating adoption of the guidance recommendations,” the investigators wrote, noting that several Institute of Medicine reports have identified variable and poor-quality drug labeling as a major cause of confusion among consumers – and therefore as a potential risk factor for unintentional misuse of products.

Indeed, many of the unintentional overdoses that prompted the FDA guidance in 2009 were attributed, at least in part, to products with inconsistent or confusing labels and measuring devices. The FDA recommendations state that:

▸ All OTC liquid medication products include a measuring device.

▸ Consistent abbreviations and units of measurement be used for a given product's device.

▸ The devices bear only necessary markings and not hold significantly more medication than the largest prescribed dose.

▸ Abbreviations conform to standards and be defined.

▸ Decimals and fractions be used with care.

▸ Studies on accurate use of the medications by consumers be conducted.

More than half of all U.S. children are exposed to at least one medication in a given week – and more than half of those medications are OTC. Also at least one in three U.S. adults and at least one in four U.S. parents have limited health literacy and even worse numeracy.

For these reasons, the findings support these recommendations and particularly underscore the need for standardized measuring devices with all nonprescription liquid products, consistency between dosing directions and markings on the measuring device, and standardization of measurement units, abbreviations, and numeric formats across products, Dr. Yin and associates said.

“Even frequently used terms like teaspoon and tablespoon may be misinterpreted,” they wrote, noting that errors in understanding teaspoon vs. tablespoon have been found to contribute to threefold errors.

Dosing directions and measuring devices included with top-selling pediatric over-the-counter liquid medications were highly inconsistent as of November 2009, when the Food and Drug Administration issued voluntary industry guidelines in response to numerous reports of unintentional overdoses among children, according to a descriptive study of 200 such medications.

The study, conducted to provide baseline data for assessing the degree and pace of industry conformity with the new guidelines, showed that 146 of 148 medications (98.6%) that included measuring devices had one or more inconsistencies between the dosing directions and the markings on the device, Dr. H. Shonna Yin of New York University and colleagues reported.

The inconsistencies included missing markings in 24% of the products, superfluous markings in 81% of the products, and inconsistencies between the product's label and the measuring device in 89% of products.

Furthermore, 5.5% of the products used atypical units of measurement, such as cubic centimeters, drams, or fluid ounces; 71.5% used milliliters (although 97 products used a nonstandard abbreviation for milliliter); 77.5% used teaspoon units; and 18.5% used the tablespoon (JAMA 2010 Nov. 30[doi:10.1001/jama.2010.1797]).

Other potentially problematic findings included the lack of a leading zero in 12.5% of 40 products with a dose smaller than 1 presented in decimal format, the use of nonstandard fraction formats in 64.5% of 110 products that used fractions, and the lack of a statement that the measuring device should be used only with its associated product in 62% of the 148 medications that included a device.

The investigators evaluated 200 products representing 99% of the U.S. market of analgesic, cough/cold, allergy, and gastrointestinal OTC liquid products – including 58 private-label products – that contained dosing information for children under age 12 years. The medications were studied during the 52 weeks ending Oct. 30, 2009.

“Given the high prevalence of baseline inconsistencies, regulatory oversight may be helpful in accelerating adoption of the guidance recommendations,” the investigators wrote, noting that several Institute of Medicine reports have identified variable and poor-quality drug labeling as a major cause of confusion among consumers – and therefore as a potential risk factor for unintentional misuse of products.

Indeed, many of the unintentional overdoses that prompted the FDA guidance in 2009 were attributed, at least in part, to products with inconsistent or confusing labels and measuring devices. The FDA recommendations state that:

▸ All OTC liquid medication products include a measuring device.

▸ Consistent abbreviations and units of measurement be used for a given product's device.

▸ The devices bear only necessary markings and not hold significantly more medication than the largest prescribed dose.

▸ Abbreviations conform to standards and be defined.

▸ Decimals and fractions be used with care.

▸ Studies on accurate use of the medications by consumers be conducted.

More than half of all U.S. children are exposed to at least one medication in a given week – and more than half of those medications are OTC. Also at least one in three U.S. adults and at least one in four U.S. parents have limited health literacy and even worse numeracy.

For these reasons, the findings support these recommendations and particularly underscore the need for standardized measuring devices with all nonprescription liquid products, consistency between dosing directions and markings on the measuring device, and standardization of measurement units, abbreviations, and numeric formats across products, Dr. Yin and associates said.

“Even frequently used terms like teaspoon and tablespoon may be misinterpreted,” they wrote, noting that errors in understanding teaspoon vs. tablespoon have been found to contribute to threefold errors.

Dosing directions and measuring devices included with top-selling pediatric over-the-counter liquid medications were highly inconsistent as of November 2009, when the Food and Drug Administration issued voluntary industry guidelines in response to numerous reports of unintentional overdoses among children, according to a descriptive study of 200 such medications.

The study, conducted to provide baseline data for assessing the degree and pace of industry conformity with the new guidelines, showed that 146 of 148 medications (98.6%) that included measuring devices had one or more inconsistencies between the dosing directions and the markings on the device, Dr. H. Shonna Yin of New York University and colleagues reported.

The inconsistencies included missing markings in 24% of the products, superfluous markings in 81% of the products, and inconsistencies between the product's label and the measuring device in 89% of products.

Furthermore, 5.5% of the products used atypical units of measurement, such as cubic centimeters, drams, or fluid ounces; 71.5% used milliliters (although 97 products used a nonstandard abbreviation for milliliter); 77.5% used teaspoon units; and 18.5% used the tablespoon (JAMA 2010 Nov. 30[doi:10.1001/jama.2010.1797]).

Other potentially problematic findings included the lack of a leading zero in 12.5% of 40 products with a dose smaller than 1 presented in decimal format, the use of nonstandard fraction formats in 64.5% of 110 products that used fractions, and the lack of a statement that the measuring device should be used only with its associated product in 62% of the 148 medications that included a device.

The investigators evaluated 200 products representing 99% of the U.S. market of analgesic, cough/cold, allergy, and gastrointestinal OTC liquid products – including 58 private-label products – that contained dosing information for children under age 12 years. The medications were studied during the 52 weeks ending Oct. 30, 2009.

“Given the high prevalence of baseline inconsistencies, regulatory oversight may be helpful in accelerating adoption of the guidance recommendations,” the investigators wrote, noting that several Institute of Medicine reports have identified variable and poor-quality drug labeling as a major cause of confusion among consumers – and therefore as a potential risk factor for unintentional misuse of products.

Indeed, many of the unintentional overdoses that prompted the FDA guidance in 2009 were attributed, at least in part, to products with inconsistent or confusing labels and measuring devices. The FDA recommendations state that:

▸ All OTC liquid medication products include a measuring device.

▸ Consistent abbreviations and units of measurement be used for a given product's device.

▸ The devices bear only necessary markings and not hold significantly more medication than the largest prescribed dose.

▸ Abbreviations conform to standards and be defined.

▸ Decimals and fractions be used with care.

▸ Studies on accurate use of the medications by consumers be conducted.

More than half of all U.S. children are exposed to at least one medication in a given week – and more than half of those medications are OTC. Also at least one in three U.S. adults and at least one in four U.S. parents have limited health literacy and even worse numeracy.

For these reasons, the findings support these recommendations and particularly underscore the need for standardized measuring devices with all nonprescription liquid products, consistency between dosing directions and markings on the measuring device, and standardization of measurement units, abbreviations, and numeric formats across products, Dr. Yin and associates said.

“Even frequently used terms like teaspoon and tablespoon may be misinterpreted,” they wrote, noting that errors in understanding teaspoon vs. tablespoon have been found to contribute to threefold errors.

The recent headway of two treatments for addiction to heroin and other opiates represents a major advancement and has the potential to put opioid addiction therapy within the purview of primary care providers, according to several experts.

The approval in October of a new indication for an injectable, extended-release formulation of the opioid receptor antagonist naltrexone, marketed as Vivitrol (Alkermes Inc.), allows for its use as a treatment for preventing relapses in people who have undergone opioid detoxification. Moreover, an implantable form of the opiate agonist buprenorphine, which delivers a continuous dose of medication for up to 6 months, showed promise in a recently published phase III study.

Both advances have the potential for broadening access to care and improving treatment compliance, according to Dr. Nora D. Volkow, a psychiatrist and the director of the National Institute on Drug Abuse (NIDA).

Ultimately, the treatment options could help improve outcomes for the more than 800,000 people in the United States who are believed to be addicted to heroin, and the 1.85 million who abuse or are dependent on opioid pain relievers, such as Oxycontin and Vicodin, Dr. Volkow said in an interview.

Dr. Volkow said she envisions an expanded role not just for psychiatrists and addiction medicine specialists, who have traditionally managed opioid-dependent patients, but also for primary care doctors and infectious disease specialists who could provide integrated care for heroin-addicted HIV patients.

Access to care for all people with opioid dependence would improve if more physicians adopt these new treatment options. Compliance also would improve, largely because both treatments involve extended dosing, Dr. Volkow said.

Older treatment options such as methadone and daily sublingual buprenorphine can be effective, particularly when combined with counseling. However, they require more frequent dosing, a daunting hurdle for patients whose ability to be compliant is easily derailed by the forces of craving and the risk of relapse. Diversion is an issue with sublingual buprenorphine. Many treatment centers reject the idea of using opiates, even synthetic ones, to treat opioid addiction.

Vivitrol, approved in 2006 for the treatment of alcohol dependence, is the first nonnarcotic, nonaddictive extended-release medication approved to treat opioid dependence. In a 6-month study of 250 patients, monthly intramuscular injection with the drug proved significantly more effective than placebo for preventing relapses: 36% of treated patients, compared with 23% of those on placebo, used no opioids between the 5th week and the end of the study, according to a statement released by the Food and Drug Administration following its approval of this new indication.

Importantly, all the patients in the trial were completing or had recently completed detoxification and were no longer physically dependent on opioids at baseline. Despite concerns that patients wouldn't return for repeat injections, Dr. Volkow said she was particularly encouraged to learn that patients did return routinely in the Russian studies on which the new Vivitrol approval was based.

“Patients were very compliant, which was not necessarily predictable,” she explained. “That made me very excited about this particular medication.”

NIDA is funding a study to replicate and expand on the Russian studies, to verify that U.S. patients would respond similarly. Investigators also plan to compare outcomes associated with Vivitrol vs. buprenorphine, she said.

In a phase III, randomized controlled study of 108 opioid addicts, implantable buprenorphine was associated with a 6-month significant reduction in drug use among 40% of patients, compared with 20% of those taking placebo.

About 60% of the treated participants completed the study without experiencing withdrawal symptoms or cravings that compelled them to drop out. By comparison, studies of the daily sublingual dose of buprenorphine currently available for use showed a median adherence of only 40 days in clinical settings, and retention rates in 6-month clinical trials were only 35%–38% (JAMA 2010;14:1576–83).

Dr. Volkow said she hopes implantable buprenorphine will soon become part of the arsenal of weapons against the crippling effects of opioid addiction.

But will more primary care physicians and other specialists start to provide addiction care?

“It's going to be very interesting to watch,” said Dr. Peter D. Friedmann, professor of medicine and community health at Brown University, Providence, R.I.

“Traditionally, primary care doctors have not been very proactive in taking on the care of these patients,” he said. However, he suggested that opioid dependence could be the new depression. That is, until the advent of relatively safe and easy-to-use depression medications in the early 1980s, the care of depressed patients was not seen as the purview of primary care doctors, but now they are routinely treating depression in their practices. It remains unclear whether that will be the case now, however, given that Vivitrol has been available for years for the treatment of alcohol abuse and primary care doctors have not exactly “flocked to take that on,” he said.

These are complicated patients who at times are difficult to manage, and there is still a lot of stigma and unease among doctors about how to care for them, he said.

“It's clearly a positive for the field. It's going to improve things, but is it going to be a panacea? I doubt it,” he said, adding: “I'm cautiously optimistic.”

Dr. Thomas Kosten, former director of the U.S. National Buprenorphine Implementation Program and currently a professor in the psychiatry and neuroscience departments at Baylor College of Medicine, Houston, also expressed cautious optimism about expanded access to care for opioid-dependent patients.

“I can't imagine psychiatrists performing the minor surgical procedure involved with buprenorphine implants, but it is certainly within the purview of many internists and general practitioners,” he said, noting that in many cases in primary care, the machinery is already set up for providing such office procedures, and – in the case of Vivitrol – for providing injections.

“In fact, they would be more comfortable and better equipped to do this,” said Dr. Kosten, who also is research director of the Veterans Health Administration's National Substance Use Disorders Quality Enhancement Research Initiative, based in Houston.

A challenge might be in ensuring that patients receive counseling as needed, but research is increasingly indicating that patients can do well on medications alone if they remain compliant, so concern may be moot, he added.

Another deterrent for many providers has been the requirement of government-sponsored training and oversight of physicians who wish to prescribe buprenorphine.

Dr. H. Berryman Edwards, a psychiatrist in private practice in Bellevue, Wash., and an outspoken critic of the U.S. Drug Enforcement Administration's “disruptive” approach to the oversight of physicians who do prescribe buprenorphine, agreed that psychiatrists aren't likely to use the implantable formulation. But he acknowledged that for primary care doctors and others who embrace this new formulation, it eliminates many of the concerns about diversion and compliance that have deterred physicians from using the treatment in the past.

It will take a certain level of commitment from those who have a desire to use these treatments in the primary care office setting, said Dr. Andrew J. Saxon, a professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and one of the site investigators for the implantable buprenorphine study.

While most primary care doctors probably won't have an interest, those who are willing to learn the implantation procedure – which can be a bit time consuming – and who undergo the required training, will certainly be able to provide this treatment in the office setting. In some cases, it may be that the implants are done elsewhere but patients are followed by their primary care physician, he said.

Vivitrol, on the other hand, could quite easily be provided in the primary care setting. He described Vivitrol as “a pharmacological treatment that is almost perfection,” largely because of the requirement that patients be off opioids before they can receive it.

Vivitrol is safe, he said, with one exception: Patients receiving it will have a decreased tolerance for opioids, and may be at an increased risk of overdose. The overdose risk must be closely monitored, but overall, the treatment has the potential to be a tremendous advantage, Dr. Saxon said.

Dr. Volkow and Dr. Edwards reported having no conflicts of interest. Dr. Friedmann has studied Vivitrol and has received in-kind donations of the medication for his research. He is on the speakers bureau for Reckitt Benckiser Pharmaceuticals, the maker of the sublingual formulation of buprenorphine. Dr. Kosten has served as a consultant to Reckitt Benckiser and to Alkermes. He has served on the data safety monitoring board for Titan Pharmaceuticals, which makes the implantable buprenorphine. Dr. Saxon has served as a consultant to Reckitt Benckiser, and was a site investigator for the Titan-sponsored buprenorphine implant study.

Vivitrol and the implantable form of buprenorphine could improve outcomes for patients who abuse opioids and those addicted to heroin, Dr. Nora D. Volkow says.

Source Courtesy National Institute on Drug Abuse (NIDA)

The recent headway of two treatments for addiction to heroin and other opiates represents a major advancement and has the potential to put opioid addiction therapy within the purview of primary care providers, according to several experts.

The approval in October of a new indication for an injectable, extended-release formulation of the opioid receptor antagonist naltrexone, marketed as Vivitrol (Alkermes Inc.), allows for its use as a treatment for preventing relapses in people who have undergone opioid detoxification. Moreover, an implantable form of the opiate agonist buprenorphine, which delivers a continuous dose of medication for up to 6 months, showed promise in a recently published phase III study.

Both advances have the potential for broadening access to care and improving treatment compliance, according to Dr. Nora D. Volkow, a psychiatrist and the director of the National Institute on Drug Abuse (NIDA).

Ultimately, the treatment options could help improve outcomes for the more than 800,000 people in the United States who are believed to be addicted to heroin, and the 1.85 million who abuse or are dependent on opioid pain relievers, such as Oxycontin and Vicodin, Dr. Volkow said in an interview.

Dr. Volkow said she envisions an expanded role not just for psychiatrists and addiction medicine specialists, who have traditionally managed opioid-dependent patients, but also for primary care doctors and infectious disease specialists who could provide integrated care for heroin-addicted HIV patients.

Access to care for all people with opioid dependence would improve if more physicians adopt these new treatment options. Compliance also would improve, largely because both treatments involve extended dosing, Dr. Volkow said.

Older treatment options such as methadone and daily sublingual buprenorphine can be effective, particularly when combined with counseling. However, they require more frequent dosing, a daunting hurdle for patients whose ability to be compliant is easily derailed by the forces of craving and the risk of relapse. Diversion is an issue with sublingual buprenorphine. Many treatment centers reject the idea of using opiates, even synthetic ones, to treat opioid addiction.

Vivitrol, approved in 2006 for the treatment of alcohol dependence, is the first nonnarcotic, nonaddictive extended-release medication approved to treat opioid dependence. In a 6-month study of 250 patients, monthly intramuscular injection with the drug proved significantly more effective than placebo for preventing relapses: 36% of treated patients, compared with 23% of those on placebo, used no opioids between the 5th week and the end of the study, according to a statement released by the Food and Drug Administration following its approval of this new indication.

Importantly, all the patients in the trial were completing or had recently completed detoxification and were no longer physically dependent on opioids at baseline. Despite concerns that patients wouldn't return for repeat injections, Dr. Volkow said she was particularly encouraged to learn that patients did return routinely in the Russian studies on which the new Vivitrol approval was based.

“Patients were very compliant, which was not necessarily predictable,” she explained. “That made me very excited about this particular medication.”

NIDA is funding a study to replicate and expand on the Russian studies, to verify that U.S. patients would respond similarly. Investigators also plan to compare outcomes associated with Vivitrol vs. buprenorphine, she said.

In a phase III, randomized controlled study of 108 opioid addicts, implantable buprenorphine was associated with a 6-month significant reduction in drug use among 40% of patients, compared with 20% of those taking placebo.

About 60% of the treated participants completed the study without experiencing withdrawal symptoms or cravings that compelled them to drop out. By comparison, studies of the daily sublingual dose of buprenorphine currently available for use showed a median adherence of only 40 days in clinical settings, and retention rates in 6-month clinical trials were only 35%–38% (JAMA 2010;14:1576–83).

Dr. Volkow said she hopes implantable buprenorphine will soon become part of the arsenal of weapons against the crippling effects of opioid addiction.

But will more primary care physicians and other specialists start to provide addiction care?

“It's going to be very interesting to watch,” said Dr. Peter D. Friedmann, professor of medicine and community health at Brown University, Providence, R.I.

“Traditionally, primary care doctors have not been very proactive in taking on the care of these patients,” he said. However, he suggested that opioid dependence could be the new depression. That is, until the advent of relatively safe and easy-to-use depression medications in the early 1980s, the care of depressed patients was not seen as the purview of primary care doctors, but now they are routinely treating depression in their practices. It remains unclear whether that will be the case now, however, given that Vivitrol has been available for years for the treatment of alcohol abuse and primary care doctors have not exactly “flocked to take that on,” he said.

These are complicated patients who at times are difficult to manage, and there is still a lot of stigma and unease among doctors about how to care for them, he said.

“It's clearly a positive for the field. It's going to improve things, but is it going to be a panacea? I doubt it,” he said, adding: “I'm cautiously optimistic.”

Dr. Thomas Kosten, former director of the U.S. National Buprenorphine Implementation Program and currently a professor in the psychiatry and neuroscience departments at Baylor College of Medicine, Houston, also expressed cautious optimism about expanded access to care for opioid-dependent patients.

“I can't imagine psychiatrists performing the minor surgical procedure involved with buprenorphine implants, but it is certainly within the purview of many internists and general practitioners,” he said, noting that in many cases in primary care, the machinery is already set up for providing such office procedures, and – in the case of Vivitrol – for providing injections.

“In fact, they would be more comfortable and better equipped to do this,” said Dr. Kosten, who also is research director of the Veterans Health Administration's National Substance Use Disorders Quality Enhancement Research Initiative, based in Houston.

A challenge might be in ensuring that patients receive counseling as needed, but research is increasingly indicating that patients can do well on medications alone if they remain compliant, so concern may be moot, he added.

Another deterrent for many providers has been the requirement of government-sponsored training and oversight of physicians who wish to prescribe buprenorphine.

Dr. H. Berryman Edwards, a psychiatrist in private practice in Bellevue, Wash., and an outspoken critic of the U.S. Drug Enforcement Administration's “disruptive” approach to the oversight of physicians who do prescribe buprenorphine, agreed that psychiatrists aren't likely to use the implantable formulation. But he acknowledged that for primary care doctors and others who embrace this new formulation, it eliminates many of the concerns about diversion and compliance that have deterred physicians from using the treatment in the past.

It will take a certain level of commitment from those who have a desire to use these treatments in the primary care office setting, said Dr. Andrew J. Saxon, a professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and one of the site investigators for the implantable buprenorphine study.

While most primary care doctors probably won't have an interest, those who are willing to learn the implantation procedure – which can be a bit time consuming – and who undergo the required training, will certainly be able to provide this treatment in the office setting. In some cases, it may be that the implants are done elsewhere but patients are followed by their primary care physician, he said.

Vivitrol, on the other hand, could quite easily be provided in the primary care setting. He described Vivitrol as “a pharmacological treatment that is almost perfection,” largely because of the requirement that patients be off opioids before they can receive it.

Vivitrol is safe, he said, with one exception: Patients receiving it will have a decreased tolerance for opioids, and may be at an increased risk of overdose. The overdose risk must be closely monitored, but overall, the treatment has the potential to be a tremendous advantage, Dr. Saxon said.

Dr. Volkow and Dr. Edwards reported having no conflicts of interest. Dr. Friedmann has studied Vivitrol and has received in-kind donations of the medication for his research. He is on the speakers bureau for Reckitt Benckiser Pharmaceuticals, the maker of the sublingual formulation of buprenorphine. Dr. Kosten has served as a consultant to Reckitt Benckiser and to Alkermes. He has served on the data safety monitoring board for Titan Pharmaceuticals, which makes the implantable buprenorphine. Dr. Saxon has served as a consultant to Reckitt Benckiser, and was a site investigator for the Titan-sponsored buprenorphine implant study.

Vivitrol and the implantable form of buprenorphine could improve outcomes for patients who abuse opioids and those addicted to heroin, Dr. Nora D. Volkow says.

Source Courtesy National Institute on Drug Abuse (NIDA)

The recent headway of two treatments for addiction to heroin and other opiates represents a major advancement and has the potential to put opioid addiction therapy within the purview of primary care providers, according to several experts.

The approval in October of a new indication for an injectable, extended-release formulation of the opioid receptor antagonist naltrexone, marketed as Vivitrol (Alkermes Inc.), allows for its use as a treatment for preventing relapses in people who have undergone opioid detoxification. Moreover, an implantable form of the opiate agonist buprenorphine, which delivers a continuous dose of medication for up to 6 months, showed promise in a recently published phase III study.

Both advances have the potential for broadening access to care and improving treatment compliance, according to Dr. Nora D. Volkow, a psychiatrist and the director of the National Institute on Drug Abuse (NIDA).

Ultimately, the treatment options could help improve outcomes for the more than 800,000 people in the United States who are believed to be addicted to heroin, and the 1.85 million who abuse or are dependent on opioid pain relievers, such as Oxycontin and Vicodin, Dr. Volkow said in an interview.

Dr. Volkow said she envisions an expanded role not just for psychiatrists and addiction medicine specialists, who have traditionally managed opioid-dependent patients, but also for primary care doctors and infectious disease specialists who could provide integrated care for heroin-addicted HIV patients.

Access to care for all people with opioid dependence would improve if more physicians adopt these new treatment options. Compliance also would improve, largely because both treatments involve extended dosing, Dr. Volkow said.

Older treatment options such as methadone and daily sublingual buprenorphine can be effective, particularly when combined with counseling. However, they require more frequent dosing, a daunting hurdle for patients whose ability to be compliant is easily derailed by the forces of craving and the risk of relapse. Diversion is an issue with sublingual buprenorphine. Many treatment centers reject the idea of using opiates, even synthetic ones, to treat opioid addiction.

Vivitrol, approved in 2006 for the treatment of alcohol dependence, is the first nonnarcotic, nonaddictive extended-release medication approved to treat opioid dependence. In a 6-month study of 250 patients, monthly intramuscular injection with the drug proved significantly more effective than placebo for preventing relapses: 36% of treated patients, compared with 23% of those on placebo, used no opioids between the 5th week and the end of the study, according to a statement released by the Food and Drug Administration following its approval of this new indication.

Importantly, all the patients in the trial were completing or had recently completed detoxification and were no longer physically dependent on opioids at baseline. Despite concerns that patients wouldn't return for repeat injections, Dr. Volkow said she was particularly encouraged to learn that patients did return routinely in the Russian studies on which the new Vivitrol approval was based.

“Patients were very compliant, which was not necessarily predictable,” she explained. “That made me very excited about this particular medication.”

NIDA is funding a study to replicate and expand on the Russian studies, to verify that U.S. patients would respond similarly. Investigators also plan to compare outcomes associated with Vivitrol vs. buprenorphine, she said.

In a phase III, randomized controlled study of 108 opioid addicts, implantable buprenorphine was associated with a 6-month significant reduction in drug use among 40% of patients, compared with 20% of those taking placebo.

About 60% of the treated participants completed the study without experiencing withdrawal symptoms or cravings that compelled them to drop out. By comparison, studies of the daily sublingual dose of buprenorphine currently available for use showed a median adherence of only 40 days in clinical settings, and retention rates in 6-month clinical trials were only 35%–38% (JAMA 2010;14:1576–83).

Dr. Volkow said she hopes implantable buprenorphine will soon become part of the arsenal of weapons against the crippling effects of opioid addiction.

But will more primary care physicians and other specialists start to provide addiction care?

“It's going to be very interesting to watch,” said Dr. Peter D. Friedmann, professor of medicine and community health at Brown University, Providence, R.I.

“Traditionally, primary care doctors have not been very proactive in taking on the care of these patients,” he said. However, he suggested that opioid dependence could be the new depression. That is, until the advent of relatively safe and easy-to-use depression medications in the early 1980s, the care of depressed patients was not seen as the purview of primary care doctors, but now they are routinely treating depression in their practices. It remains unclear whether that will be the case now, however, given that Vivitrol has been available for years for the treatment of alcohol abuse and primary care doctors have not exactly “flocked to take that on,” he said.

These are complicated patients who at times are difficult to manage, and there is still a lot of stigma and unease among doctors about how to care for them, he said.

“It's clearly a positive for the field. It's going to improve things, but is it going to be a panacea? I doubt it,” he said, adding: “I'm cautiously optimistic.”

Dr. Thomas Kosten, former director of the U.S. National Buprenorphine Implementation Program and currently a professor in the psychiatry and neuroscience departments at Baylor College of Medicine, Houston, also expressed cautious optimism about expanded access to care for opioid-dependent patients.

“I can't imagine psychiatrists performing the minor surgical procedure involved with buprenorphine implants, but it is certainly within the purview of many internists and general practitioners,” he said, noting that in many cases in primary care, the machinery is already set up for providing such office procedures, and – in the case of Vivitrol – for providing injections.

“In fact, they would be more comfortable and better equipped to do this,” said Dr. Kosten, who also is research director of the Veterans Health Administration's National Substance Use Disorders Quality Enhancement Research Initiative, based in Houston.

A challenge might be in ensuring that patients receive counseling as needed, but research is increasingly indicating that patients can do well on medications alone if they remain compliant, so concern may be moot, he added.

Another deterrent for many providers has been the requirement of government-sponsored training and oversight of physicians who wish to prescribe buprenorphine.

Dr. H. Berryman Edwards, a psychiatrist in private practice in Bellevue, Wash., and an outspoken critic of the U.S. Drug Enforcement Administration's “disruptive” approach to the oversight of physicians who do prescribe buprenorphine, agreed that psychiatrists aren't likely to use the implantable formulation. But he acknowledged that for primary care doctors and others who embrace this new formulation, it eliminates many of the concerns about diversion and compliance that have deterred physicians from using the treatment in the past.

It will take a certain level of commitment from those who have a desire to use these treatments in the primary care office setting, said Dr. Andrew J. Saxon, a professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and one of the site investigators for the implantable buprenorphine study.

While most primary care doctors probably won't have an interest, those who are willing to learn the implantation procedure – which can be a bit time consuming – and who undergo the required training, will certainly be able to provide this treatment in the office setting. In some cases, it may be that the implants are done elsewhere but patients are followed by their primary care physician, he said.

Vivitrol, on the other hand, could quite easily be provided in the primary care setting. He described Vivitrol as “a pharmacological treatment that is almost perfection,” largely because of the requirement that patients be off opioids before they can receive it.

Vivitrol is safe, he said, with one exception: Patients receiving it will have a decreased tolerance for opioids, and may be at an increased risk of overdose. The overdose risk must be closely monitored, but overall, the treatment has the potential to be a tremendous advantage, Dr. Saxon said.

Dr. Volkow and Dr. Edwards reported having no conflicts of interest. Dr. Friedmann has studied Vivitrol and has received in-kind donations of the medication for his research. He is on the speakers bureau for Reckitt Benckiser Pharmaceuticals, the maker of the sublingual formulation of buprenorphine. Dr. Kosten has served as a consultant to Reckitt Benckiser and to Alkermes. He has served on the data safety monitoring board for Titan Pharmaceuticals, which makes the implantable buprenorphine. Dr. Saxon has served as a consultant to Reckitt Benckiser, and was a site investigator for the Titan-sponsored buprenorphine implant study.

Vivitrol and the implantable form of buprenorphine could improve outcomes for patients who abuse opioids and those addicted to heroin, Dr. Nora D. Volkow says.

Source Courtesy National Institute on Drug Abuse (NIDA)

Major Finding: The genome-wide burden of CNVs was significantly greater in the ADHD patients, compared with the controls (rates of 0.156 vs. 0.075, respectively).

Data Source: A genome-wide analysis of CNVs in 366 children with ADHD and 1,047 controls.

Disclosures: The study was funded primarily by Wellcome Trust. Additional funding was provided by Action Research, Baily Thomas Charitable Trust, UK Medical Research Council, and the European Union. Study authors stated that they had no conflicts to report.

Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder, rather than a purely social construct, according to British researchers who have found that a type of genetic variation associated with brain disorders such as schizophrenia and autism also occurs in excess in ADHD patients.

The findings, published online, provide the first direct evidence of a genetic basis for ADHD, Dr. Nigel Williams of Cardiff University, Wales, and his colleagues reported (Lancet 2010 [doi: 10.1016/S0140–6736(10)61109–9]).

The investigators performed a genome-wide analysis of large, rare chromosomal deletions and duplications known as copy number variants (CNVs) in 366 children with ADHD and 1,047 controls. The genome-wide burden of CNVs was significantly greater in the ADHD patients, compared with that in the controls – rates of 0.156 and 0.075, respectively, they found.

The CNVs identified in this study are similar to those found in patients with schizophrenia and autism, and are significantly enriched for loci that have previously been implicated in those disorders – with particular overlap at a region on chromosome 16 that spans numerous genes, including one that affects brain development.

Furthermore, although the rate of CNVs was significantly higher in children with ADHD with and without intellectual disability, compared with the general population, the rate was particularly high in those with intellectual disability, defined as those with an IQ of less than 70 (rates of 0.424 and 0.075, respectively).

The findings are noteworthy because despite evidence that ADHD might be a genetic condition – for example, it has an estimated heritability of 76% – there has been a great deal of debate over whether it is a result of bad parenting or other external factors, coauthor Dr. Anita Thapar said during a press conference on the findings. “ADHD can be stigmatizing … and finding this direct genetic link to ADHD should help clear this misunderstanding and address this issue of stigma,” said Dr. Thapar, professor of child and adolescent psychiatry at Cardiff University.

In addition to providing a window into the biology of the brain, the findings also will influence the way in which ADHD is classified and will improve communication between scientists and clinicians about “what we mean by ADHD,” she said.

“This will be the start of a much more scientific venture, because our findings are going to help us unravel the biologic basis of ADHD, and that's going to be really important in turn in the further future to help us develop new and much more effective treatments for affected individuals.”

The subjects were aged 5–17 years (mean, 10.5 years), were of white U.K. origin, and had a mean IQ of 86. Controls were unrelated, ethnically matched children from the 1958 British Birth Cohort.

The findings have important implications. “Our results emphasize that further investigation of CNVs in ADHD is a priority for research into this disorder,” the investigators wrote.

Major Finding: The genome-wide burden of CNVs was significantly greater in the ADHD patients, compared with the controls (rates of 0.156 vs. 0.075, respectively).

Data Source: A genome-wide analysis of CNVs in 366 children with ADHD and 1,047 controls.

Disclosures: The study was funded primarily by Wellcome Trust. Additional funding was provided by Action Research, Baily Thomas Charitable Trust, UK Medical Research Council, and the European Union. Study authors stated that they had no conflicts to report.

Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder, rather than a purely social construct, according to British researchers who have found that a type of genetic variation associated with brain disorders such as schizophrenia and autism also occurs in excess in ADHD patients.

The findings, published online, provide the first direct evidence of a genetic basis for ADHD, Dr. Nigel Williams of Cardiff University, Wales, and his colleagues reported (Lancet 2010 [doi: 10.1016/S0140–6736(10)61109–9]).

The investigators performed a genome-wide analysis of large, rare chromosomal deletions and duplications known as copy number variants (CNVs) in 366 children with ADHD and 1,047 controls. The genome-wide burden of CNVs was significantly greater in the ADHD patients, compared with that in the controls – rates of 0.156 and 0.075, respectively, they found.

The CNVs identified in this study are similar to those found in patients with schizophrenia and autism, and are significantly enriched for loci that have previously been implicated in those disorders – with particular overlap at a region on chromosome 16 that spans numerous genes, including one that affects brain development.

Furthermore, although the rate of CNVs was significantly higher in children with ADHD with and without intellectual disability, compared with the general population, the rate was particularly high in those with intellectual disability, defined as those with an IQ of less than 70 (rates of 0.424 and 0.075, respectively).

The findings are noteworthy because despite evidence that ADHD might be a genetic condition – for example, it has an estimated heritability of 76% – there has been a great deal of debate over whether it is a result of bad parenting or other external factors, coauthor Dr. Anita Thapar said during a press conference on the findings. “ADHD can be stigmatizing … and finding this direct genetic link to ADHD should help clear this misunderstanding and address this issue of stigma,” said Dr. Thapar, professor of child and adolescent psychiatry at Cardiff University.

In addition to providing a window into the biology of the brain, the findings also will influence the way in which ADHD is classified and will improve communication between scientists and clinicians about “what we mean by ADHD,” she said.

“This will be the start of a much more scientific venture, because our findings are going to help us unravel the biologic basis of ADHD, and that's going to be really important in turn in the further future to help us develop new and much more effective treatments for affected individuals.”

The subjects were aged 5–17 years (mean, 10.5 years), were of white U.K. origin, and had a mean IQ of 86. Controls were unrelated, ethnically matched children from the 1958 British Birth Cohort.

The findings have important implications. “Our results emphasize that further investigation of CNVs in ADHD is a priority for research into this disorder,” the investigators wrote.

Major Finding: The genome-wide burden of CNVs was significantly greater in the ADHD patients, compared with the controls (rates of 0.156 vs. 0.075, respectively).

Data Source: A genome-wide analysis of CNVs in 366 children with ADHD and 1,047 controls.

Disclosures: The study was funded primarily by Wellcome Trust. Additional funding was provided by Action Research, Baily Thomas Charitable Trust, UK Medical Research Council, and the European Union. Study authors stated that they had no conflicts to report.

Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder, rather than a purely social construct, according to British researchers who have found that a type of genetic variation associated with brain disorders such as schizophrenia and autism also occurs in excess in ADHD patients.

The findings, published online, provide the first direct evidence of a genetic basis for ADHD, Dr. Nigel Williams of Cardiff University, Wales, and his colleagues reported (Lancet 2010 [doi: 10.1016/S0140–6736(10)61109–9]).

The investigators performed a genome-wide analysis of large, rare chromosomal deletions and duplications known as copy number variants (CNVs) in 366 children with ADHD and 1,047 controls. The genome-wide burden of CNVs was significantly greater in the ADHD patients, compared with that in the controls – rates of 0.156 and 0.075, respectively, they found.

The CNVs identified in this study are similar to those found in patients with schizophrenia and autism, and are significantly enriched for loci that have previously been implicated in those disorders – with particular overlap at a region on chromosome 16 that spans numerous genes, including one that affects brain development.

Furthermore, although the rate of CNVs was significantly higher in children with ADHD with and without intellectual disability, compared with the general population, the rate was particularly high in those with intellectual disability, defined as those with an IQ of less than 70 (rates of 0.424 and 0.075, respectively).

The findings are noteworthy because despite evidence that ADHD might be a genetic condition – for example, it has an estimated heritability of 76% – there has been a great deal of debate over whether it is a result of bad parenting or other external factors, coauthor Dr. Anita Thapar said during a press conference on the findings. “ADHD can be stigmatizing … and finding this direct genetic link to ADHD should help clear this misunderstanding and address this issue of stigma,” said Dr. Thapar, professor of child and adolescent psychiatry at Cardiff University.

In addition to providing a window into the biology of the brain, the findings also will influence the way in which ADHD is classified and will improve communication between scientists and clinicians about “what we mean by ADHD,” she said.

“This will be the start of a much more scientific venture, because our findings are going to help us unravel the biologic basis of ADHD, and that's going to be really important in turn in the further future to help us develop new and much more effective treatments for affected individuals.”

The subjects were aged 5–17 years (mean, 10.5 years), were of white U.K. origin, and had a mean IQ of 86. Controls were unrelated, ethnically matched children from the 1958 British Birth Cohort.

The findings have important implications. “Our results emphasize that further investigation of CNVs in ADHD is a priority for research into this disorder,” the investigators wrote.

Dosing directions and measuring devices included with top-selling pediatric over-the-counter liquid medications were highly inconsistent as of November 2009, when the Food and Drug Administration issued voluntary industry guidelines in response to numerous reports of unintentional overdoses among children, according to a descriptive study of 200 such medications.

© Larry Allen/Fotolia.com

The study, conducted to provide baseline data for assessing the degree and pace of industry conformity with the new guidelines, showed that 146 of 148 medications (98.6%) that included measuring devices had one or more inconsistencies between the dosing directions and the markings on the device, Dr. H. Shonna Yin of New York University and colleagues reported online in the Nov. 30 issue of JAMA.

[Read: Tylenol Cold Products and Children's Benadryl, Motrin Recalled.]

The inconsistencies included missing markings in 24% of the products, superfluous markings in 81% of the products, and inconsistencies between the product’s label and the measuring device in 89% of products.

Furthermore, 5.5% of the products used atypical units of measurement, such as cubic centimeters, drams, or fluid ounces; 71.5% used milliliters (although 97 products used a nonstandard abbreviation for milliliter); 77.5% used teaspoon units; and 18.5% used the tablespoon (JAMA 2010 Nov. 30[doi:10.1001/jama.2010.1797]).

Other potentially problematic findings included the lack of a leading zero in 12.5% of 40 products with a dose smaller than 1 presented in decimal format, the use of nonstandard fraction formats in 64.5% of 110 products that used fractions, and the lack of a statement that the measuring device should be used only with its associated product in 62% of the 148 medications that included a device.

The investigators evaluated 200 products representing 99% of the U.S. market of analgesic, cough/cold, allergy, and gastrointestinal OTC liquid products – including 58 private-label products – that contained dosing information for children under age 12 years. The medications were studied during the 52 weeks ending Oct. 30, 2009.

"Given the high prevalence of baseline inconsistencies, regulatory oversight may be helpful in accelerating adoption of the guidance recommendations," the investigators wrote, noting that several Institute of Medicine reports have identified variable and poor-quality drug labeling as a major cause of confusion among consumers – and therefore as a potential risk factor for unintentional misuse of products.

Indeed, many of the unintentional overdoses that prompted the FDA guidance in 2009 were attributed, at least in part, to products with inconsistent or confusing labels and measuring devices. The FDA recommendations state that:

• All OTC liquid medication products include a measuring device.

• Consistent abbreviations and units of measurement be used for a given product’s device.

• The devices bear only necessary markings and not hold significantly more medication than the largest prescribed dose.

• Abbreviations conform to standards and be defined.

• Decimals and fractions be used with care.

• Studies on accurate use of the medications by consumers be conducted.

More than half of all U.S. children are exposed to at least one medication in a given week – and more than half of those medications are OTC. Also at least one in three U.S. adults and at least one in four U.S. parents have limited health literacy and even worse numeracy. For these reasons, the findings support these recommendations and particularly underscore the need for standardized measuring devices with all nonprescription liquid products, consistency between dosing directions and markings on the measuring device, and standardization of measurement units, abbreviations, and numeric formats across products, Dr. Yin and associates said.

"Even frequently used terms like teaspoon and tablespoon may be misinterpreted," they wrote, noting that errors in understanding teaspoon vs. tablespoon have been found to contribute to threefold errors, and that the use of these terms endorses the use of kitchen spoons, which are known to be associated with measurement error.

More patient-centered research is needed to adequately address best practices under the FDA guidance, and to evaluate other aspects of product packaging and safe medication use, they said, concluding that since the FDA’s guidelines are voluntary, subsequent systematic product analyses may help monitor progress in terms of industry compliance – and assess whether additional regulatory oversight is needed to ensure safe and effective use of OTC medications.

This study was funded by a career development grant to Dr. Yin from the Robert Wood Johnson Physician Faculty Scholars Program. Dr. Yin also reported receiving funds from Pfizer and McKing Consulting Corp. Other authors on the study also said they received funding from Pfizer, McNeil Consumer Healthcare, Abbott, Johnson & Johnson, and/or McKing Consulting.

Dosing directions and measuring devices included with top-selling pediatric over-the-counter liquid medications were highly inconsistent as of November 2009, when the Food and Drug Administration issued voluntary industry guidelines in response to numerous reports of unintentional overdoses among children, according to a descriptive study of 200 such medications.

© Larry Allen/Fotolia.com

The study, conducted to provide baseline data for assessing the degree and pace of industry conformity with the new guidelines, showed that 146 of 148 medications (98.6%) that included measuring devices had one or more inconsistencies between the dosing directions and the markings on the device, Dr. H. Shonna Yin of New York University and colleagues reported online in the Nov. 30 issue of JAMA.

[Read: Tylenol Cold Products and Children's Benadryl, Motrin Recalled.]

The inconsistencies included missing markings in 24% of the products, superfluous markings in 81% of the products, and inconsistencies between the product’s label and the measuring device in 89% of products.

Furthermore, 5.5% of the products used atypical units of measurement, such as cubic centimeters, drams, or fluid ounces; 71.5% used milliliters (although 97 products used a nonstandard abbreviation for milliliter); 77.5% used teaspoon units; and 18.5% used the tablespoon (JAMA 2010 Nov. 30[doi:10.1001/jama.2010.1797]).

Other potentially problematic findings included the lack of a leading zero in 12.5% of 40 products with a dose smaller than 1 presented in decimal format, the use of nonstandard fraction formats in 64.5% of 110 products that used fractions, and the lack of a statement that the measuring device should be used only with its associated product in 62% of the 148 medications that included a device.

The investigators evaluated 200 products representing 99% of the U.S. market of analgesic, cough/cold, allergy, and gastrointestinal OTC liquid products – including 58 private-label products – that contained dosing information for children under age 12 years. The medications were studied during the 52 weeks ending Oct. 30, 2009.

"Given the high prevalence of baseline inconsistencies, regulatory oversight may be helpful in accelerating adoption of the guidance recommendations," the investigators wrote, noting that several Institute of Medicine reports have identified variable and poor-quality drug labeling as a major cause of confusion among consumers – and therefore as a potential risk factor for unintentional misuse of products.

Indeed, many of the unintentional overdoses that prompted the FDA guidance in 2009 were attributed, at least in part, to products with inconsistent or confusing labels and measuring devices. The FDA recommendations state that:

• All OTC liquid medication products include a measuring device.

• Consistent abbreviations and units of measurement be used for a given product’s device.

• The devices bear only necessary markings and not hold significantly more medication than the largest prescribed dose.

• Abbreviations conform to standards and be defined.

• Decimals and fractions be used with care.

• Studies on accurate use of the medications by consumers be conducted.

More than half of all U.S. children are exposed to at least one medication in a given week – and more than half of those medications are OTC. Also at least one in three U.S. adults and at least one in four U.S. parents have limited health literacy and even worse numeracy. For these reasons, the findings support these recommendations and particularly underscore the need for standardized measuring devices with all nonprescription liquid products, consistency between dosing directions and markings on the measuring device, and standardization of measurement units, abbreviations, and numeric formats across products, Dr. Yin and associates said.

"Even frequently used terms like teaspoon and tablespoon may be misinterpreted," they wrote, noting that errors in understanding teaspoon vs. tablespoon have been found to contribute to threefold errors, and that the use of these terms endorses the use of kitchen spoons, which are known to be associated with measurement error.

More patient-centered research is needed to adequately address best practices under the FDA guidance, and to evaluate other aspects of product packaging and safe medication use, they said, concluding that since the FDA’s guidelines are voluntary, subsequent systematic product analyses may help monitor progress in terms of industry compliance – and assess whether additional regulatory oversight is needed to ensure safe and effective use of OTC medications.

This study was funded by a career development grant to Dr. Yin from the Robert Wood Johnson Physician Faculty Scholars Program. Dr. Yin also reported receiving funds from Pfizer and McKing Consulting Corp. Other authors on the study also said they received funding from Pfizer, McNeil Consumer Healthcare, Abbott, Johnson & Johnson, and/or McKing Consulting.

Dosing directions and measuring devices included with top-selling pediatric over-the-counter liquid medications were highly inconsistent as of November 2009, when the Food and Drug Administration issued voluntary industry guidelines in response to numerous reports of unintentional overdoses among children, according to a descriptive study of 200 such medications.

© Larry Allen/Fotolia.com

The study, conducted to provide baseline data for assessing the degree and pace of industry conformity with the new guidelines, showed that 146 of 148 medications (98.6%) that included measuring devices had one or more inconsistencies between the dosing directions and the markings on the device, Dr. H. Shonna Yin of New York University and colleagues reported online in the Nov. 30 issue of JAMA.

[Read: Tylenol Cold Products and Children's Benadryl, Motrin Recalled.]

The inconsistencies included missing markings in 24% of the products, superfluous markings in 81% of the products, and inconsistencies between the product’s label and the measuring device in 89% of products.

Furthermore, 5.5% of the products used atypical units of measurement, such as cubic centimeters, drams, or fluid ounces; 71.5% used milliliters (although 97 products used a nonstandard abbreviation for milliliter); 77.5% used teaspoon units; and 18.5% used the tablespoon (JAMA 2010 Nov. 30[doi:10.1001/jama.2010.1797]).

Other potentially problematic findings included the lack of a leading zero in 12.5% of 40 products with a dose smaller than 1 presented in decimal format, the use of nonstandard fraction formats in 64.5% of 110 products that used fractions, and the lack of a statement that the measuring device should be used only with its associated product in 62% of the 148 medications that included a device.

The investigators evaluated 200 products representing 99% of the U.S. market of analgesic, cough/cold, allergy, and gastrointestinal OTC liquid products – including 58 private-label products – that contained dosing information for children under age 12 years. The medications were studied during the 52 weeks ending Oct. 30, 2009.

"Given the high prevalence of baseline inconsistencies, regulatory oversight may be helpful in accelerating adoption of the guidance recommendations," the investigators wrote, noting that several Institute of Medicine reports have identified variable and poor-quality drug labeling as a major cause of confusion among consumers – and therefore as a potential risk factor for unintentional misuse of products.

Indeed, many of the unintentional overdoses that prompted the FDA guidance in 2009 were attributed, at least in part, to products with inconsistent or confusing labels and measuring devices. The FDA recommendations state that:

• All OTC liquid medication products include a measuring device.

• Consistent abbreviations and units of measurement be used for a given product’s device.

• The devices bear only necessary markings and not hold significantly more medication than the largest prescribed dose.

• Abbreviations conform to standards and be defined.

• Decimals and fractions be used with care.

• Studies on accurate use of the medications by consumers be conducted.

More than half of all U.S. children are exposed to at least one medication in a given week – and more than half of those medications are OTC. Also at least one in three U.S. adults and at least one in four U.S. parents have limited health literacy and even worse numeracy. For these reasons, the findings support these recommendations and particularly underscore the need for standardized measuring devices with all nonprescription liquid products, consistency between dosing directions and markings on the measuring device, and standardization of measurement units, abbreviations, and numeric formats across products, Dr. Yin and associates said.

"Even frequently used terms like teaspoon and tablespoon may be misinterpreted," they wrote, noting that errors in understanding teaspoon vs. tablespoon have been found to contribute to threefold errors, and that the use of these terms endorses the use of kitchen spoons, which are known to be associated with measurement error.

More patient-centered research is needed to adequately address best practices under the FDA guidance, and to evaluate other aspects of product packaging and safe medication use, they said, concluding that since the FDA’s guidelines are voluntary, subsequent systematic product analyses may help monitor progress in terms of industry compliance – and assess whether additional regulatory oversight is needed to ensure safe and effective use of OTC medications.

This study was funded by a career development grant to Dr. Yin from the Robert Wood Johnson Physician Faculty Scholars Program. Dr. Yin also reported receiving funds from Pfizer and McKing Consulting Corp. Other authors on the study also said they received funding from Pfizer, McNeil Consumer Healthcare, Abbott, Johnson & Johnson, and/or McKing Consulting.