If you are a busy primary care physician, wouldn’t you like to get some quick confirmation that your patient with a fever and runny nose has a viral upper respiratory infection? If there were a test or a simple physical finding that could give you the answer while the patient was still in the office, you could dispense a quick dose of reassurance and send him or her on their way. It would probably help you inch a bit closer to relieving the congestion in your waiting room.

I am sure most of you realize that relying on the patient’s temperature or the color of his or her nasal mucus is not going to give you that reliable and swift answer you would like. There have been rapid diagnostic tests for influenza on the market for several years, but I have not been aware of a similar test for rhinovirus. But I recently came across a study that offers some hope that such a test might become a reality in the future (EBioMedicine. 2017 Mar;17:172-81). In the study, researchers at Duke University and elsewhere identified a group of proteins in mucus that can confirm – with 86% accuracy – that the patient is infected with a cold or flu virus. They anticipate that this discovery could be adapted into a rapid test that could be performed in the doctor’s office.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@frontlinemedcom.com.

If you are a busy primary care physician, wouldn’t you like to get some quick confirmation that your patient with a fever and runny nose has a viral upper respiratory infection? If there were a test or a simple physical finding that could give you the answer while the patient was still in the office, you could dispense a quick dose of reassurance and send him or her on their way. It would probably help you inch a bit closer to relieving the congestion in your waiting room.

I am sure most of you realize that relying on the patient’s temperature or the color of his or her nasal mucus is not going to give you that reliable and swift answer you would like. There have been rapid diagnostic tests for influenza on the market for several years, but I have not been aware of a similar test for rhinovirus. But I recently came across a study that offers some hope that such a test might become a reality in the future (EBioMedicine. 2017 Mar;17:172-81). In the study, researchers at Duke University and elsewhere identified a group of proteins in mucus that can confirm – with 86% accuracy – that the patient is infected with a cold or flu virus. They anticipate that this discovery could be adapted into a rapid test that could be performed in the doctor’s office.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@frontlinemedcom.com.

If you are a busy primary care physician, wouldn’t you like to get some quick confirmation that your patient with a fever and runny nose has a viral upper respiratory infection? If there were a test or a simple physical finding that could give you the answer while the patient was still in the office, you could dispense a quick dose of reassurance and send him or her on their way. It would probably help you inch a bit closer to relieving the congestion in your waiting room.

I am sure most of you realize that relying on the patient’s temperature or the color of his or her nasal mucus is not going to give you that reliable and swift answer you would like. There have been rapid diagnostic tests for influenza on the market for several years, but I have not been aware of a similar test for rhinovirus. But I recently came across a study that offers some hope that such a test might become a reality in the future (EBioMedicine. 2017 Mar;17:172-81). In the study, researchers at Duke University and elsewhere identified a group of proteins in mucus that can confirm – with 86% accuracy – that the patient is infected with a cold or flu virus. They anticipate that this discovery could be adapted into a rapid test that could be performed in the doctor’s office.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@frontlinemedcom.com.

Bacterial vaginosis (BV) is caused by a complex change in vaginal bacterial flora, with a reduction in lactobacilli (which help maintain an acidic environment) and an increase in anaerobic gram-negative organisms including Gardnerella vaginalis species and Bacteroides, Prevotella, and Mobiluncus genera. Infection with G vaginalis is thought to trigger a cascade of changes in vaginal flora that leads to BV.¹

Photo: CDC/ M. Rein

BV is present in 30% to 50% of sexually active women, and of these women 50% to 75% have an abnormal vaginal discharge, which is gray, thin, and homogeneous and may have a fishy odor.² In addition to causing an abnormal vaginal discharge, BV is a cause of postpartum fever, posthysterectomy vaginal cuff cellulitis, and postabortion infection, and it increases the risk of acquiring HIV, herpes simplex type 2, gonorrhea, chlamydia, and trichomoniasis infection.³

When using microscopy and the Amsel criteria, the diagnosis of BV is made when at least 3 of the following 4 criteria are present:  

1. homogeneous, thin, gray discharge  
2. vaginal pH >4.5  
3. positive whiff-amine test when applying a drop of 10% KOH to a sample of the vaginal discharge  
4. clue cells detected with microscopy on a saline wet mount.  

If microscopy is not available, the Affirm VPIII test (BD Diagnostic Systems, Franklin Lakes, New Jersey) for DNA sequences of G vaginalis has high sensitivity and specificity.⁴ The OSOM BVBlue test (Sekisui Diagnostics, Lexington, Massachusetts), a Clinical Laboratory Improvement Amendments-waived point of service test, measures vaginal sialidase, which is produced by Gardnerella and other pathogens associated with BV.⁵ BV may be detected in routine cervical cytology testing and, if the patient is symptomatic, treatment is recommended.

Initial treatment of BV. The Centers for Disease Control and Prevention (CDC) has recommended 3 treatment regimens for BV and 4 alternative treatment options (TABLE).⁶ In addition to antimicrobial treatment, the CDC recommends that women with BV use condoms with sexual intercourse. The CDC also advises that clinicians should con-sider testing women with BV for HIV and other sexually transmitted infections.

Related article:
Successful treatment of chronic vaginitis

Treatment of recurrent BV

A major problem with BV is that, although initial treatment is successful in about 80% of cases, up to 50% of women will have a recurrence of BV within 12 months of initial treatment.² Preliminary studies suggest that for women with 3 or more episodes of BV, the regimens below may be effective.  

Regimen 1
Following the completion of a CDC-recommended treatment regimen (see TABLE), prescribe metronidazole vaginal gel 0.75%, one full applicator, twice weekly for 6 months.⁷

In a prospective randomized trial examining this regimen, following initial treatment with a 10-day metronidazole vaginal gel regimen 112 women were randomly assigned to chronic suppressive therapy with metronidazole vaginal gel 0.75%, one full applicator, twice weekly for 16 weeks or a placebo. During the treatment period, recurrent BV was diagnosed in 26% of the women taking metronidazole gel and 59% of the women taking placebo.⁷ This regimen may be complicated by secondary vaginal candidiasis, which may be treated with a vaginal or oral antifungal agent. 

Regimen 2
Initiate a 21-day course of vaginal boric acid capsules 600 mg once daily at bedtime and simultaneously prescribe a standard CDC treatment regimen (see TABLE). At the completion of the vaginal boric acid treatment initiate metronidazole vaginal gel 0.75% twice weekly for 6 months.⁸

NOTE: Boric acid can cause death if consumed orally.⁹ Boric acid capsules should be stored securely to ensure that they are not accidentally taken orally. Boric acid poisoning may present with vomiting, fever, skin rash, neutropenia, thrombocytopenia, metabolic acidosis, and renal failure.¹⁰ Boric acid should not be used by pregnant women because it is a teratogen.¹¹

The bacterial organisms responsible for BV reside in a self-produced matrix, referred to as a biofilm, that protect the organisms from antimicrobial agents.¹² Boric acid may prevent the formation of a biofilm and increase the effectiveness of anti-microbial treatment.

Regimen 3
Following the completion of a standard treatment regimen (see TABLE), prescribe oral metronidazole 2 g and fluconazole 150 mg administered once every month.¹³

In a randomized clinical trial, 310 female sex workers were randomly assigned to monthly treatment with oral metronidazole 2 g plus fluconazole 150 mg or placebo for up to 12 months.¹³ In the treatment and placebo groups episodes of BV were 199 and 326 per 100 person-years, respectively (hazard ratio, 0.55; 95% confidence interval, 0.49-0.63; P<.001). In Canada, a vaginal ovule containing both a high dose of metronidazole (500 mg) and nystatin (10,000 IU) is available and could be used intermittently to prevent recurrence.¹⁴

Treatment of partners

The CDC does not recommend treatment of the partners of women with BV because there are no definitive data to support such a recommendation. However, the 6 published clinical trials testing the utility of treating sex partners of women with BV have significant methodologic flaws, including underpowered studies and suboptimal antibiotic treatment regimens.¹⁵ Hence, whether partners should be treated remains an open question. Many experts believe that, in most cases, BV is a sexually transmitted disease.^16,17 For women who have sex with women, the rate of BV concordance among partners is high. If one woman has diagnosed BV and symptoms are present in her partner, treatment of the partner is reasonable. For women with BV who have sex with men, sexual intercourse influences disease activity, and consistent use of condoms may reduce the rate of recurrence.¹⁸ Male circumcision may reduce the risk of BV in female partners.¹⁹

Related article:
Bacterial vaginosis: Meet patients' needs with effective diagnosis and treatment

Over-the-counter treatments

In women with BV it is thought that the vaginal administration of lactic acid can help restore the normal acidic pH of the vagina, encourage the growth of lactobacilli, and suppress the growth of the bacteria that cause BV.²⁰ Many products containing lactic acid in a formulation for vaginal use are available (among them Luvena and Gynofit gel).

Lactobacilli play an important role in maintaining vaginal health. Lactobacillus rhamnosus and Lactobacillus reuteri are available for purchase as supplements for oral administration. It is thought that oral administration of lactobacilli can help improve the vaginal microbiome. In one clinical trial, 125 women with BV were randomly assigned to receive the combination of 1 week of metronidazole plus oral Lactobacillus twice daily for 30 days or metronidazole plus placebo.²¹ Resolution of symptoms was reported as 88% and 40% in the metronidazole-lactobacilli and metronidazole-placebo groups, respectively.²¹ By contrast, one systematic review of probiotic treatment of BV concluded that there is insufficient evidence to recommend for or against probiotic treatment of BV.²² Patients with recurrent BV commonly report that they believe a probiotic was helpful in resolving their symptoms.

On the horizon

In one trial, a single 2-g oral dose of secnidazole was as effective as a 7-day course of oral metronidazole 500 mg twice daily.²³ In a small dose-finding study, a single dose of either secnidazole 1 g or 2 g was equally effective in treating BV.²⁴ An effective single-dose treatment of BV would likely improve patient adherence with therapy. Symbiomix is preparing for FDA review of this medication (secnidazole, Solosec) for use in the United States.

BV is a prevalent problem and often adversely impacts a woman's quality of life and love relationships. BV recurrence is very common. Many women report that their BV was resistant to intermittet treatment and recurred, repetitively  over many years. The 3 treatment options presented in this editorial may help to suppress the recurrence rate and improve symptoms.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Bacterial vaginosis (BV) is caused by a complex change in vaginal bacterial flora, with a reduction in lactobacilli (which help maintain an acidic environment) and an increase in anaerobic gram-negative organisms including Gardnerella vaginalis species and Bacteroides, Prevotella, and Mobiluncus genera. Infection with G vaginalis is thought to trigger a cascade of changes in vaginal flora that leads to BV.¹

Photo: CDC/ M. Rein

BV is present in 30% to 50% of sexually active women, and of these women 50% to 75% have an abnormal vaginal discharge, which is gray, thin, and homogeneous and may have a fishy odor.² In addition to causing an abnormal vaginal discharge, BV is a cause of postpartum fever, posthysterectomy vaginal cuff cellulitis, and postabortion infection, and it increases the risk of acquiring HIV, herpes simplex type 2, gonorrhea, chlamydia, and trichomoniasis infection.³

When using microscopy and the Amsel criteria, the diagnosis of BV is made when at least 3 of the following 4 criteria are present:  

1. homogeneous, thin, gray discharge  
2. vaginal pH >4.5  
3. positive whiff-amine test when applying a drop of 10% KOH to a sample of the vaginal discharge  
4. clue cells detected with microscopy on a saline wet mount.  

If microscopy is not available, the Affirm VPIII test (BD Diagnostic Systems, Franklin Lakes, New Jersey) for DNA sequences of G vaginalis has high sensitivity and specificity.⁴ The OSOM BVBlue test (Sekisui Diagnostics, Lexington, Massachusetts), a Clinical Laboratory Improvement Amendments-waived point of service test, measures vaginal sialidase, which is produced by Gardnerella and other pathogens associated with BV.⁵ BV may be detected in routine cervical cytology testing and, if the patient is symptomatic, treatment is recommended.

Initial treatment of BV. The Centers for Disease Control and Prevention (CDC) has recommended 3 treatment regimens for BV and 4 alternative treatment options (TABLE).⁶ In addition to antimicrobial treatment, the CDC recommends that women with BV use condoms with sexual intercourse. The CDC also advises that clinicians should con-sider testing women with BV for HIV and other sexually transmitted infections.

Related article:
Successful treatment of chronic vaginitis

Treatment of recurrent BV

A major problem with BV is that, although initial treatment is successful in about 80% of cases, up to 50% of women will have a recurrence of BV within 12 months of initial treatment.² Preliminary studies suggest that for women with 3 or more episodes of BV, the regimens below may be effective.  

Regimen 1
Following the completion of a CDC-recommended treatment regimen (see TABLE), prescribe metronidazole vaginal gel 0.75%, one full applicator, twice weekly for 6 months.⁷

In a prospective randomized trial examining this regimen, following initial treatment with a 10-day metronidazole vaginal gel regimen 112 women were randomly assigned to chronic suppressive therapy with metronidazole vaginal gel 0.75%, one full applicator, twice weekly for 16 weeks or a placebo. During the treatment period, recurrent BV was diagnosed in 26% of the women taking metronidazole gel and 59% of the women taking placebo.⁷ This regimen may be complicated by secondary vaginal candidiasis, which may be treated with a vaginal or oral antifungal agent. 

Regimen 2
Initiate a 21-day course of vaginal boric acid capsules 600 mg once daily at bedtime and simultaneously prescribe a standard CDC treatment regimen (see TABLE). At the completion of the vaginal boric acid treatment initiate metronidazole vaginal gel 0.75% twice weekly for 6 months.⁸

NOTE: Boric acid can cause death if consumed orally.⁹ Boric acid capsules should be stored securely to ensure that they are not accidentally taken orally. Boric acid poisoning may present with vomiting, fever, skin rash, neutropenia, thrombocytopenia, metabolic acidosis, and renal failure.¹⁰ Boric acid should not be used by pregnant women because it is a teratogen.¹¹

The bacterial organisms responsible for BV reside in a self-produced matrix, referred to as a biofilm, that protect the organisms from antimicrobial agents.¹² Boric acid may prevent the formation of a biofilm and increase the effectiveness of anti-microbial treatment.

Regimen 3
Following the completion of a standard treatment regimen (see TABLE), prescribe oral metronidazole 2 g and fluconazole 150 mg administered once every month.¹³

In a randomized clinical trial, 310 female sex workers were randomly assigned to monthly treatment with oral metronidazole 2 g plus fluconazole 150 mg or placebo for up to 12 months.¹³ In the treatment and placebo groups episodes of BV were 199 and 326 per 100 person-years, respectively (hazard ratio, 0.55; 95% confidence interval, 0.49-0.63; P<.001). In Canada, a vaginal ovule containing both a high dose of metronidazole (500 mg) and nystatin (10,000 IU) is available and could be used intermittently to prevent recurrence.¹⁴

Treatment of partners

The CDC does not recommend treatment of the partners of women with BV because there are no definitive data to support such a recommendation. However, the 6 published clinical trials testing the utility of treating sex partners of women with BV have significant methodologic flaws, including underpowered studies and suboptimal antibiotic treatment regimens.¹⁵ Hence, whether partners should be treated remains an open question. Many experts believe that, in most cases, BV is a sexually transmitted disease.^16,17 For women who have sex with women, the rate of BV concordance among partners is high. If one woman has diagnosed BV and symptoms are present in her partner, treatment of the partner is reasonable. For women with BV who have sex with men, sexual intercourse influences disease activity, and consistent use of condoms may reduce the rate of recurrence.¹⁸ Male circumcision may reduce the risk of BV in female partners.¹⁹

Related article:
Bacterial vaginosis: Meet patients' needs with effective diagnosis and treatment

Over-the-counter treatments

In women with BV it is thought that the vaginal administration of lactic acid can help restore the normal acidic pH of the vagina, encourage the growth of lactobacilli, and suppress the growth of the bacteria that cause BV.²⁰ Many products containing lactic acid in a formulation for vaginal use are available (among them Luvena and Gynofit gel).

Lactobacilli play an important role in maintaining vaginal health. Lactobacillus rhamnosus and Lactobacillus reuteri are available for purchase as supplements for oral administration. It is thought that oral administration of lactobacilli can help improve the vaginal microbiome. In one clinical trial, 125 women with BV were randomly assigned to receive the combination of 1 week of metronidazole plus oral Lactobacillus twice daily for 30 days or metronidazole plus placebo.²¹ Resolution of symptoms was reported as 88% and 40% in the metronidazole-lactobacilli and metronidazole-placebo groups, respectively.²¹ By contrast, one systematic review of probiotic treatment of BV concluded that there is insufficient evidence to recommend for or against probiotic treatment of BV.²² Patients with recurrent BV commonly report that they believe a probiotic was helpful in resolving their symptoms.

On the horizon

In one trial, a single 2-g oral dose of secnidazole was as effective as a 7-day course of oral metronidazole 500 mg twice daily.²³ In a small dose-finding study, a single dose of either secnidazole 1 g or 2 g was equally effective in treating BV.²⁴ An effective single-dose treatment of BV would likely improve patient adherence with therapy. Symbiomix is preparing for FDA review of this medication (secnidazole, Solosec) for use in the United States.

BV is a prevalent problem and often adversely impacts a woman's quality of life and love relationships. BV recurrence is very common. Many women report that their BV was resistant to intermittet treatment and recurred, repetitively  over many years. The 3 treatment options presented in this editorial may help to suppress the recurrence rate and improve symptoms.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Bacterial vaginosis (BV) is caused by a complex change in vaginal bacterial flora, with a reduction in lactobacilli (which help maintain an acidic environment) and an increase in anaerobic gram-negative organisms including Gardnerella vaginalis species and Bacteroides, Prevotella, and Mobiluncus genera. Infection with G vaginalis is thought to trigger a cascade of changes in vaginal flora that leads to BV.¹

Photo: CDC/ M. Rein

BV is present in 30% to 50% of sexually active women, and of these women 50% to 75% have an abnormal vaginal discharge, which is gray, thin, and homogeneous and may have a fishy odor.² In addition to causing an abnormal vaginal discharge, BV is a cause of postpartum fever, posthysterectomy vaginal cuff cellulitis, and postabortion infection, and it increases the risk of acquiring HIV, herpes simplex type 2, gonorrhea, chlamydia, and trichomoniasis infection.³

When using microscopy and the Amsel criteria, the diagnosis of BV is made when at least 3 of the following 4 criteria are present:  

1. homogeneous, thin, gray discharge  
2. vaginal pH >4.5  
3. positive whiff-amine test when applying a drop of 10% KOH to a sample of the vaginal discharge  
4. clue cells detected with microscopy on a saline wet mount.  

If microscopy is not available, the Affirm VPIII test (BD Diagnostic Systems, Franklin Lakes, New Jersey) for DNA sequences of G vaginalis has high sensitivity and specificity.⁴ The OSOM BVBlue test (Sekisui Diagnostics, Lexington, Massachusetts), a Clinical Laboratory Improvement Amendments-waived point of service test, measures vaginal sialidase, which is produced by Gardnerella and other pathogens associated with BV.⁵ BV may be detected in routine cervical cytology testing and, if the patient is symptomatic, treatment is recommended.

Initial treatment of BV. The Centers for Disease Control and Prevention (CDC) has recommended 3 treatment regimens for BV and 4 alternative treatment options (TABLE).⁶ In addition to antimicrobial treatment, the CDC recommends that women with BV use condoms with sexual intercourse. The CDC also advises that clinicians should con-sider testing women with BV for HIV and other sexually transmitted infections.

Related article:
Successful treatment of chronic vaginitis

Treatment of recurrent BV

A major problem with BV is that, although initial treatment is successful in about 80% of cases, up to 50% of women will have a recurrence of BV within 12 months of initial treatment.² Preliminary studies suggest that for women with 3 or more episodes of BV, the regimens below may be effective.  

Regimen 1
Following the completion of a CDC-recommended treatment regimen (see TABLE), prescribe metronidazole vaginal gel 0.75%, one full applicator, twice weekly for 6 months.⁷

In a prospective randomized trial examining this regimen, following initial treatment with a 10-day metronidazole vaginal gel regimen 112 women were randomly assigned to chronic suppressive therapy with metronidazole vaginal gel 0.75%, one full applicator, twice weekly for 16 weeks or a placebo. During the treatment period, recurrent BV was diagnosed in 26% of the women taking metronidazole gel and 59% of the women taking placebo.⁷ This regimen may be complicated by secondary vaginal candidiasis, which may be treated with a vaginal or oral antifungal agent. 

Regimen 2
Initiate a 21-day course of vaginal boric acid capsules 600 mg once daily at bedtime and simultaneously prescribe a standard CDC treatment regimen (see TABLE). At the completion of the vaginal boric acid treatment initiate metronidazole vaginal gel 0.75% twice weekly for 6 months.⁸

NOTE: Boric acid can cause death if consumed orally.⁹ Boric acid capsules should be stored securely to ensure that they are not accidentally taken orally. Boric acid poisoning may present with vomiting, fever, skin rash, neutropenia, thrombocytopenia, metabolic acidosis, and renal failure.¹⁰ Boric acid should not be used by pregnant women because it is a teratogen.¹¹

The bacterial organisms responsible for BV reside in a self-produced matrix, referred to as a biofilm, that protect the organisms from antimicrobial agents.¹² Boric acid may prevent the formation of a biofilm and increase the effectiveness of anti-microbial treatment.

Regimen 3
Following the completion of a standard treatment regimen (see TABLE), prescribe oral metronidazole 2 g and fluconazole 150 mg administered once every month.¹³

In a randomized clinical trial, 310 female sex workers were randomly assigned to monthly treatment with oral metronidazole 2 g plus fluconazole 150 mg or placebo for up to 12 months.¹³ In the treatment and placebo groups episodes of BV were 199 and 326 per 100 person-years, respectively (hazard ratio, 0.55; 95% confidence interval, 0.49-0.63; P<.001). In Canada, a vaginal ovule containing both a high dose of metronidazole (500 mg) and nystatin (10,000 IU) is available and could be used intermittently to prevent recurrence.¹⁴

Treatment of partners

The CDC does not recommend treatment of the partners of women with BV because there are no definitive data to support such a recommendation. However, the 6 published clinical trials testing the utility of treating sex partners of women with BV have significant methodologic flaws, including underpowered studies and suboptimal antibiotic treatment regimens.¹⁵ Hence, whether partners should be treated remains an open question. Many experts believe that, in most cases, BV is a sexually transmitted disease.^16,17 For women who have sex with women, the rate of BV concordance among partners is high. If one woman has diagnosed BV and symptoms are present in her partner, treatment of the partner is reasonable. For women with BV who have sex with men, sexual intercourse influences disease activity, and consistent use of condoms may reduce the rate of recurrence.¹⁸ Male circumcision may reduce the risk of BV in female partners.¹⁹

Related article:
Bacterial vaginosis: Meet patients' needs with effective diagnosis and treatment

Over-the-counter treatments

In women with BV it is thought that the vaginal administration of lactic acid can help restore the normal acidic pH of the vagina, encourage the growth of lactobacilli, and suppress the growth of the bacteria that cause BV.²⁰ Many products containing lactic acid in a formulation for vaginal use are available (among them Luvena and Gynofit gel).

Lactobacilli play an important role in maintaining vaginal health. Lactobacillus rhamnosus and Lactobacillus reuteri are available for purchase as supplements for oral administration. It is thought that oral administration of lactobacilli can help improve the vaginal microbiome. In one clinical trial, 125 women with BV were randomly assigned to receive the combination of 1 week of metronidazole plus oral Lactobacillus twice daily for 30 days or metronidazole plus placebo.²¹ Resolution of symptoms was reported as 88% and 40% in the metronidazole-lactobacilli and metronidazole-placebo groups, respectively.²¹ By contrast, one systematic review of probiotic treatment of BV concluded that there is insufficient evidence to recommend for or against probiotic treatment of BV.²² Patients with recurrent BV commonly report that they believe a probiotic was helpful in resolving their symptoms.

On the horizon

In one trial, a single 2-g oral dose of secnidazole was as effective as a 7-day course of oral metronidazole 500 mg twice daily.²³ In a small dose-finding study, a single dose of either secnidazole 1 g or 2 g was equally effective in treating BV.²⁴ An effective single-dose treatment of BV would likely improve patient adherence with therapy. Symbiomix is preparing for FDA review of this medication (secnidazole, Solosec) for use in the United States.

BV is a prevalent problem and often adversely impacts a woman's quality of life and love relationships. BV recurrence is very common. Many women report that their BV was resistant to intermittet treatment and recurred, repetitively  over many years. The 3 treatment options presented in this editorial may help to suppress the recurrence rate and improve symptoms.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

BOSTON – Promising results were evident in an ongoing phase I study of a gene therapy for spinal muscular atrophy type 1 (SMA1), with children in the trial walking, talking, and moving.

After a single intravenous infusion of the therapy, AVXS-101, children in the industry-funded study achieved unexpected progress in terms of physical achievement ad survival, researchers reported at the annual meeting of the American Academy of Neurology.

Video clips showed children in the trial rolling, sitting unassisted, and showing normal levels of hand and fine motor control. No other children with SMA1 have been reported to reach any major motor milestone.

In one clip, an 18-month-old boy toddles down a hallway and carries an electronic toy to an elevator where he reaches up to press the button. “He’s basically completely back to normal. You see and examine him; it just about takes your breath away,” said the study’s lead investigator, Jerry R. Mendell, MD, a neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

BOSTON – Promising results were evident in an ongoing phase I study of a gene therapy for spinal muscular atrophy type 1 (SMA1), with children in the trial walking, talking, and moving.

After a single intravenous infusion of the therapy, AVXS-101, children in the industry-funded study achieved unexpected progress in terms of physical achievement ad survival, researchers reported at the annual meeting of the American Academy of Neurology.

Video clips showed children in the trial rolling, sitting unassisted, and showing normal levels of hand and fine motor control. No other children with SMA1 have been reported to reach any major motor milestone.

In one clip, an 18-month-old boy toddles down a hallway and carries an electronic toy to an elevator where he reaches up to press the button. “He’s basically completely back to normal. You see and examine him; it just about takes your breath away,” said the study’s lead investigator, Jerry R. Mendell, MD, a neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

BOSTON – Promising results were evident in an ongoing phase I study of a gene therapy for spinal muscular atrophy type 1 (SMA1), with children in the trial walking, talking, and moving.

After a single intravenous infusion of the therapy, AVXS-101, children in the industry-funded study achieved unexpected progress in terms of physical achievement ad survival, researchers reported at the annual meeting of the American Academy of Neurology.

Video clips showed children in the trial rolling, sitting unassisted, and showing normal levels of hand and fine motor control. No other children with SMA1 have been reported to reach any major motor milestone.

In one clip, an 18-month-old boy toddles down a hallway and carries an electronic toy to an elevator where he reaches up to press the button. “He’s basically completely back to normal. You see and examine him; it just about takes your breath away,” said the study’s lead investigator, Jerry R. Mendell, MD, a neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

SAN DIEGO – Based on their analysis of a cohort of more than half a million people, Swedish researchers now believe that mildly elevated fasting plasma glucose and triglyceride levels could indicate an increased risk for type 2 diabetes a quarter-century before diagnosis.

“Previous studies have shown that risk factors for type 2 diabetes, including obesity and elevated fasting glucose, may be present up to 10 years before disease onset. Our study extends this period to more than 20 years before diagnosis,” said the study’s lead author Håkan Malmström, PhD, an epidemiologist with the Karolinska Institute, Stockholm. “Even small elevations in subjects over time early in life may be important to recognize, in particular for people who are overweight or obese.” The study findings were presented in an oral presentation at the scientific sessions of the American Diabetes Association.

The researchers identified 47,997 new type 2 diabetes cases in a Swedish cohort of 537,119 people tracked from 1985-2012. For each case, they compared risk factors from clinical examinations performed from 1985-1996 with those of five matched controls.

SAN DIEGO – Based on their analysis of a cohort of more than half a million people, Swedish researchers now believe that mildly elevated fasting plasma glucose and triglyceride levels could indicate an increased risk for type 2 diabetes a quarter-century before diagnosis.

“Previous studies have shown that risk factors for type 2 diabetes, including obesity and elevated fasting glucose, may be present up to 10 years before disease onset. Our study extends this period to more than 20 years before diagnosis,” said the study’s lead author Håkan Malmström, PhD, an epidemiologist with the Karolinska Institute, Stockholm. “Even small elevations in subjects over time early in life may be important to recognize, in particular for people who are overweight or obese.” The study findings were presented in an oral presentation at the scientific sessions of the American Diabetes Association.

The researchers identified 47,997 new type 2 diabetes cases in a Swedish cohort of 537,119 people tracked from 1985-2012. For each case, they compared risk factors from clinical examinations performed from 1985-1996 with those of five matched controls.

SAN DIEGO – Based on their analysis of a cohort of more than half a million people, Swedish researchers now believe that mildly elevated fasting plasma glucose and triglyceride levels could indicate an increased risk for type 2 diabetes a quarter-century before diagnosis.

“Previous studies have shown that risk factors for type 2 diabetes, including obesity and elevated fasting glucose, may be present up to 10 years before disease onset. Our study extends this period to more than 20 years before diagnosis,” said the study’s lead author Håkan Malmström, PhD, an epidemiologist with the Karolinska Institute, Stockholm. “Even small elevations in subjects over time early in life may be important to recognize, in particular for people who are overweight or obese.” The study findings were presented in an oral presentation at the scientific sessions of the American Diabetes Association.

The researchers identified 47,997 new type 2 diabetes cases in a Swedish cohort of 537,119 people tracked from 1985-2012. For each case, they compared risk factors from clinical examinations performed from 1985-1996 with those of five matched controls.

App overload is a challenge for both providers and patients. As of September 2015, the number of health apps in the US Apple iTunes and Google Play stores exceeded 165,000, with approximately 7% focused on women's health and pregnancy.¹ Clinicians express interest in promoting the use of health apps with their patients and seek guidance about making app recommendations.² In my prior articles in this "App review" series, I have recommended due date calculator and drug reference apps.

One area in which an app may enhance your patient care is in menstrual cycle tracking. Patients may be more honest with their phones than with their health care professionals, and the results are more accurate than paper questionnaires and calendars.³ Of note, menstrual cycle tracking apps are the fourth most popular health app among adults and likely even more popular if limited to adult women.⁴

Dr. Paula Castano and her team systematically identified and evaluated free menstrual cycle tracking apps.⁵ The accuracy of each app was determined by menstrual cycle predictions based on average cycle lengths of at least 3 previous cycles, ovulation predicted at 13 to 15 days prior to the start of the next cycle, and qualification that the application contained no misinformation.⁵

The top 3 recommended menstrual cycle tracking apps from Dr. Castano and colleagues' study are listed in the TABLE alphabetically and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature use, and important special features).⁶ I hope this column will allow you to feel more comfortable recommending these "vetted" apps to your patients.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

App overload is a challenge for both providers and patients. As of September 2015, the number of health apps in the US Apple iTunes and Google Play stores exceeded 165,000, with approximately 7% focused on women's health and pregnancy.¹ Clinicians express interest in promoting the use of health apps with their patients and seek guidance about making app recommendations.² In my prior articles in this "App review" series, I have recommended due date calculator and drug reference apps.

One area in which an app may enhance your patient care is in menstrual cycle tracking. Patients may be more honest with their phones than with their health care professionals, and the results are more accurate than paper questionnaires and calendars.³ Of note, menstrual cycle tracking apps are the fourth most popular health app among adults and likely even more popular if limited to adult women.⁴

Dr. Paula Castano and her team systematically identified and evaluated free menstrual cycle tracking apps.⁵ The accuracy of each app was determined by menstrual cycle predictions based on average cycle lengths of at least 3 previous cycles, ovulation predicted at 13 to 15 days prior to the start of the next cycle, and qualification that the application contained no misinformation.⁵

The top 3 recommended menstrual cycle tracking apps from Dr. Castano and colleagues' study are listed in the TABLE alphabetically and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature use, and important special features).⁶ I hope this column will allow you to feel more comfortable recommending these "vetted" apps to your patients.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

App overload is a challenge for both providers and patients. As of September 2015, the number of health apps in the US Apple iTunes and Google Play stores exceeded 165,000, with approximately 7% focused on women's health and pregnancy.¹ Clinicians express interest in promoting the use of health apps with their patients and seek guidance about making app recommendations.² In my prior articles in this "App review" series, I have recommended due date calculator and drug reference apps.

One area in which an app may enhance your patient care is in menstrual cycle tracking. Patients may be more honest with their phones than with their health care professionals, and the results are more accurate than paper questionnaires and calendars.³ Of note, menstrual cycle tracking apps are the fourth most popular health app among adults and likely even more popular if limited to adult women.⁴

Dr. Paula Castano and her team systematically identified and evaluated free menstrual cycle tracking apps.⁵ The accuracy of each app was determined by menstrual cycle predictions based on average cycle lengths of at least 3 previous cycles, ovulation predicted at 13 to 15 days prior to the start of the next cycle, and qualification that the application contained no misinformation.⁵

The top 3 recommended menstrual cycle tracking apps from Dr. Castano and colleagues' study are listed in the TABLE alphabetically and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature use, and important special features).⁶ I hope this column will allow you to feel more comfortable recommending these "vetted" apps to your patients.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

From the Nationwide Children’s Hospital, Columbus, OH (Dr. Patel) and Cook Children’s Medical Center, Fort Worth, TX (Dr. Perry).

Abstract

• Objective: To review the current understanding and management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as-needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients should be aware of the clinical considerations in managing patients with febrile seizures.

Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19; FIRES; complex febrile seizure.

A febrile seizure is defined as a seizure in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [1]. The mechanism by which fever provokes a febrile seizure is unclear [2]. Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children [1]. The age of onset is between 6 months and 5 years [3]; peak incidence occurs at about 18 months of age. Simple febrile seizures are the most common type of febrile seizure. By definition, they are generalized, last less than 10 minutes and only occur once in a 24-hour time-period. A complex febrile seizure is one with focal onset or one that occurs more than once during a febrile illness, or lasts more than 10 minutes. Febrile status epilepticus, a subtype of complex febrile seizures, represents about 25% of all episodes of childhood status epilepticus. They account for more than two-thirds of cases during the first 2 years of life.

The risk of reoccurrence after presenting with one febrile seizure is approximately 30%, with the risk being 60% after 2 febrile seizures and 90% after 3 [4–6]. Some families have an autosomal dominant inheritance pattern with polygenic inheritance suspected for the majority of patients presenting with febrile seizures.

Multiple chromosomes have been postulated to be associated with genetic susceptibility for febrile seizures, with siblings having a 25% increased risk and high concordance noted in monozygotic twins [7]. The pathophysiology for febrile seizures has been associated with a genetic risk associated with the rate of temperature rise with animal studies suggesting temperature regulation of c-aminobutyric acid (GABA) a receptors [2]. Other studies propose a link between genetic and environmental factors resulting in an inflammatory process which influences neuronal excitement predisposing one to a febrile seizure [8].

Debate exists between the relation of febrile seizures and childhood vaccinations. Seizures are rare following administration of childhood vaccines. Most seizures following administration of vaccines are simple febrile seizures [9]. Febrile seizures associated with vaccines are more associated with underlying epilepsy. In a study of patients with vaccine-related encephalopathy and febrile status epilepticus, the majority of patients were found to have Dravet syndrome; it was determined that the vaccine may have triggered an earlier onset of the presentation for Dravet in those predestined to develop this disease but did not adversely impact ultimate outcome [10].

In this article, we review simple and complex febrile seizures with a focus on clinical management. Epilepsy syndromes associated with febrile seizures are also discussed. Cases are provided to highlight important clinical considerations.

Case 1: Simple Febrile Seizure

A 9-month-old infant and his mother present to the pediatrician. The mother notes that the infant had an event of concern. She notes the infant had stiffness in all 4 extremities followed by jerking that lasted 30 to 60 seconds. The infant was not responsive during the event. He was sleepy afterward, but returned to normal soon after the event ended. After, she noted that the infant felt warm and she checked his temperature. He had a fever of 101°F. The infant has normal development and no other medical problems.

• What are management considerations for simple febrile seizure?

A simple febrile seizure is the most common type of febrile seizure. They are generalized, lasting less than 10 minutes and only occur once in a 24-hour period. There is no increased risk of developing epilepsy or developmental delay for patients after the first simple febrile seizures when compared to other children [5,6]. The diagnosis is based on history provided and a physical examination including evaluation of body temperature [11,12].

No routine laboratory tests are needed as a result of a simple febrile seizure unless obtained to assist in identifying the fever source [3,11]. Routine EEG testing is not recommended for these patients [3,11]. Routine imaging of the brain is also not needed [3,11]. Only if a patient has signs of meningitis should a lumbar puncture be performed [11]. The American Academy of Pediatrics states that a lumbar puncture is strongly considered for those younger than 12 months if they present with their first complex febrile seizure as signs of meningitis may be absent in young children. For infants 6 to 12 months of age, a lumbar puncture can be considered when immunization status is deficient or unknown [13,14]. Also, a lumbar puncture is an option for children who are pretreated with antibiotics [11]. For patients younger than 6 months, data is lacking on the percentage of patients with bacterial meningitis following a simple febrile seizure.

Daily preventative therapy with an anti-epilepsy medication is not necessary [3,11]. A review of several treatment studies shows that some anti-epileptic medications are effective in preventing recurrent simple febrile seizures. Studies have demonstrated the effectiveness of phenobarbital, primidone, and valproic acid in preventing the recurrence of simple febrile seizures; however, the side effects of each medication outweighed the benefit [3]. Carbamazepine and phenytoin have not been shown to be effective in preventing recurrent febrile seizures [3].

For anxious caregivers with children having recurrent febrile seizures, a daily medication or treating with an abortive seizure medication at the time of a febrile illness can be considered [3,5,6,15]. Treating with an abortive medication may mask signs and symptoms of meningitis making evaluation more challenging [16]. Evidence does not support that using antipyretic medications such as acetaminophen or ibuprofen will reduce the recurrence of febrile seizures. The seizure usually is the first noticed symptom due to the rise of temperature being the cause of the febrile seizure in an otherwise well child prior to the seizure [11,17]. Damage to the brain and associated structures is not found with patients presenting with simple febrile seizures [5,6]. Education on all of these principles is strongly recommended for caregiver reassurance.

Case 2: Complex Febrile Seizure

A 1-year-old child presents to the emergency department. Mother was with the child and she noticed stiffness followed by jerking of the left arm and leg, which quickly became noted in both arms and legs. The episode appeared to last for 15 minutes before EMS arrived to the house. A medication was given to the child by EMS that stopped the event. EMS noted the child had a temperature of 101.5°F. The child was previously healthy and has had normal development thus far.

• What is the epidemiology of complex febrile seizure?

A complex febrile seizure is one with focal onset, or one that occurs more than once during a febrile illness or lasts more than 10 minutes. They are less common, representing only 20% to 30% of all febrile seizures [18–20]. In The National Collaborative Perinatal Project (NCPP), 1706 children with febrile seizures were identified from 54,000 and were followed from birth until 7 years of age. The initial febrile seizure was defined as complex in about 28%. For all febrile seizures, focal features were present in 4%, prolonged duration (> 10 minutes) in 7.6%, and recurrent episodes within 24 hours in 16.2% [21]. Similar observations have been reported by Berg and Shinnar [5,6]. Of 136 children who had recurrences, 41.2% had one or more complex features and the strongest correlate of having recurrent complex febrile seizure was the number of recurrent seizures. They also found that children with complex recurrences had other recurrences that were not complex; however, complex features had a tendency to recur. Further, a strong association between focal onset and prolonged duration was found [5,6]. Previous studies established a correlation between complex attacks, particularly prolonged ones and young age (age < 1 year) [5,6]. Additionally, children with seizures with a relatively low fever (< 102°F) were slightly more likely to have a complex febrile seizure as the initial episode [5,6].

Children with febrile seizures are already at 4- to 5-fold increased risk for subsequent unprovoked seizures. A history of febrile seizures has been found in 13% to 18% of children with new-onset epilepsy. In the NCPP study, the predictors identified for the development of epilepsy following febrile seizures were an abnormal neurological and developmental status of the child before the seizure, a history of afebrile seizures in a parent or prior-born sibling, or complex features [21]. Ten percent of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy and 13% of them had seizures without fever [20,22]. Further, intractable epilepsy and neurological impair-ment have been found to be more common in children with prior prolonged febrile seizure, with no association to any specific seizure type [18,23–25]. The association between febrile seizures and mesial temporal sclerosis (MTS) is a commonly debated topic. Retrospective studies have reported an association between prolonged or atypical febrile seizures and intractable temporal lobe epilepsy. Epidemiological studies fail to show a causal relationship between febrile seizures and temporal lobe epilepsy [26]. This suggests that febrile seizures are a marker of susceptibility to seizures and future epilepsy (in some cases) rather than a direct cause. It is clear that a minority of cases of MTS or complex partial seizures are associated with prior febrile seizures [20,22].

• What is the risk of intracranial pathology in complex febrile seizure?

Patients with complex febrile seizures usually seek medical attention [27]. However, the risk of acute pathology necessitating treatment changes based on neuroimaging was found to be very low and likely not necessary in the evaluation of complex febrile seizures during the acute presentation [27]. Imaging with a high-resolution brain MRI could be considered later on a routine basis for prolonged febrile seizures due to the possible association between prolonged febrile seizures and mesial temporal sclerosis [19,28,29].

Neuroimaging has provided evidence that hippocampal injury can occasionally occur during prolonged and focal febrile seizures in infants who otherwise appear normal. It has been speculated that a pre-existing abnormality increases the propensity to focal prolonged seizures and further hippocampal damage. Hesdorffer and colleagues [30] found definite abnormalities on MRI in 14.8% of children with complex febrile seizures and 11.4 % of simple febrile seizures among 159 children with a first febrile seizure. However, MRI abnormalities were related to a specific subtype of complex seizures: focal and prolonged. The most common abnormalities observed were subcortical focal hyperintensity, an abnormal white matter signal, and focal cortical dysplasia.

• What are important aspects of the clinical evaluation?

The evaluation and management of the child with complex febrile seizures is debated as well. The most important part in the history and examination is to look for the source of the fever and rule out the presence of a CNS infection, since complex febrile seizures are much more frequently associated with meningitis than simple febrile seizures [16]. The American Academy of Pediatrics recommended that a lumbar puncture be strongly considered in infants younger than 12 months after a first febrile seizure and should be considered in children between 12 and 18 months of age, since signs of meningitis may be absent in young children [13]. If the threshold for a lumbar puncture is low in infants with febrile seizures in general, it should be even lower for children with complex febrile episodes for all the factors mentioned above. The guidelines developed in 1990 by the Royal College of Physicians and the British Paediatric Association concluded that indications for performing an lumbar puncture were complex febrile seizure, signs of meningismus, or a child who is unduly drowsy and irritable or systematically ill [21].

Obtaining an EEG within 24 hours of presentation may show generalized background slowing, which could make identifying possible epileptiform abnormalities difficult [22]. Therefore, a routine sleep deprived EEG when the child is back to baseline can be more useful in identifying if epileptiform abnormalities are present. If epileptiform abnormalities are present on a routine sleep deprived EEG, this may suggest the patient is at higher risk for developing future epilepsy and the febrile illness lowered the seizure threshold; however, it is unclear whether clinical management would change as a result [31].

• What treatment options are available?

Complications with prolonged and/or recurrent seizures can occur. Treatments options can be stratified into 3 possible categories: emergency rescue treatment for prolonged or a cluster of febrile seizures, intermittent treatment at the time of illness, and chronic use of medication. Treatment options for complex febrile seizures may include the use of a rescue seizure medication when the febrile seizure is prolonged. Rectal preparations of diazepam gel can be effective in stopping an ongoing seizure and can be provided for home use in patients with known recurrence of febrile status epilepticus [3]. For children and adolescents where a rectal administration is not ideal, intranasal versed can be utilized instead of rectal diazepam. In addition, the use of an intermittent benzodiazepine at the onset of febrile illness can also be considered a treatment option. Using oral diazepam at the time of a febrile illness has been demonstrated in reducing the recurrence of febrile seizures [3]. Other studies have shown similar results when using buccal midazolam [32]. No adequate studies have been performed using second- or third-generation anti-epilepsy medications in the treatment of recurrent of complex febrile seizures [3].

It is unclear whether benefit is present to using intermittent benzodiazepine doses prior or during a febrile illness for those prone for recurrent febrile seizures [33]. Physicians may consider this option in patients with frequent recurrent seizures, when caregivers can identify the fever before the seizure occurs.

Overall, parental education of efficacy and side effect profiles should be discussed in detail when considering any treatment options for complex febrile seizures [34]. It is important to remember that the long-term prognosis in terms of developing epilepsy or neurological and cognitive problems is not influenced by the use of antiepileptic medications for recurrent febrile seizures [17]. Even in the case of prolonged febrile seizures in otherwise neurodevelopmentally normal children, antiepileptics have not been shown to cause damage to the brain [19].

Febrile Status Epilepticus

Febrile status epilepticus is a subtype of complex febrile seizures and is defined as a febrile seizure lasting greater than 30 minutes. Overall, febrile status epilepticus accounts for approximately 5% of all presentations of febrile seizures [35]. It represents about 25% of all episodes of childhood status epilepticus and more than two-thirds of cases during the first 2 years of life. Literature suggests that an increased risk for focal epilepsy exists [36]. Children presenting with febrile status epilepticus are more likely to have a family history of epilepsy and a history of a previous neurological abnormality [22]. It is likely to reoccur if the first presentation was febrile status epilepticus. However, increased risk for death or developmental disability as a result of the seizure is not seen [37].

The prospective multicenter study of the consequences of prolonged febrile seizures in childhood (FEBSTAT) has been conducted. The study reported that febrile status epilepticus is usually focal (67% of episodes), occurs in very young children (median age 1.3 years), and is frequently the first febrile seizure [22]. In this study, the median duration of the seizure was about 68 minutes and 24% of children had an episode lasting more than 2 hours. In 87% of the events, seizures did not stop spontaneously and benzodiazepines were needed. Focal features observed were eye and head deviation, staring, and impaired consciousness prior to the seizure and an asymmetric convulsion or Todd’s paresis.

Case 3: Epilepsy Syndromes Associated With Febrile Seizures

A 1-year-old female presents for evaluation of seizures that began at age 8 months. Seizures are described as occurring in the setting of fever with bilateral symmetric tonic clonic activity lasting durations of less than 10 minutes on average, but at least 2 instances of seizure lasting 20 minutes or more. The family notes that seizures have occurred almost every time the child has had a febrile illness and often cluster over several days. They report at least 1 seizure that occurred in the absence of fever. Development has been normal to date and an EEG done by their primary provider was also normal.

• What epilepsy syndromes are associated with febrile seizures?

Genetic Epilepsy with Febrile Seizures Plus

GEFS+ was first described in 1997 following recognition of a pattern of febrile seizures followed later by the development of various epilepsy syndromes within the same family [38]. As such, the syndrome is defined based on the familial occurrence of febrile and afebrile seizures in at least 2 family members and can have a wide range of phenotypes. The most common presentation is of typical febrile seizures which can persist beyond the typical upper age limit of 6 years. Unprovoked generalized seizures of multiple types (ie, myoclonic, absence, atonic) occur at a later age, though focal seizures may also be present. The presence of focal onset seizures led to the naming change from “generalized” epilepsy with febrile seizures plus as it was previously referred. Seizure frequency and severity may vary between family members, as can response to treatment, making prognosis difficult to predict. As even in typical febrile seizures a family history of febrile seizure may be common, it may be difficult to diagnose the syndrome after the initial febrile seizure. However, if the family history is strong for a family member with a GEFS+ phenotype, one can appropriately counsel the family on the possibility that a similar course may evolve. While the majority of GEFS+ patients have milder phenotypes, some more severe phenotypes can have cognitive delays. Dravet syndrome falls within the spectrum of GEFS+ and is a prime example of the phenotypic continuum to more severe presentations in some patients.

The syndrome is believed to be inherited in an auto-somal dominant fashion with incomplete penetrance. Multiple genes have been implicated as a cause, though only 11.5% of families with clinical GEFS+ may have mutations [39]. SCN1A, encoding the α-subunit of the voltage-gated sodium channel is most frequently reported in GEFS+ families, yet is only found in 10% [38]. When associated with GEFS+, SCN1A mutations are more often missense type, whereas truncating and nonsense mutations are more commonly encountered in Dravet syndrome. Mutations in SCN1B encoding the β1 subunit of the voltage-gated sodium channel has also been reported [40]. Finally, the GABA(A) receptor gamma 2 subunit GABRG2 has been found in < 1% of GEFS+ families [39]. The variability in causative genes underscores the reasons for phenotype variability and it is likely that other modifier genes are responsible for the heterogeneity within GEFS+ families [41].

Dravet Syndrome

Dravet syndrome, often referred to as severe myoclonic epilepsy of infancy, was first described in 1978 and has since become one of the most recognized genetic epilepsy syndromes [42]. The clinical presentation often begins with seizures in the first year of life, frequently in the setting of febrile illness. The initial seizures are generalized or hemiclonic in the majority and are often prolonged evolving to status epilepticus. Unlike typical febrile seizures, one should suspect Dravet syndrome in children that present with repetitive bouts of complex febrile seizures or febrile status epilepticus, especially if the associated seizure semiology is of hemiclonic type. In addition, seizures in the setting of modest hyperthermia (ie, hot baths) should raise suspicion for this condition. Commonly EEG and MRI are normal in the first year of life and psychomotor development remains normal until typically the second year of life [43].

By the second year, other seizure types including myoclonic, atypical absence, clonic, and tonic seizures arise. The EEG frequently begins to show generalized spike wave and polyspike wave discharges. Seizures continue occurring frequently during early childhood, often resulting in status epilepticus. Cognitive development begins to stagnate between the ages of 1 and 4 years with emergence of autistic traits and hyperactivity [44]. Development may stabilize between the ages of 5 and 16 years, but fails to demonstrate much improvement [44]. Higher frequency of seizures may correlate with increase in cognitive impairment and behavior problems, supporting the need for rapid diagnosis and appropriate therapy [44].

Over the years, several cases of atypical or borderline Dravet syndrome have been described, most highlighting the absence of myoclonic seizures [45]. Others may present with primarily clonic or tonic-clonic type seizures only [46]. Despite these differences, all cases share a similar drug resistance and cognitive delay and are categorized as Dravet syndrome.

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, anup.patel@nationwidechildrens.org.

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.

From the Nationwide Children’s Hospital, Columbus, OH (Dr. Patel) and Cook Children’s Medical Center, Fort Worth, TX (Dr. Perry).

Abstract

• Objective: To review the current understanding and management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as-needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients should be aware of the clinical considerations in managing patients with febrile seizures.

Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19; FIRES; complex febrile seizure.

A febrile seizure is defined as a seizure in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [1]. The mechanism by which fever provokes a febrile seizure is unclear [2]. Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children [1]. The age of onset is between 6 months and 5 years [3]; peak incidence occurs at about 18 months of age. Simple febrile seizures are the most common type of febrile seizure. By definition, they are generalized, last less than 10 minutes and only occur once in a 24-hour time-period. A complex febrile seizure is one with focal onset or one that occurs more than once during a febrile illness, or lasts more than 10 minutes. Febrile status epilepticus, a subtype of complex febrile seizures, represents about 25% of all episodes of childhood status epilepticus. They account for more than two-thirds of cases during the first 2 years of life.

The risk of reoccurrence after presenting with one febrile seizure is approximately 30%, with the risk being 60% after 2 febrile seizures and 90% after 3 [4–6]. Some families have an autosomal dominant inheritance pattern with polygenic inheritance suspected for the majority of patients presenting with febrile seizures.

Multiple chromosomes have been postulated to be associated with genetic susceptibility for febrile seizures, with siblings having a 25% increased risk and high concordance noted in monozygotic twins [7]. The pathophysiology for febrile seizures has been associated with a genetic risk associated with the rate of temperature rise with animal studies suggesting temperature regulation of c-aminobutyric acid (GABA) a receptors [2]. Other studies propose a link between genetic and environmental factors resulting in an inflammatory process which influences neuronal excitement predisposing one to a febrile seizure [8].

Debate exists between the relation of febrile seizures and childhood vaccinations. Seizures are rare following administration of childhood vaccines. Most seizures following administration of vaccines are simple febrile seizures [9]. Febrile seizures associated with vaccines are more associated with underlying epilepsy. In a study of patients with vaccine-related encephalopathy and febrile status epilepticus, the majority of patients were found to have Dravet syndrome; it was determined that the vaccine may have triggered an earlier onset of the presentation for Dravet in those predestined to develop this disease but did not adversely impact ultimate outcome [10].

In this article, we review simple and complex febrile seizures with a focus on clinical management. Epilepsy syndromes associated with febrile seizures are also discussed. Cases are provided to highlight important clinical considerations.

Case 1: Simple Febrile Seizure

A 9-month-old infant and his mother present to the pediatrician. The mother notes that the infant had an event of concern. She notes the infant had stiffness in all 4 extremities followed by jerking that lasted 30 to 60 seconds. The infant was not responsive during the event. He was sleepy afterward, but returned to normal soon after the event ended. After, she noted that the infant felt warm and she checked his temperature. He had a fever of 101°F. The infant has normal development and no other medical problems.

• What are management considerations for simple febrile seizure?

A simple febrile seizure is the most common type of febrile seizure. They are generalized, lasting less than 10 minutes and only occur once in a 24-hour period. There is no increased risk of developing epilepsy or developmental delay for patients after the first simple febrile seizures when compared to other children [5,6]. The diagnosis is based on history provided and a physical examination including evaluation of body temperature [11,12].

No routine laboratory tests are needed as a result of a simple febrile seizure unless obtained to assist in identifying the fever source [3,11]. Routine EEG testing is not recommended for these patients [3,11]. Routine imaging of the brain is also not needed [3,11]. Only if a patient has signs of meningitis should a lumbar puncture be performed [11]. The American Academy of Pediatrics states that a lumbar puncture is strongly considered for those younger than 12 months if they present with their first complex febrile seizure as signs of meningitis may be absent in young children. For infants 6 to 12 months of age, a lumbar puncture can be considered when immunization status is deficient or unknown [13,14]. Also, a lumbar puncture is an option for children who are pretreated with antibiotics [11]. For patients younger than 6 months, data is lacking on the percentage of patients with bacterial meningitis following a simple febrile seizure.

Daily preventative therapy with an anti-epilepsy medication is not necessary [3,11]. A review of several treatment studies shows that some anti-epileptic medications are effective in preventing recurrent simple febrile seizures. Studies have demonstrated the effectiveness of phenobarbital, primidone, and valproic acid in preventing the recurrence of simple febrile seizures; however, the side effects of each medication outweighed the benefit [3]. Carbamazepine and phenytoin have not been shown to be effective in preventing recurrent febrile seizures [3].

For anxious caregivers with children having recurrent febrile seizures, a daily medication or treating with an abortive seizure medication at the time of a febrile illness can be considered [3,5,6,15]. Treating with an abortive medication may mask signs and symptoms of meningitis making evaluation more challenging [16]. Evidence does not support that using antipyretic medications such as acetaminophen or ibuprofen will reduce the recurrence of febrile seizures. The seizure usually is the first noticed symptom due to the rise of temperature being the cause of the febrile seizure in an otherwise well child prior to the seizure [11,17]. Damage to the brain and associated structures is not found with patients presenting with simple febrile seizures [5,6]. Education on all of these principles is strongly recommended for caregiver reassurance.

Case 2: Complex Febrile Seizure

A 1-year-old child presents to the emergency department. Mother was with the child and she noticed stiffness followed by jerking of the left arm and leg, which quickly became noted in both arms and legs. The episode appeared to last for 15 minutes before EMS arrived to the house. A medication was given to the child by EMS that stopped the event. EMS noted the child had a temperature of 101.5°F. The child was previously healthy and has had normal development thus far.

• What is the epidemiology of complex febrile seizure?

A complex febrile seizure is one with focal onset, or one that occurs more than once during a febrile illness or lasts more than 10 minutes. They are less common, representing only 20% to 30% of all febrile seizures [18–20]. In The National Collaborative Perinatal Project (NCPP), 1706 children with febrile seizures were identified from 54,000 and were followed from birth until 7 years of age. The initial febrile seizure was defined as complex in about 28%. For all febrile seizures, focal features were present in 4%, prolonged duration (> 10 minutes) in 7.6%, and recurrent episodes within 24 hours in 16.2% [21]. Similar observations have been reported by Berg and Shinnar [5,6]. Of 136 children who had recurrences, 41.2% had one or more complex features and the strongest correlate of having recurrent complex febrile seizure was the number of recurrent seizures. They also found that children with complex recurrences had other recurrences that were not complex; however, complex features had a tendency to recur. Further, a strong association between focal onset and prolonged duration was found [5,6]. Previous studies established a correlation between complex attacks, particularly prolonged ones and young age (age < 1 year) [5,6]. Additionally, children with seizures with a relatively low fever (< 102°F) were slightly more likely to have a complex febrile seizure as the initial episode [5,6].

Children with febrile seizures are already at 4- to 5-fold increased risk for subsequent unprovoked seizures. A history of febrile seizures has been found in 13% to 18% of children with new-onset epilepsy. In the NCPP study, the predictors identified for the development of epilepsy following febrile seizures were an abnormal neurological and developmental status of the child before the seizure, a history of afebrile seizures in a parent or prior-born sibling, or complex features [21]. Ten percent of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy and 13% of them had seizures without fever [20,22]. Further, intractable epilepsy and neurological impair-ment have been found to be more common in children with prior prolonged febrile seizure, with no association to any specific seizure type [18,23–25]. The association between febrile seizures and mesial temporal sclerosis (MTS) is a commonly debated topic. Retrospective studies have reported an association between prolonged or atypical febrile seizures and intractable temporal lobe epilepsy. Epidemiological studies fail to show a causal relationship between febrile seizures and temporal lobe epilepsy [26]. This suggests that febrile seizures are a marker of susceptibility to seizures and future epilepsy (in some cases) rather than a direct cause. It is clear that a minority of cases of MTS or complex partial seizures are associated with prior febrile seizures [20,22].

• What is the risk of intracranial pathology in complex febrile seizure?

Patients with complex febrile seizures usually seek medical attention [27]. However, the risk of acute pathology necessitating treatment changes based on neuroimaging was found to be very low and likely not necessary in the evaluation of complex febrile seizures during the acute presentation [27]. Imaging with a high-resolution brain MRI could be considered later on a routine basis for prolonged febrile seizures due to the possible association between prolonged febrile seizures and mesial temporal sclerosis [19,28,29].

Neuroimaging has provided evidence that hippocampal injury can occasionally occur during prolonged and focal febrile seizures in infants who otherwise appear normal. It has been speculated that a pre-existing abnormality increases the propensity to focal prolonged seizures and further hippocampal damage. Hesdorffer and colleagues [30] found definite abnormalities on MRI in 14.8% of children with complex febrile seizures and 11.4 % of simple febrile seizures among 159 children with a first febrile seizure. However, MRI abnormalities were related to a specific subtype of complex seizures: focal and prolonged. The most common abnormalities observed were subcortical focal hyperintensity, an abnormal white matter signal, and focal cortical dysplasia.

• What are important aspects of the clinical evaluation?

The evaluation and management of the child with complex febrile seizures is debated as well. The most important part in the history and examination is to look for the source of the fever and rule out the presence of a CNS infection, since complex febrile seizures are much more frequently associated with meningitis than simple febrile seizures [16]. The American Academy of Pediatrics recommended that a lumbar puncture be strongly considered in infants younger than 12 months after a first febrile seizure and should be considered in children between 12 and 18 months of age, since signs of meningitis may be absent in young children [13]. If the threshold for a lumbar puncture is low in infants with febrile seizures in general, it should be even lower for children with complex febrile episodes for all the factors mentioned above. The guidelines developed in 1990 by the Royal College of Physicians and the British Paediatric Association concluded that indications for performing an lumbar puncture were complex febrile seizure, signs of meningismus, or a child who is unduly drowsy and irritable or systematically ill [21].

Obtaining an EEG within 24 hours of presentation may show generalized background slowing, which could make identifying possible epileptiform abnormalities difficult [22]. Therefore, a routine sleep deprived EEG when the child is back to baseline can be more useful in identifying if epileptiform abnormalities are present. If epileptiform abnormalities are present on a routine sleep deprived EEG, this may suggest the patient is at higher risk for developing future epilepsy and the febrile illness lowered the seizure threshold; however, it is unclear whether clinical management would change as a result [31].

• What treatment options are available?

Complications with prolonged and/or recurrent seizures can occur. Treatments options can be stratified into 3 possible categories: emergency rescue treatment for prolonged or a cluster of febrile seizures, intermittent treatment at the time of illness, and chronic use of medication. Treatment options for complex febrile seizures may include the use of a rescue seizure medication when the febrile seizure is prolonged. Rectal preparations of diazepam gel can be effective in stopping an ongoing seizure and can be provided for home use in patients with known recurrence of febrile status epilepticus [3]. For children and adolescents where a rectal administration is not ideal, intranasal versed can be utilized instead of rectal diazepam. In addition, the use of an intermittent benzodiazepine at the onset of febrile illness can also be considered a treatment option. Using oral diazepam at the time of a febrile illness has been demonstrated in reducing the recurrence of febrile seizures [3]. Other studies have shown similar results when using buccal midazolam [32]. No adequate studies have been performed using second- or third-generation anti-epilepsy medications in the treatment of recurrent of complex febrile seizures [3].

It is unclear whether benefit is present to using intermittent benzodiazepine doses prior or during a febrile illness for those prone for recurrent febrile seizures [33]. Physicians may consider this option in patients with frequent recurrent seizures, when caregivers can identify the fever before the seizure occurs.

Overall, parental education of efficacy and side effect profiles should be discussed in detail when considering any treatment options for complex febrile seizures [34]. It is important to remember that the long-term prognosis in terms of developing epilepsy or neurological and cognitive problems is not influenced by the use of antiepileptic medications for recurrent febrile seizures [17]. Even in the case of prolonged febrile seizures in otherwise neurodevelopmentally normal children, antiepileptics have not been shown to cause damage to the brain [19].

Febrile Status Epilepticus

Febrile status epilepticus is a subtype of complex febrile seizures and is defined as a febrile seizure lasting greater than 30 minutes. Overall, febrile status epilepticus accounts for approximately 5% of all presentations of febrile seizures [35]. It represents about 25% of all episodes of childhood status epilepticus and more than two-thirds of cases during the first 2 years of life. Literature suggests that an increased risk for focal epilepsy exists [36]. Children presenting with febrile status epilepticus are more likely to have a family history of epilepsy and a history of a previous neurological abnormality [22]. It is likely to reoccur if the first presentation was febrile status epilepticus. However, increased risk for death or developmental disability as a result of the seizure is not seen [37].

The prospective multicenter study of the consequences of prolonged febrile seizures in childhood (FEBSTAT) has been conducted. The study reported that febrile status epilepticus is usually focal (67% of episodes), occurs in very young children (median age 1.3 years), and is frequently the first febrile seizure [22]. In this study, the median duration of the seizure was about 68 minutes and 24% of children had an episode lasting more than 2 hours. In 87% of the events, seizures did not stop spontaneously and benzodiazepines were needed. Focal features observed were eye and head deviation, staring, and impaired consciousness prior to the seizure and an asymmetric convulsion or Todd’s paresis.

Case 3: Epilepsy Syndromes Associated With Febrile Seizures

A 1-year-old female presents for evaluation of seizures that began at age 8 months. Seizures are described as occurring in the setting of fever with bilateral symmetric tonic clonic activity lasting durations of less than 10 minutes on average, but at least 2 instances of seizure lasting 20 minutes or more. The family notes that seizures have occurred almost every time the child has had a febrile illness and often cluster over several days. They report at least 1 seizure that occurred in the absence of fever. Development has been normal to date and an EEG done by their primary provider was also normal.

• What epilepsy syndromes are associated with febrile seizures?

Genetic Epilepsy with Febrile Seizures Plus

GEFS+ was first described in 1997 following recognition of a pattern of febrile seizures followed later by the development of various epilepsy syndromes within the same family [38]. As such, the syndrome is defined based on the familial occurrence of febrile and afebrile seizures in at least 2 family members and can have a wide range of phenotypes. The most common presentation is of typical febrile seizures which can persist beyond the typical upper age limit of 6 years. Unprovoked generalized seizures of multiple types (ie, myoclonic, absence, atonic) occur at a later age, though focal seizures may also be present. The presence of focal onset seizures led to the naming change from “generalized” epilepsy with febrile seizures plus as it was previously referred. Seizure frequency and severity may vary between family members, as can response to treatment, making prognosis difficult to predict. As even in typical febrile seizures a family history of febrile seizure may be common, it may be difficult to diagnose the syndrome after the initial febrile seizure. However, if the family history is strong for a family member with a GEFS+ phenotype, one can appropriately counsel the family on the possibility that a similar course may evolve. While the majority of GEFS+ patients have milder phenotypes, some more severe phenotypes can have cognitive delays. Dravet syndrome falls within the spectrum of GEFS+ and is a prime example of the phenotypic continuum to more severe presentations in some patients.

The syndrome is believed to be inherited in an auto-somal dominant fashion with incomplete penetrance. Multiple genes have been implicated as a cause, though only 11.5% of families with clinical GEFS+ may have mutations [39]. SCN1A, encoding the α-subunit of the voltage-gated sodium channel is most frequently reported in GEFS+ families, yet is only found in 10% [38]. When associated with GEFS+, SCN1A mutations are more often missense type, whereas truncating and nonsense mutations are more commonly encountered in Dravet syndrome. Mutations in SCN1B encoding the β1 subunit of the voltage-gated sodium channel has also been reported [40]. Finally, the GABA(A) receptor gamma 2 subunit GABRG2 has been found in < 1% of GEFS+ families [39]. The variability in causative genes underscores the reasons for phenotype variability and it is likely that other modifier genes are responsible for the heterogeneity within GEFS+ families [41].

Dravet Syndrome

Dravet syndrome, often referred to as severe myoclonic epilepsy of infancy, was first described in 1978 and has since become one of the most recognized genetic epilepsy syndromes [42]. The clinical presentation often begins with seizures in the first year of life, frequently in the setting of febrile illness. The initial seizures are generalized or hemiclonic in the majority and are often prolonged evolving to status epilepticus. Unlike typical febrile seizures, one should suspect Dravet syndrome in children that present with repetitive bouts of complex febrile seizures or febrile status epilepticus, especially if the associated seizure semiology is of hemiclonic type. In addition, seizures in the setting of modest hyperthermia (ie, hot baths) should raise suspicion for this condition. Commonly EEG and MRI are normal in the first year of life and psychomotor development remains normal until typically the second year of life [43].

By the second year, other seizure types including myoclonic, atypical absence, clonic, and tonic seizures arise. The EEG frequently begins to show generalized spike wave and polyspike wave discharges. Seizures continue occurring frequently during early childhood, often resulting in status epilepticus. Cognitive development begins to stagnate between the ages of 1 and 4 years with emergence of autistic traits and hyperactivity [44]. Development may stabilize between the ages of 5 and 16 years, but fails to demonstrate much improvement [44]. Higher frequency of seizures may correlate with increase in cognitive impairment and behavior problems, supporting the need for rapid diagnosis and appropriate therapy [44].

Over the years, several cases of atypical or borderline Dravet syndrome have been described, most highlighting the absence of myoclonic seizures [45]. Others may present with primarily clonic or tonic-clonic type seizures only [46]. Despite these differences, all cases share a similar drug resistance and cognitive delay and are categorized as Dravet syndrome.

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, anup.patel@nationwidechildrens.org.

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.

From the Nationwide Children’s Hospital, Columbus, OH (Dr. Patel) and Cook Children’s Medical Center, Fort Worth, TX (Dr. Perry).

Abstract

• Objective: To review the current understanding and management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as-needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients should be aware of the clinical considerations in managing patients with febrile seizures.

Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19; FIRES; complex febrile seizure.

A febrile seizure is defined as a seizure in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [1]. The mechanism by which fever provokes a febrile seizure is unclear [2]. Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children [1]. The age of onset is between 6 months and 5 years [3]; peak incidence occurs at about 18 months of age. Simple febrile seizures are the most common type of febrile seizure. By definition, they are generalized, last less than 10 minutes and only occur once in a 24-hour time-period. A complex febrile seizure is one with focal onset or one that occurs more than once during a febrile illness, or lasts more than 10 minutes. Febrile status epilepticus, a subtype of complex febrile seizures, represents about 25% of all episodes of childhood status epilepticus. They account for more than two-thirds of cases during the first 2 years of life.

The risk of reoccurrence after presenting with one febrile seizure is approximately 30%, with the risk being 60% after 2 febrile seizures and 90% after 3 [4–6]. Some families have an autosomal dominant inheritance pattern with polygenic inheritance suspected for the majority of patients presenting with febrile seizures.

Multiple chromosomes have been postulated to be associated with genetic susceptibility for febrile seizures, with siblings having a 25% increased risk and high concordance noted in monozygotic twins [7]. The pathophysiology for febrile seizures has been associated with a genetic risk associated with the rate of temperature rise with animal studies suggesting temperature regulation of c-aminobutyric acid (GABA) a receptors [2]. Other studies propose a link between genetic and environmental factors resulting in an inflammatory process which influences neuronal excitement predisposing one to a febrile seizure [8].

Debate exists between the relation of febrile seizures and childhood vaccinations. Seizures are rare following administration of childhood vaccines. Most seizures following administration of vaccines are simple febrile seizures [9]. Febrile seizures associated with vaccines are more associated with underlying epilepsy. In a study of patients with vaccine-related encephalopathy and febrile status epilepticus, the majority of patients were found to have Dravet syndrome; it was determined that the vaccine may have triggered an earlier onset of the presentation for Dravet in those predestined to develop this disease but did not adversely impact ultimate outcome [10].

In this article, we review simple and complex febrile seizures with a focus on clinical management. Epilepsy syndromes associated with febrile seizures are also discussed. Cases are provided to highlight important clinical considerations.

Case 1: Simple Febrile Seizure

A 9-month-old infant and his mother present to the pediatrician. The mother notes that the infant had an event of concern. She notes the infant had stiffness in all 4 extremities followed by jerking that lasted 30 to 60 seconds. The infant was not responsive during the event. He was sleepy afterward, but returned to normal soon after the event ended. After, she noted that the infant felt warm and she checked his temperature. He had a fever of 101°F. The infant has normal development and no other medical problems.

• What are management considerations for simple febrile seizure?

A simple febrile seizure is the most common type of febrile seizure. They are generalized, lasting less than 10 minutes and only occur once in a 24-hour period. There is no increased risk of developing epilepsy or developmental delay for patients after the first simple febrile seizures when compared to other children [5,6]. The diagnosis is based on history provided and a physical examination including evaluation of body temperature [11,12].

No routine laboratory tests are needed as a result of a simple febrile seizure unless obtained to assist in identifying the fever source [3,11]. Routine EEG testing is not recommended for these patients [3,11]. Routine imaging of the brain is also not needed [3,11]. Only if a patient has signs of meningitis should a lumbar puncture be performed [11]. The American Academy of Pediatrics states that a lumbar puncture is strongly considered for those younger than 12 months if they present with their first complex febrile seizure as signs of meningitis may be absent in young children. For infants 6 to 12 months of age, a lumbar puncture can be considered when immunization status is deficient or unknown [13,14]. Also, a lumbar puncture is an option for children who are pretreated with antibiotics [11]. For patients younger than 6 months, data is lacking on the percentage of patients with bacterial meningitis following a simple febrile seizure.

Daily preventative therapy with an anti-epilepsy medication is not necessary [3,11]. A review of several treatment studies shows that some anti-epileptic medications are effective in preventing recurrent simple febrile seizures. Studies have demonstrated the effectiveness of phenobarbital, primidone, and valproic acid in preventing the recurrence of simple febrile seizures; however, the side effects of each medication outweighed the benefit [3]. Carbamazepine and phenytoin have not been shown to be effective in preventing recurrent febrile seizures [3].

For anxious caregivers with children having recurrent febrile seizures, a daily medication or treating with an abortive seizure medication at the time of a febrile illness can be considered [3,5,6,15]. Treating with an abortive medication may mask signs and symptoms of meningitis making evaluation more challenging [16]. Evidence does not support that using antipyretic medications such as acetaminophen or ibuprofen will reduce the recurrence of febrile seizures. The seizure usually is the first noticed symptom due to the rise of temperature being the cause of the febrile seizure in an otherwise well child prior to the seizure [11,17]. Damage to the brain and associated structures is not found with patients presenting with simple febrile seizures [5,6]. Education on all of these principles is strongly recommended for caregiver reassurance.

Case 2: Complex Febrile Seizure

A 1-year-old child presents to the emergency department. Mother was with the child and she noticed stiffness followed by jerking of the left arm and leg, which quickly became noted in both arms and legs. The episode appeared to last for 15 minutes before EMS arrived to the house. A medication was given to the child by EMS that stopped the event. EMS noted the child had a temperature of 101.5°F. The child was previously healthy and has had normal development thus far.

• What is the epidemiology of complex febrile seizure?

A complex febrile seizure is one with focal onset, or one that occurs more than once during a febrile illness or lasts more than 10 minutes. They are less common, representing only 20% to 30% of all febrile seizures [18–20]. In The National Collaborative Perinatal Project (NCPP), 1706 children with febrile seizures were identified from 54,000 and were followed from birth until 7 years of age. The initial febrile seizure was defined as complex in about 28%. For all febrile seizures, focal features were present in 4%, prolonged duration (> 10 minutes) in 7.6%, and recurrent episodes within 24 hours in 16.2% [21]. Similar observations have been reported by Berg and Shinnar [5,6]. Of 136 children who had recurrences, 41.2% had one or more complex features and the strongest correlate of having recurrent complex febrile seizure was the number of recurrent seizures. They also found that children with complex recurrences had other recurrences that were not complex; however, complex features had a tendency to recur. Further, a strong association between focal onset and prolonged duration was found [5,6]. Previous studies established a correlation between complex attacks, particularly prolonged ones and young age (age < 1 year) [5,6]. Additionally, children with seizures with a relatively low fever (< 102°F) were slightly more likely to have a complex febrile seizure as the initial episode [5,6].

Children with febrile seizures are already at 4- to 5-fold increased risk for subsequent unprovoked seizures. A history of febrile seizures has been found in 13% to 18% of children with new-onset epilepsy. In the NCPP study, the predictors identified for the development of epilepsy following febrile seizures were an abnormal neurological and developmental status of the child before the seizure, a history of afebrile seizures in a parent or prior-born sibling, or complex features [21]. Ten percent of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy and 13% of them had seizures without fever [20,22]. Further, intractable epilepsy and neurological impair-ment have been found to be more common in children with prior prolonged febrile seizure, with no association to any specific seizure type [18,23–25]. The association between febrile seizures and mesial temporal sclerosis (MTS) is a commonly debated topic. Retrospective studies have reported an association between prolonged or atypical febrile seizures and intractable temporal lobe epilepsy. Epidemiological studies fail to show a causal relationship between febrile seizures and temporal lobe epilepsy [26]. This suggests that febrile seizures are a marker of susceptibility to seizures and future epilepsy (in some cases) rather than a direct cause. It is clear that a minority of cases of MTS or complex partial seizures are associated with prior febrile seizures [20,22].

• What is the risk of intracranial pathology in complex febrile seizure?

Patients with complex febrile seizures usually seek medical attention [27]. However, the risk of acute pathology necessitating treatment changes based on neuroimaging was found to be very low and likely not necessary in the evaluation of complex febrile seizures during the acute presentation [27]. Imaging with a high-resolution brain MRI could be considered later on a routine basis for prolonged febrile seizures due to the possible association between prolonged febrile seizures and mesial temporal sclerosis [19,28,29].

Neuroimaging has provided evidence that hippocampal injury can occasionally occur during prolonged and focal febrile seizures in infants who otherwise appear normal. It has been speculated that a pre-existing abnormality increases the propensity to focal prolonged seizures and further hippocampal damage. Hesdorffer and colleagues [30] found definite abnormalities on MRI in 14.8% of children with complex febrile seizures and 11.4 % of simple febrile seizures among 159 children with a first febrile seizure. However, MRI abnormalities were related to a specific subtype of complex seizures: focal and prolonged. The most common abnormalities observed were subcortical focal hyperintensity, an abnormal white matter signal, and focal cortical dysplasia.

• What are important aspects of the clinical evaluation?

The evaluation and management of the child with complex febrile seizures is debated as well. The most important part in the history and examination is to look for the source of the fever and rule out the presence of a CNS infection, since complex febrile seizures are much more frequently associated with meningitis than simple febrile seizures [16]. The American Academy of Pediatrics recommended that a lumbar puncture be strongly considered in infants younger than 12 months after a first febrile seizure and should be considered in children between 12 and 18 months of age, since signs of meningitis may be absent in young children [13]. If the threshold for a lumbar puncture is low in infants with febrile seizures in general, it should be even lower for children with complex febrile episodes for all the factors mentioned above. The guidelines developed in 1990 by the Royal College of Physicians and the British Paediatric Association concluded that indications for performing an lumbar puncture were complex febrile seizure, signs of meningismus, or a child who is unduly drowsy and irritable or systematically ill [21].

Obtaining an EEG within 24 hours of presentation may show generalized background slowing, which could make identifying possible epileptiform abnormalities difficult [22]. Therefore, a routine sleep deprived EEG when the child is back to baseline can be more useful in identifying if epileptiform abnormalities are present. If epileptiform abnormalities are present on a routine sleep deprived EEG, this may suggest the patient is at higher risk for developing future epilepsy and the febrile illness lowered the seizure threshold; however, it is unclear whether clinical management would change as a result [31].

• What treatment options are available?

Complications with prolonged and/or recurrent seizures can occur. Treatments options can be stratified into 3 possible categories: emergency rescue treatment for prolonged or a cluster of febrile seizures, intermittent treatment at the time of illness, and chronic use of medication. Treatment options for complex febrile seizures may include the use of a rescue seizure medication when the febrile seizure is prolonged. Rectal preparations of diazepam gel can be effective in stopping an ongoing seizure and can be provided for home use in patients with known recurrence of febrile status epilepticus [3]. For children and adolescents where a rectal administration is not ideal, intranasal versed can be utilized instead of rectal diazepam. In addition, the use of an intermittent benzodiazepine at the onset of febrile illness can also be considered a treatment option. Using oral diazepam at the time of a febrile illness has been demonstrated in reducing the recurrence of febrile seizures [3]. Other studies have shown similar results when using buccal midazolam [32]. No adequate studies have been performed using second- or third-generation anti-epilepsy medications in the treatment of recurrent of complex febrile seizures [3].

It is unclear whether benefit is present to using intermittent benzodiazepine doses prior or during a febrile illness for those prone for recurrent febrile seizures [33]. Physicians may consider this option in patients with frequent recurrent seizures, when caregivers can identify the fever before the seizure occurs.

Overall, parental education of efficacy and side effect profiles should be discussed in detail when considering any treatment options for complex febrile seizures [34]. It is important to remember that the long-term prognosis in terms of developing epilepsy or neurological and cognitive problems is not influenced by the use of antiepileptic medications for recurrent febrile seizures [17]. Even in the case of prolonged febrile seizures in otherwise neurodevelopmentally normal children, antiepileptics have not been shown to cause damage to the brain [19].

Febrile Status Epilepticus

Febrile status epilepticus is a subtype of complex febrile seizures and is defined as a febrile seizure lasting greater than 30 minutes. Overall, febrile status epilepticus accounts for approximately 5% of all presentations of febrile seizures [35]. It represents about 25% of all episodes of childhood status epilepticus and more than two-thirds of cases during the first 2 years of life. Literature suggests that an increased risk for focal epilepsy exists [36]. Children presenting with febrile status epilepticus are more likely to have a family history of epilepsy and a history of a previous neurological abnormality [22]. It is likely to reoccur if the first presentation was febrile status epilepticus. However, increased risk for death or developmental disability as a result of the seizure is not seen [37].

The prospective multicenter study of the consequences of prolonged febrile seizures in childhood (FEBSTAT) has been conducted. The study reported that febrile status epilepticus is usually focal (67% of episodes), occurs in very young children (median age 1.3 years), and is frequently the first febrile seizure [22]. In this study, the median duration of the seizure was about 68 minutes and 24% of children had an episode lasting more than 2 hours. In 87% of the events, seizures did not stop spontaneously and benzodiazepines were needed. Focal features observed were eye and head deviation, staring, and impaired consciousness prior to the seizure and an asymmetric convulsion or Todd’s paresis.

Case 3: Epilepsy Syndromes Associated With Febrile Seizures

A 1-year-old female presents for evaluation of seizures that began at age 8 months. Seizures are described as occurring in the setting of fever with bilateral symmetric tonic clonic activity lasting durations of less than 10 minutes on average, but at least 2 instances of seizure lasting 20 minutes or more. The family notes that seizures have occurred almost every time the child has had a febrile illness and often cluster over several days. They report at least 1 seizure that occurred in the absence of fever. Development has been normal to date and an EEG done by their primary provider was also normal.

• What epilepsy syndromes are associated with febrile seizures?

Genetic Epilepsy with Febrile Seizures Plus

GEFS+ was first described in 1997 following recognition of a pattern of febrile seizures followed later by the development of various epilepsy syndromes within the same family [38]. As such, the syndrome is defined based on the familial occurrence of febrile and afebrile seizures in at least 2 family members and can have a wide range of phenotypes. The most common presentation is of typical febrile seizures which can persist beyond the typical upper age limit of 6 years. Unprovoked generalized seizures of multiple types (ie, myoclonic, absence, atonic) occur at a later age, though focal seizures may also be present. The presence of focal onset seizures led to the naming change from “generalized” epilepsy with febrile seizures plus as it was previously referred. Seizure frequency and severity may vary between family members, as can response to treatment, making prognosis difficult to predict. As even in typical febrile seizures a family history of febrile seizure may be common, it may be difficult to diagnose the syndrome after the initial febrile seizure. However, if the family history is strong for a family member with a GEFS+ phenotype, one can appropriately counsel the family on the possibility that a similar course may evolve. While the majority of GEFS+ patients have milder phenotypes, some more severe phenotypes can have cognitive delays. Dravet syndrome falls within the spectrum of GEFS+ and is a prime example of the phenotypic continuum to more severe presentations in some patients.

The syndrome is believed to be inherited in an auto-somal dominant fashion with incomplete penetrance. Multiple genes have been implicated as a cause, though only 11.5% of families with clinical GEFS+ may have mutations [39]. SCN1A, encoding the α-subunit of the voltage-gated sodium channel is most frequently reported in GEFS+ families, yet is only found in 10% [38]. When associated with GEFS+, SCN1A mutations are more often missense type, whereas truncating and nonsense mutations are more commonly encountered in Dravet syndrome. Mutations in SCN1B encoding the β1 subunit of the voltage-gated sodium channel has also been reported [40]. Finally, the GABA(A) receptor gamma 2 subunit GABRG2 has been found in < 1% of GEFS+ families [39]. The variability in causative genes underscores the reasons for phenotype variability and it is likely that other modifier genes are responsible for the heterogeneity within GEFS+ families [41].

Dravet Syndrome

Dravet syndrome, often referred to as severe myoclonic epilepsy of infancy, was first described in 1978 and has since become one of the most recognized genetic epilepsy syndromes [42]. The clinical presentation often begins with seizures in the first year of life, frequently in the setting of febrile illness. The initial seizures are generalized or hemiclonic in the majority and are often prolonged evolving to status epilepticus. Unlike typical febrile seizures, one should suspect Dravet syndrome in children that present with repetitive bouts of complex febrile seizures or febrile status epilepticus, especially if the associated seizure semiology is of hemiclonic type. In addition, seizures in the setting of modest hyperthermia (ie, hot baths) should raise suspicion for this condition. Commonly EEG and MRI are normal in the first year of life and psychomotor development remains normal until typically the second year of life [43].

By the second year, other seizure types including myoclonic, atypical absence, clonic, and tonic seizures arise. The EEG frequently begins to show generalized spike wave and polyspike wave discharges. Seizures continue occurring frequently during early childhood, often resulting in status epilepticus. Cognitive development begins to stagnate between the ages of 1 and 4 years with emergence of autistic traits and hyperactivity [44]. Development may stabilize between the ages of 5 and 16 years, but fails to demonstrate much improvement [44]. Higher frequency of seizures may correlate with increase in cognitive impairment and behavior problems, supporting the need for rapid diagnosis and appropriate therapy [44].

Over the years, several cases of atypical or borderline Dravet syndrome have been described, most highlighting the absence of myoclonic seizures [45]. Others may present with primarily clonic or tonic-clonic type seizures only [46]. Despite these differences, all cases share a similar drug resistance and cognitive delay and are categorized as Dravet syndrome.

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, anup.patel@nationwidechildrens.org.

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

bjancin@frontlinemedcom.com
 

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

bjancin@frontlinemedcom.com
 

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

bjancin@frontlinemedcom.com